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951.
The direct ghrelin (Ghr) involvement in cardiovascular (CV) system homeostasis has been suggested by the expression of its receptor in CV tissues and by evidence that ghrelin mediates CV activities in animals and in humans. Moreover, low Ghr plasma levels have been reported in pathological conditions characterized by high cardiovascular risk. In the present study, we investigated Ghr effect on proliferation of human aortic endothelial cell (HAEC) and involved transduction pathways. Our results indicate that ghrelin elicited proliferation in a dose-dependent manner (EC(50) about of 5nmol/L) in cultured HAEC, and that this effect was inhibited by the receptor antagonist (D-Lys3)-GHRP-6. Western blot experiments documented an activation of external receptor activated kinases (ERK1/2) and Akt in a dose-dependent fashion, as well as involvement of the cAMP pathway in ERK1/2 phosphorylation. Experiments conducted with appropriate pharmacological inhibitors to investigate Ghr-induced HAEC proliferation confirmed the involvement of ERK1/2 and I3P/Akt pathways, as well as the role of AMP cyclase/PKA pathway in ERK1/2 phosphorylation. Our results indicate that Ghr promotes HAEC proliferation, and thus may be a protective factor against vascular damage. The low ghrelin serum levels reported in insulin-resistant states may not be able to effectively counteract endothelial cell injury. 相似文献
952.
953.
Casini A Hartinger C Gabbiani C Mini E Dyson PJ Keppler BK Messori L 《Journal of inorganic biochemistry》2008,102(3):564-575
Gold(III) compounds constitute an emerging class of biologically active substances, of special interest as potential anticancer agents. During the past decade a number of structurally diverse gold(III) complexes were reported to be acceptably stable under physiological-like conditions and to manifest very promising cytotoxic effects against selected human tumour cell lines, making them good candidates as anti-tumour drugs. Some representative examples will be described in detail. There is considerable interest in understanding the precise biochemical mechanisms of these novel cytotoxic agents. Based on experimental evidence collected so far we hypothesize that these metallodrugs, at variance with classical platinum(II) drugs, produce in most cases their growth inhibition effects through a variety of "DNA-independent" mechanisms. Notably, strong inhibition of the selenoenzyme thioredoxin reductase and associated disregulation of mitochondrial functions were clearly documented in some selected cases, thus providing a solid biochemical basis for the pronounced proapoptotic effects. These observations led us to investigate in detail the reactions of gold(III) compounds with a few model proteins in order to gain molecular-level information on the possible interaction modes with possible protein targets. Valuable insight on the formation and the nature of gold-protein adducts was gained through ESI MS (electrospray ionization mass spectrometry) and spectrophotometric studies of appropriate model systems as it is exemplified here by the reactions of two representative gold(III) compounds with cytochrome c and ubiquitin. The mechanistic relevance of gold(III)-induced oxidative protein damage and of direct gold coordination to protein sidechains is specifically assessed. Perspectives for the future of this topics are briefly outlined. 相似文献
954.
Di Natale G Damante CA Nagy Z Osz K Pappalardo G Rizzarelli E Sóvágó I 《Journal of inorganic biochemistry》2008,102(11):2012-2019
The solution conformation and the copper(II) binding properties have comparatively been investigated for the two novel hexapeptides Ac-HPSGHA-NH2 (P2) and Ac-HGSPHA-NH2 (P4). The study has been carried out by means of CD, NMR, EPR and UV-Vis spectroscopic techniques in addition to potentiometric measurements to determine the stability constants of the different copper(II) complex species formed in the pH range 3-11. The peptides contain two histidine residues as anchor sites for the metal ion and differ only for the exchanged position of the proline residue with glycine. CD and NMR results for the uncomplexed peptide ligands suggest a predominantly unstructured peptide chain in aqueous solution. Potentiometric and spectroscopic data (UV-Vis, CD and EPR) show that both peptides strongly interact with copper(II) ions by forming complexes with identical stoichiometries but different structures. Furthermore, Far-UV CD experiments indicate that the conformation of the peptides is dramatically affected following copper(II) complexation with the P4 peptide adopting a β-turn-like conformation. 相似文献
955.
