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Biomedical subjects

G Peluffo

Publications and source records attributed to G Peluffo.

At least 19 recordsLinked to original sources
PubMed2006

Protein tyrosine nitration in hydrophilic and hydrophobic environments.

In this review we address current concepts on the biological occurrence, levels and consequences of protein tyrosine nitration in biological systems. We focused on mechanistic aspects, emphasizing on the free radical mechanisms of protein 3-nitrotyrosine formation and critically analyzed the restrictions for obtaining large tyrosine nitration yields in vivo, mainly due to the presence of strong reducing systems (e.g. glutathione) that can potently inhibit at different levels the nitration process. Evidence is provided to show that the existence of metal-catalyzed processes, the assistance of nitric oxide-dependent nitration steps and the facilitation by hydrophobic environments, provide individually and/or in combination, feasible scenarios for nitration in complex biological milieux. Recent studies using hydrophobic tyrosine analogs and tyrosine-containing peptides have revealed that factors controlling nitration in hydrophobic environments such as biomembranes and lipoproteins can differ to those in aqueous compartments. In particular, exclusion of key soluble reductants from the lipid phase will more easily allow nitration and lipid-derived radicals are suggested as important mediators of the one-electron oxidation of tyrosine to tyrosyl radical in proteins associated to hydrophobic environments. Development and testing of hydrophilic and hydrophobic probes that can compete with endogenous constituents for the nitrating intermediates provide tools to unravel nitration mechanisms in vitro and in vivo; additionally, they could also serve to play cellular and tissue protective functions against the toxic effects of protein tyrosine nitration.

Cell Membrane↗
PubMed2001

L-arginine-dependent suppression of apoptosis in Trypanosoma cruzi: contribution of the nitric oxide and polyamine pathways.

Until recently, a capacity for apoptosis and synthesis of nitric oxide *NO) were viewed as exclusive to multicellular organisms. The existence of these processes in unicellular parasites was recently described, with their biological significance remaining to be elucidated. We have evaluated L-arginine metabolism in Trypanosoma cruzi in the context of human serum-induced apoptotic death. Apoptosis was evidenced by the induction of DNA fragmentation and the inhibition of [3H]thymidine incorporation, which were inhibited by the caspase inhibitor Ac-Asp-Glu-Val-aspartic acid aldehyde (DEVD-CHO). In T. cruzi exposed to death stimuli, supplementation with L-arginine inhibited DNA fragmentation, restored [3H]thymidine incorporation, and augmented parasite *NO production. These effects were inhibited by the *NO synthase inhibitor N(omega)-nitroarginine methyl ester (L-NAME). Exogenous *NO limited DNA fragmentation but did not restore proliferation rates. Because L-arginine is also a substrate for arginine decarboxylase (ADC), and its product agmatine is a precursor for polyamine synthesis, we evaluated the contribution of polyamines to limiting apoptosis. Addition of agmatine, putrescine, and the polyamines spermine and spermidine to T. cruzi sustained parasite proliferation and inhibited DNA fragmentation. Also, the ADC inhibitor difluoromethylarginine inhibited L-arginine-dependent restoration of parasite replication rates, while the protection from DNA fragmentation persisted. In aggregate, these results indicate that T. cruzi epimastigotes can undergo programmed cell death that can be inhibited by L-arginine by means of (i) a *NO synthase-dependent *NO production that suppresses apoptosis and (ii) an ADC-dependent production of polyamines that support parasite proliferation.

Agmatine↗
PubMed2001

Unraveling peroxynitrite formation in biological systems.

Peroxynitrite promotes oxidative damage and is implicated in the pathophysiology of various diseases that involve accelerated rates of nitric oxide and superoxide formation. The unambiguous detection of peroxynitrite in biological systems is, however, difficult due to the combination of a short biological half-life, limited diffusion, multiple target molecule reactions, and participation of alternative oxidation/nitration pathways. In this review, we provide the conceptual framework and a comprehensive analysis of the current experimental strategies that can serve to unequivocally define the existence and quantitation of peroxynitrite in biological systems of different levels of organization and complexity.

Animals↗
PubMed2000

Synthesis and antitrypanosomal evaluation of E-isomers of 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives. structure-activity relationships.

