1,721,046 research outputs found
Red blood cells as a physiological source of glutathione for extracellular fluids
No full textPlasma low molecular mass thiols are represented by glutathione, cysteine, cysteinylglycine and homocysteine. The physiological mechanisms responsible for maintaining the homeostasis of these compounds in the intracellular and extracellular spaces have not been fully clarified. Erythrocytes possess the enzymatic machinery to synthesize glutathione and an efflux of glutathione disulfide and glutathione conjugates from erythrocytes under various conditions occurs. In this study, the property of red blood cells (RBCs) to export low molecular mass thiols has been assessed. Plasma concentration of low molecular mass thiols has been measured in healthy volunteers by HPLC and a significant correlation with RBC number has been observed for glutathione and cysteinylglycine. A sustained export of reduced glutathione has been observed (about 21 nmol/h/ml RBCs) together with a lower, though significant, efflux of both cysteine and homocysteine. These results suggest that erythrocytes can contribute significantly to the extracellular pool of glutathione (GSH), thus cooperating with liver and other tissues to the dynamics of inter-organ GSH metabolism
Modulation of thiol homeostasis induced by a novel H2S-releasing compound
No full textRecently, the physiological function of hydrogen sulfide (H2S) has been discovered and a potential therapeutic use of this gas for the treatment of diseases characterized by its altered concentrations has been suggested. A possible approach for a therapeutic administration of H2S is represented by molecules able to release H2S in a controlled manner, mimicking what happens physiologically. Dithiolethiones have been found to behave as H2S donors in physiological conditions.
N-Acetylcysteine (NAC) is under investigation as potential therapeutic agent against several different pathologies characterized by the occurrence of oxidative stress and a decrease in GSH although results deriving from large, multi-center, prospective clinical trials are on most case contradictory and inconclusive. It is possible that the scarce efficacy of NAC is due to its low oral bioavailability (about 8%).
We have recently observed that both dithiolethione containing molecules and the derivative of NAC, N-acetylcysteine ethylester (NACET) are able to significantly reduce circulating and tissue levels of hyperomocysteinemia (hCys), probably via an increase of the thiol to disulfide ratio in extracellular fluids. Mild hCys is considered an independent risk factor for cardiovascular and cerebrovascular disease.
Starting from these observations, we synthesized new dithiolethione–cysteine hybrids (ACS94, ACS96, ACS97) with the assumption that they could have synergic effect in reducing plasma hCys, as well (by tissue glutathione increase) correcting the redox imbalance process present in several diseases.
The effects on thiols pool in different organs and in plasma, after iv or oral administration of NAC (10mg/kg) or equimolar ACS94 to healthy rats and after ip administration of paracetamol (as a model of hepatic toxicity), have been investigated.
The results clearly indicate that ACS94 protects from paracetamol induced hepatic toxicity better than NAC and that ACS94 prevents paracetamol induced thiol depletion in kidney and liver. In addition a more significant decrease of hCys compared to NAC, was observed in some rat target organs and in plasma
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Protein S-glutathionylation: a regulatory device from bacteria to humans
No full textS-Glutathionylation is the specific post-translational modification of protein cysteine residues by the addition of the tripeptide glutathione, the most abundant and important low-molecular-mass thiol within most cell types. Protein S-glutathionylation is promoted by oxidative or nitrosative stress but also occurs in unstressed cells. It can serve to regulate a variety of cellular processes by modulating protein function and to prevent irreversible oxidation of protein thiols. Recent findings support an essential role for S-glutathionylation in the control of cell-signalling pathways associated with viral infections and with tumour necrosis factor-(-induced apoptosis. Glyceraldehyde-3-phosphate dehydrogenase has recently been implicated in the regulation of endothelin-1 synthesis by a novel, S-glutathionylation-based mechanism involving messenger RNA stability. Moreover, recent studies have identified S-glutathionylation as a redox signalling mechanism in plants
H2S-releasing L-DOPA derivatives for Parkinson disease