Hanton SL Chatre L Matheson LA Rossi M Held MA Brandizzi F 《Plant molecular biology》2008,67(3):283-294
In plants, differentiation of subdomains of the endoplasmic reticulum (ER) dedicated to protein export, the ER export sites (ERES), is influenced by the type of export-competent membrane cargo to be delivered to the Golgi. This raises a fundamental biological question: is the formation of transport intermediates at the ER for trafficking to the Golgi always regulated in the same manner? To test this, we followed the distribution and activity of two plant Sar1 isoforms. Sar1 is the small GTPase that regulates assembly of COPII (coat protein complex II) on carriers that transport secretory cargo from ER to Golgi. We show that, in contrast to a tobacco Sar1 isoform, the two Arabidopsis Sar1 GTPases were localised at ERES, independently of co-expression of Golgi-destined membrane cargo in tobacco cells. Although both isoforms labelled ERES, one was found to partition with the membrane fraction to a greater extent. The different distribution of fluorescent fusions of the two isoforms was influenced by the nature of an amino acid residue at the C-terminus of the protein, suggesting that the requirements for membrane association of the two GTPases are not equal. Furthermore, functional analyses based on the secretion of the bulk flow marker α-amylase indicated that over-expression of GTP-restricted mutants of the two isoforms caused different levels of ER export inhibition. These novel results indicate a functional heterogeneity among plant Sar1 isoforms. 相似文献
956.
Rotundo RL Ruiz CA Marrero E Kimbell LM Rossi SG Rosenberry T Darr A Tsoulfas P 《Chemico-biological interactions》2008,175(1-3):26-29
The collagen-tailed form of acetylcholinesterase (ColQ-AChE) is the major if not unique form of the enzyme associated with the neuromuscular junction (NMJ). This enzyme form consists of catalytic and non-catalytic subunits encoded by separate genes, assembled as three enzymatic tetramers attached to the three-stranded collagen-like tail (ColQ). This synaptic form of the enzyme is tightly attached to the basal lamina associated with the glycosaminoglycan perlecan. Fasciculin-2 is a snake toxin that binds tightly to AChE. Localization of junctional AChE on frozen sections of muscle with fluorescent Fasciculin-2 shows that the labeled toxin dissociates with a half-life of about 36h. The fluorescent toxin can subsequently be taken up by the muscle fibers by endocytosis giving the appearance of enzyme recycling. Newly synthesized AChE molecules undergo a lengthy series of processing events before final transport to the cell surface and association with the synaptic basal lamina. Following co-translational glycosylation the catalytic subunit polypeptide chain interacts with several molecular chaperones, glycosidases and glycosyltransferases to produce a catalytically active enzyme that can subsequently bind to one of two non-catalytic subunits. These molecular chaperones can be rate limiting steps in the assembly process. Treatment of muscle cells with a synthetic peptide containing the PRAD attachment sequence and a KDEL retention signal results in a large increase in assembled and exportable AChE, providing an additional level of post-translational control. Finally, we have found that Pumilio2, a member of the PUF family of RNA-binding proteins, is highly concentrated at the vertebrate neuromuscular junction where it plays an important role in regulating AChE translation through binding to a highly conserved NANOS response element in the 3'-UTR. Together, these studies define several new levels of AChE regulation in electrically excitable cells. 相似文献
957.
Sannella AR Casini A Gabbiani C Messori L Bilia AR Vincieri FF Majori G Severini C 《FEBS letters》2008,582(6):844-847
The clinically established gold-based antiarthritic drug auranofin (AF) manifests a pronounced reactivity toward thiol and selenol groups of proteins. In particular, AF behaves as a potent inhibitor of mammalian thioredoxin reductases causing severe intracellular oxidative stress. Given the high sensitivity of Plasmodium falciparum to oxidative stress, we thought that auranofin might act as an effective antimalarial agent. Thus, we report here new experimental results showing that auranofin and a few related gold complexes strongly inhibit P. falciparum growth in vitro. The observed antiplasmodial effects probably arise from direct inhibition of P. falciparum thioredoxin reductase. The above findings and the safe toxicity profile of auranofin warrant rapid evaluation of AF for malaria treatment in animal models. 相似文献
958.