Several novel semicarbazone derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde and semicarbazides bearing a spermidine-mimetic moiety. All derivatives presented the E-configuration, as determined by NMR-NOE experiments. These compounds were tested in vitro as potential antitrypanosomal agents, and some of them, together with the parent compounds, 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives, were also evaluated in vivo using infected mice. Structure-activity relationship studies were carried out using voltammetric response and lipophilic-hydrophilic balance as parameters. Two of the compounds (1 and 3) displayed the highest in vivo activity. A correlation was found between lipophilic-hydrophilic properties and trypanocidal activity, high R(M) values being associated with low in vivo effects.

Aldehydes↗
PubMed1999

1,2,5-Oxadiazole N-oxide derivatives and related compounds as potential antitrypanosomal drugs: structure-activity relationships.

The syntheses of a new series of derivatives of 1,2,5-oxadiazole N-oxide, benzo[1,2-c]1,2,5-oxadiazole N-oxide, and quinoxaline di-N-oxide are described. In vitro antitrypanosomal activity of these compounds was tested against epimastigote forms of Trypanosoma cruzi. For the most effective drugs, derivatives IIIe and IIIf, the 50% inhibitory dose (ID50) was determined as well as their cytotoxicity against mammalian fibroblasts. Electrochemical studies and ESR spectroscopy show that the highest activities observed are associated with the facile monoelectronation of the N-oxide moiety. Lipophilic-hydrophilic balance of the compounds could also play an important role in their effectiveness as antichagasic drugs.

Animals↗
PubMed1999

Peroxynitrite affects Ca2+ transport in Trypanosoma cruzi.

Macrophages play an important role against Trypanosoma cruzi infection, via superoxide, nitric oxide, and peroxynitrite production. Peroxynitrite has been shown to be highly cytotoxic against Trypanosoma cruzi epimastigotes. Calcium is involved in many vital functions of the parasites, being its intracellular concentration governed by several transport systems, involving mitochondrial and non-mitochondrial compartments. In this paper, we report the effect of peroxynitrite on the calcium uptake systems, as studied by digitonin-permeabilized trypanosomes in the presence of arsenazo III. Peroxynitrite, at biologically relevant concentrations produced within phagosomes (250-750 microM), inhibited calcium uptake in a dose-dependent manner. Peroxynitrite decreased the mitochondrial membrane potential obtained in the presence of tetramethyl-p-phenylenediamine (TMPD)/ascorbate. In addition, a decrease of the non-mitochondrial Ca(2+)-uptake, concomitant with the inactivation of a Ca(2+)-dependent ATPase activity, was observed. HPLC analyses of the cellular adenine nucleotide pool showed a time-dependent decrease of ATP content and energy charge of the parasite; however this drop in ATP levels was significantly delayed with respect to decrease of the ATP-dependent Ca(2+)-transport. We conclude that the disruption of calcium homeostasis by peroxynitrite may contribute to the observed cytotoxic effects of macrophages against T. cruzi.

Adenine Nucleotides↗
PubMed1998

Xanthine oxidase-mediated decomposition of S-nitrosothiols.

S-Nitrosothiols (RSNO) occur in vivo and have been proposed as nitric oxide (.NO) storage and transport biomolecules. Still, the biochemical mechanisms by which RSNO release .NO in biological systems are not well defined, and in particular, the interactions between reactive oxygen species and RSNO have not been studied. In this work, we show that xanthine oxidase (XO), in the presence of purine (hypoxanthine, xanthine) or pteridine (lumazine) substrates, induces S-nitrosocysteine (CysNO) and S-nitrosoglutathione (GSNO) decomposition under aerobic conditions. The decomposition of RSNO by XO was inhibitable by copper-zinc superoxide dismutase, in agreement with the participation of superoxide anion (O-2) in the process. However, while superoxide dismutase could totally inhibit aerobic decomposition of GSNO, it was only partially inhibitory for CysNO. Competition experiments indicated that O-2 reacted with GSNO with a rate constant of 1 x 10(4) M-1.s-1 at pH 7.4 and 25 degreesC. The decomposition of RSNO was accompanied by peroxynitrite formation as assessed by the oxidation of dihydrorhodamine and of cytochrome c2+. The proposed mechanism involves the O-2-dependent reduction of RSNO to yield .NO, which in turn reacts fast with a second O-2 molecule to yield peroxynitrite. Under anaerobic conditions, CysNO incubated with xanthine plus XO resulted in CysNO decomposition, .NO detection, and cysteine and uric acid formation. We found that CysNO is an electron acceptor substrate for XO with a Km of 0.7 mM. In agreement with this concept, the enzymatic reduction of CysNO by XO was inhibitable by oxypurinol and diphenyliodonium, inhibitors that interfere with the catalytic cycle at the molybdenum and flavin sites, respectively. In conclusion, XO decomposes RSNO by O-2-dependent and -independent pathways, and in the presence of oxygen it leads to peroxynitrite formation.