No full textL-DOPA is the most widely used therapy for Parkinson disease but it does not arrest progression of the disorder. Factors that contribute to the continuing neuronal loss are oxidative stress, including oxidation of L-DOPA, and neurotoxins generated by locally activated microglia and astrocytes. A possible method of reducing these factors is to produce L-DOPA hybrid compounds that have antioxidant and antiinflammatory properties. We have prepared four such L-DOPA hybrids, based on coupling L-DOPA to different hydrogen sulfide donating compounds. They show promise as disease modifying agents. This capability was demonstrated by in vivo results with one of the hybrids where larger increases in brain dopamine levels were observed than with equivalent doses of L-DOPA. The H2S-releasing L-DOPA hybrid molecules also inhibited MAO B activity which could explain why they increased dopamine levels in vivo. The donors themselves were shown to be capable of conversion to H2S or equivalent SH- ions by isolated mitochondria. When human microglia, astrocytes and SH-SY5Y neuroblastoma cells were treated with these donating agents, they all accumulated H2S intracellularly as did their derivatives coupled to L-DOPA. The donating agents and the L-DOPA hybrids reduced the release of tumor necrosis factor-α, interleukin-6 and nitric oxide from stimulated microglia, astrocytes as well as the THP-1 and U373 cell lines. They also demonstrated a neuroprotective effect by reducing the toxicity of supernatants from these stimulated cells to SH-SY5Y cells. L-DOPA itself was without effect in any of these assays. They may be useful for the treatment of PD because of their significant antiinflammatory, antioxidant and neuroprotective properties
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
S-nitrosation vs. S-glutathionylation of protein sulfhydryl groups by S-nitrosoglutathione
No full textS-Nitrosation of protein sulfhydryl groups is an established response to oxidative/nitrosative stress. The transient nature and reversibility of S-nitrosation, as well as its specificity, render this posttranslational modification an attractive mechanism of regulation of protein function and signal transduction, in analogy to S-glutathionylation. Several feasible mechanisms for protein S-nitrosation have been proposed, including transnitrosation by S-nitrosothiols, such as S-nitrosoglutathione (GSNO), where the nitrosonium moiety is directly transferred from one thiol to another. The reaction between GSNO and protein sulfhydryls can also produce a mixed disulfide by S-glutathionylation, which involves the nucleophilic attack of the sulfur of GSNO by the protein thiolate anion. In this study, we have investigated the possible occurrence of S-glutathionylation during reaction of GSNO with papain, creatine phosphokinase, glyceraldehyde-3-phosphate dehydrogenase, alcohol dehydrogenase, bovine serum albumin, and actin. Our results show that papain, creatine phosphokinase, and glyceraldehyde-3-phosphate dehydrogenase were significantly both S-nitrosated and S-glutathionylated by GSNO, whereas alcohol dehydrogenase, bovine serum albumin, and actin appeared nearly only S-nitrosated. The susceptibility of the modified proteins to denitrosation and deglutathionylation by reduced glutathione was also investigated
Pharmacological profile of a novel H2S-releasing aspirin
No full textPrevention of aspirin toxicity represents still an unmet medical need. Already several years ago, nitric oxide was utilized as a tool to reduce gastric toxicity [1], by preparing NOreleasing aspirin (NO-aspirin) and many other NO-donating agents. NO-aspirin appears unequivocally to be better tolerated in animals and humans, although consistently higher doses were needed to obtain comparable prostaglandin suppression to aspirin in humans. It remains to be understood if this could be at least partially dependent on the tachyphylaxis
responses observed for NO-aspirin.
With this general approach in mind, we were intrigued to determine whether a chemically
modified aspirin with the ability to release hydrogen sulfide (H2S) might prove of value as a novel stomach-sparing aspirin. The idea came from the evidence that this gaseous mediator possesses all of the positive effects of NO without the capacity to form peroxynitrite, the toxic metabolite, which has been thought to be involved in tachyphylaxis and related to redox imbalance disorders.
The pharmacological profile of a new safe and effective hydrogen sulfide-releasing aspirin (ACS 14) will be described. We report the synthesis of this compound and of its metabolite(ACS21) and the preliminary pharmacokinetics and in vivo metabolism with the determination of the hydrogen sulphide (H2S) plasma levels after intravenous rat
administration, using an improved validated HPLC analytical method. While it maintains the thromboxane suppressing activity owned by the parent compound, ACS14 appears to spare the gastric mucosa, by affecting redox imbalance processes via H2S/GSH increased
formation and isoprostane suppression.
In conclusion, the new H2S-donating aspirin appears to be an effective and safe compound,
with significant advantages over the native aspiri
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