Although fungi do not cause outbreaks or pandemics, the incidence of severe systemic fungal infections has increased significantly, mainly because of the explosive growth in the number of patients with compromised immune system. Thus, drug resistance in pathogenic fungi, including dermatophytes, is gaining importance. The molecular aspects involved in the resistance of dermatophytes to marketed antifungals and other cytotoxic drugs, such as modifications of target enzymes, over-expression of genes encoding ATP-binding cassette (ABC) transporters and stress-response-related proteins are reviewed. Emphasis is placed on the mechanisms used by dermatophytes to overcome the inhibitory action of terbinafine and survival in the host environment. The relevance of identifying new molecular targets, of expanding the understanding about the molecular mechanisms of resistance and of using this information to design new drugs or to modify those that have become ineffective is also discussed. 相似文献
959.
Here we summarized what is known at the present about function, structure and effect of mutations in the human prolidase.
Among the peptidases, prolidase is the only metalloenzyme that cleaves the iminodipeptides containing a proline or hydroxyproline
residue at the C-terminal end. It is relevant in the latest stage of protein catabolism, particularly of those molecules rich
in imino acids such as collagens, thus being involved in matrix remodelling. Beside its intracellular functions, prolidase
has an antitoxic effect against some organophosphorus molecules, can be used in dietary industry as bitterness reducing agent
and recently has been used as target enzyme for specific melanoma prodrug activation. Recombinant human prolidase was produced
in prokaryotic and eukaryotic hosts with biochemical properties similar to the endogenous enzyme and represents a valid tool
both to better understand the structure and biological function of the enzyme and to develop an enzyme replacement therapy
for the prolidase deficiency (PD). Prolidase deficiency is a rare recessive disorder caused by mutations in the prolidase
gene and characterized by severe skin lesions. Single amino acid substitutions, exon splicing, deletions and a duplication
were described as causative for the disease and are mainly located at highly conserved amino acids in the sequence of prolidase
from different species. The pathophysiology of PD is still poorly understood; we offer here a review of the molecular mechanisms
so far hypothesized. 相似文献
960.
Robert W. Evans Roozina Rafique Adel Zarea Chiara Rapisarda Richard Cammack Patricia J. Evans John B. Porter Robert C. Hider 《Journal of biological inorganic chemistry》2008,13(1):57-74
Despite its importance in iron-overload diseases, little is known about the composition of plasma non-transferrin-bound iron
(NTBI). Using 30-kDa ultrafiltration, plasma from thalassemic patients consisted of both filterable and non-filterable NTBI,
the filterable fraction representing less than 10% NTBI. Low filterability could result from protein binding or NTBI species
exceeding 30 kDa. The properties of iron citrate and its interaction with albumin were therefore investigated, as these represent
likely NTBI species. Iron permeated 5- or 12-kDa ultrafiltration units completely when complexes were freshly prepared and
citrate exceeded iron by tenfold, whereas with 30-kDa ultrafiltration units, permeation approached 100% at all molar ratios.
A g = 4.3 electron paramagnetic resonance signal, characteristic of mononuclear iron, was detectable only with iron-to-citrate
ratios above 1:100. The ability of both desferrioxamine and 1,2-dimethyl-3-hydroxypyridin-4-one to chelate iron in iron citrate
complexes also increased with increasing ratios of citrate to iron. Incremental molar excesses of citrate thus favour the
progressive appearance of chelatable lower molecular weight iron oligomers, dimers and ultimately monomers. Filtration of
iron citrate in the presence of albumin showed substantial binding to albumin across a wide range of iron-to-citrate ratios
and also increased accessibility of iron to chelators, reflecting a shift towards smaller oligomeric species. However, in
vitro experiments using immunodepletion or absorption of albumin to Cibacron blue–Sepharose indicate that iron is only loosely
bound in iron citrate–albumin complexes and that NTBI is unlikely to be albumin-bound to any significant extent in thalassemic
sera. 相似文献