Animals↗
PubMed1998

Synthesis and anti-trypanosomal activity of novel 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives.

Several novel semicarbazones derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde, and tested in vitro as potential anti-trypanosomal agents. The compounds were prepared in good to excellent yields in 2-3 steps from readily available starting materials. Some derivatives were found to be active against Trypanosoma cruzi with an activity similar to that of Nifurtimox.

Animals↗
PubMed1998

Prevalence and etiology of gastroduodenal ulcer in HIV-positive patients: a comparative study of 497 symptomatic subjects evaluated by endoscopy.

OBJECTIVE: In 497 HIV-positive (+) patients with upper digestive tract symptoms, 23 (5%) had gastroduodenal ulcers (GDU) at upper endoscopy. METHODS: To establish the causes of GDU in this setting, 16 of these patients who had had comprehensive histological evaluation (group I) were compared with 20 HIV+ subjects with upper gastrointestinal symptoms but without ulcer (group II), and with 16 seronegative patients with GDU (group III). Eighty-one percent of group I subjects and 90% of group II patients had C3 AIDS. The presence of gastritis and Helicobacter pylori, fungi, mycobacteria, viruses (especially cytomegalovirus [CMV] and herpes simplex [HSV]), and parasites was determined in all three groups by histopathological and microbiological studies. RESULTS: The prevalence of chronic active gastritis was 13/16 (81%) in group I, 12/20 (60%) in group II, and 15/16 (94%) in group III. It was associated with H. pylori in group III, and with opportunistic pathogens in groups I and II and with none in group III. H. pylori was detected in 5/16 patients (31%) in group I, in 12/20 (60%) in group II, and 11/16 (69%) in group III. Cytomegalovirus was histologically diagnosed in 8/16 patients (50%) in group I and in 1/20 (5%) in group II. This virus was the only factor shown to be significantly associated with GDU in these cases (p = 0.0046). Cryptosporidium was found in 2/16 (12.5%) patients in group I, in 1/20 (5%) in group II, and in none in group III. Differences between groups I and II were not statistically significant. No other organisms were observed in the three groups. CONCLUSIONS: Gastroduodenal ulcers were infrequent in HIV+ subjects with upper digestive tract symptoms and CMV was the only organism significantly associated with GDU in HIV+ patients. Among HIV+ patients, H. pylori was an uncommon cause of ulcer. Among HIV+ subjects with ulcer, chronic active gastritis was more common than H. pylori and it was associated with other pathogens. Finally, HIV+ patients with GDU should have endoscopic biopsies to detect opportunistic infections, especially CMV, because H. pylori infection is uncommon.

AIDS-Related Opportunistic Infections↗
PubMed1996

[Differences between smear positive and smear negative pulmonary tuberculosis].

UNLABELLED: The decision related to treatment initiation in smear-negative pulmonary TB is controversial. To determine differences between the characteristics of smear-negative, culture-positive pulmonary TB (Group D-) cases, we compared them with those patients who presented positive smear microscopy and cultures (Group D+). In addition, we compared the characteristics found in Group D- cases, in whom the treatment was started before confirmation by culture (sub-group D-TI) with those who were treated only after a positive culture was obtained (subgroup D-TD). We compared 270 patients of Group D+ with 48 of Group D-. The subgroups of Group D- (D-TI and D-TD) were compared with Group D+. Clinical symptoms, history, X-rays, other lung diseases and related extrapulmonary diseases were analysed Significant differences between groups D+ and D- related to age, history, X-rays and other lung diseases were found. There were no significant differences between Group D+ and subgroup D-TI, except for the age. The same and even more accentuated differences between Group D+ and D- were found between Group D+ and subgroup D-TD. CONCLUSIONS: Group D- was divided into to subgroups: D-TI, similar to D+, determined the decision to immediately start the treatment and D-TD, completely different; other possible diagnoses were considered and decision of treatment was delayed until a positive culture was obtained. This conduct proved to be the correct one in these cases where the diagnosis by culture was available.

Adolescent↗
PubMed1995

[Colonic ulcer in HIV (+) patients].

UNLABELLED: A characteristic rectocolonic endoscopic finding is the presence of ulcers, which may correspond to different diagnosis. Between January, 1989 and May, 1993, we performed 28 colonoscopies and 12 rectoscopies in patients with HIV (+). In all cases, histologic, parasitologic, bacteriologic, virologic, and micrologic studies were practised on tissue biopsies. Eighteen of them presented rectocolonic ulcers (we are not including anal and terminal ileum ulcers). The studies involved 16 males and 2 females, with an average age of 31, 21 years old (20-47), 14 of which were male homosexuals, 2 intravenous drug abusers, 1 hemophilic and an heterosexual female. Symptoms were as follows: 15 with hematochezia, 7 with proctorrhagia, 6 with enterorrhagia and 2 with both manifestations. All the rest, presented chronic diarrhea, loss of weight, anal secretion, asthenia, fever, constipation and anemia in isolated cases. Diagnosis were 6 rectocolonic cytomegalovirus (all occurred during the current year). Other related opportunistic pathogens included an intestinal TBC, a rectal Herpes and a Burkitt's lymphoma. Related etiological agents were not found in 9 patients, in spite of systematic quest. Opportunistics found in three of the cases revealed AIDS in those patients. COMMENTS: 1-The indexes of male homosexuals are strikingly higher than the rest of our HIV endoscopy statistics. 2-We observed prevailing idiopathic lesions. 3-The relationship between "CU like" pictures, already described, and the immunocomponents of the idiopathic CU is unknown. 4-All our CMV cases are recent. 5-Hematochezia was the most frequent symptom. 6- Herpetic ulcers correspond to HSV type 1. 7-Diffuse ulcers may correspond to lymphoma.

Adult↗
PubMed1988

Evaluation of the effectiveness of BCG vaccination using the case-control method in Buenos Aires, Argentina.

A retrospective case-control study was conducted in Argentina to determine the protection conferred by BCG vaccination against tuberculosis in children under six years of age, in an area where coverage is about 55%. A total of 175 tuberculosis patients were included. Five controls selected from patients treated at the same hospital as those under study for reasons other than tuberculosis were matched to each case on the basis of age, socioeconomic origin, nutritional status and place of residence. Information on BCG vaccination status was collected by an independent examiner. Tuberculosis localizations were as follows: 152 pulmonary, pleural and/or miliary; 18 meningitis; 2 lymphadenitis; 2 osteoarticular; and 1 otic. The diagnosis was based on bacteriological and histopathological tests, computerized tomography, radiology, clinical examination, endoscopy, and proved source of infection. The protective effect of BCG among those who were vaccinated was 73.0% with 95% confidence limits of 82% and 62%. According to these results BCG vaccination given early in life is very effective in preventing tuberculosis.

Argentina↗
PubMed1982

[Bacteriologic diagnosis of extrapulmonary tuberculosis in a general hospital].

In a study performed in a general hospital within a period of 19 months, a total of 233 specimens of extrapulmonary origin and 543 lung secretions were tested for mycobacteria. The biopsy and punction fluid specimens were cultured without previous decontaminating treatment in Lowenstein Jensen, Stonebrink, Middlebrook 7H9, 7H10, 7H11 media and inoculated into guinea pigs (Table 1). Urine and lung secretion specimens were decontaminated and cultured in Lowenstein Jensen and Stonebrink media. No inoculation into guinea pigs was performed with these samples. The percentages of positivity by culture were: 11.2% for all extrapulmonary specimens (15% excluding 66 urine samples) and 22.5% for the lung secretions. Positive results were obtained in direct smear examinations in 82% of all positive-culture lung secretions and in 8% of the extrapulmonary specimens. Inoculation into guinea pigs gave less positive results than cultures. On the basis of the present study, it is recommended to culture every extrapulmonary specimens for mycobacteria. These samples should be processed immediately after collection and, if possible, without previous decontamination to assure the best test sensitivity. Eight percent of the strains obtained from extrapulmonary specimens were typed as M. bovis.

Animals↗