André Arigony Souto

Modulatory effect of resveratrol on SIRT1, SIRT3, SIRT4,PGC1α and NAMPT gene expression profiles in wild-type adult zebrafish liver

Sirtuins (SIRTs) are NAD+-dependent deacetylases that catalyze the hydrolysis of acetyl-lysine residues. They play an important role in many physiological and pathophysiological processes, such as the regulation of lifespan and the prevention of metabolic diseases. In this study, we analyzed the effect of resveratrol on the gene expression levels of SIRT1, SIRT3, SIRT4, PGC1α, and NAMPT, as well as its effect on NAD+ and NADH levels, in the liver of non stressed or non impaired wild-type zebrafish. Semiquantative RT-PCR assays showed that resveratrol did not change the mRNA levels of SIRT1 and PGC1α but decreased the expression levels of the SIRT3, SIRT4, and NAMPT genes. The decrease in NAMPT mRNA levels was accompanied by an increase in NADH levels, thereby decreasing the NAD+/H ratio. Taken together, our results suggest that resveratrol plays a modulatory role in the transcription of the NAMPT, SIRT3, and SIRT4 genes. Zebrafish is an interesting tool that can be used to understand the mechanisms of SIRTs and NAMPT metabolism and to help develop therapeutic compounds. However, further investigations using healthy experimental animals are required to study the modulation of the SIRT and NAMPT genes by resveratrol before it is used as a nutraceutical compound in healthy humans.

Estudo da hidratação da pele por emulsões cosméticas para xerose e sua estabilidade por reologia

NI (nonionic) and LC (liquid crystal) emulsions were developed, and their rheological parameters were evaluated. Also, the hydrating effect of NI and LC emulsions was tested among women with 20 ± 2 years, as well as NI emulsions among women with 70 ± 7 years of age. The results showed that the emulsions were stable and they had a pseudoplastic behavior and apparent thixotropy. The data revealed the best rheological profile of the NI emulsion with the lowest pour point (13.57 ± 3.19 Pa) and the highest spreadability (4.99 ± 0.54 mm²/g). There was no significant difference in hydration between NI and LC emulsions (16.0 ± 5.1%; 14.2 ± 5.5%) among younger women. However, hydration among elderly women was of 13.1 ± 5.6% for NI emulsion, revealing that it was significantly lower in this group when compared to the younger one. These data revealed the importance of rheological evaluation as a factor of choice among similar cosmetic formulations. Age bracket selection also proved to be very important in the assessment of skin hydration by cosmetic products.

Protective Effects of Resveratrol on Hepatotoxicity Induced by Isoniazid and Rifampicin via SIRT1 Modulation

Acute liver injury was induced in male BALB/c mice by coadministering isoniazid and rifampicin. In this work, the effects of resveratrol (1) were investigated in the hepatotoxicity caused by isoniazid-rifampicin in mice. Compound 1 was administered 30 min prior to isoniazid-rifampicin. Serum biochemical tests, liver histopathological examination, oxidative stress, myeloperoxidase activity, cytokine production (TNF-α, IL-12p70, and IL-10), and mRNA expression of SIRT1-7 and PPAR-γ/PGC1-α were evaluated. The administration of 1 significantly decreased aspartate transaminase and alanine aminotransferase levels, myeloperoxidase activity, and cytokine levels. Furthermore, 1 reverted the decrease of catalase and glutathione activities and ameliorated the histopathological alterations associated with antituberculosis drugs. Modulation of SIRT1 and PPAR-γ/PGC1-α expression is likely involved in the protective effects of 1. The results presented herein show that 1 was able to largely prevent the hepatotoxicity induced by isoniazid and rifampicin in mice, mainly by modulating SIRT1 mRNA expression.

An inorganic complex that inhibits Mycobacterium tuberculosis enoyl reductase as a prototype of a new class of chemotherapeutic agents to treat tuberculosis

Here we describe the inhibitory activity of IQG607, pentacyano(isoniazid)ferrate(II), on isoniazid-sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis, its oral toxicity, and efforts to adapt IQG607 synthesis to large chemical reactors. IQG607 represents a promising chemotherapeutic agent aiming at the inhibition of a validated and druggable molecular target.

Higher Content of Trans Fatty Acids in Abdominal Visceral Fat of Morbidly Obese Individuals undergoing Bariatric Surgery compared to Non-Obese Subjects

Background: The purpose of this study was to determine the total content of trans fatty acids (TFA) in subcutaneous, retroperitoneal and visceral fat of morbidly obese and non-obese patients submitted to bariatric surgery or plastic and abdominal surgery. Methods: The adipose tissues were obtained by surgery; lipids were extracted, saponified and esterified. TFA were measured by FTIR-ATR spectroscopy. Results: The TFA average in obese patients was 6.3% for retroperitoneal and 8.7% for visceral fat. For non-obese patients, the figures were 6.9% (subcutaneous) and 9.3% (visceral). There was no difference between the groups. However, the TFA depot in visceral fat was higher than other fatty tissues for morbidly obese (P<0.001) and non-obese (P<0.05) patients. Conclusions: Our values for TFA content in all adipose tissues analyzed are higher than reported in other countries (3-6%). We showed more TFA in visceral adipose tissue than in other abdominal fat (subcutaneous and retroperitoneal) stores. The visceral adipose tissue level is worrisome because the higher rate of lipolysis in this tissue appears to be an important indicator of metabolic alterations and the levels of TFA found in adipose tissue presumably reflect the higher dietary intake of TFA by Brazilians.

Evidence for the Analgesic Activity of Resveratrol in Acute Models of Nociception in Mice

The effects of trans-resveratrol (1) were evaluated in acute nociception models induced by capsaicin or glutamate in mice, in an attempt to further characterize its mechanism of action. The oral administration of 1 (50 and 100 mg/kg) reduced significantly the licking behavior elicited by capsaicin (1.6 μg/paw) or glutamate (10 μmol/paw). The co-administration of 1 into the mouse paw (200 μg/site) markedly prevented glutamate-induced licking, without affecting capsaicin responses. In addition, the intrathecal (it) injection of 1 (150 to 600 μg/site) greatly reduced the licking behavior caused by capsaicin, but not glutamate. Similarly, the intracerebroventricular injection of 1 (300 μg/site) caused a potent inhibition of capsaicin-induced nociception, while the glutamate responses remained unaffected. However, the co-administration of 1 (300 μg/site) reduced the biting behavior induced by spinal injection of glutamate (30 μg/site, it), leaving capsaicin (6.4 μg/site)-induced biting unaltered. Notably, the oral administration of 1 (100 mg/kg) inhibited significantly the capsaicin-induced increase of c-Fos and COX-2 labeling in the spinal cord and COX-2 expression in the cortex, but failed to affect c-Fos and COX-2 expression in the glutamate model. This study has explored the effects of 1 in both the capsaicin and glutamate models, extending current knowledge on the analgesic effects of trans-resveratrol.

Zebrafish as a Model Organism to Evaluate Drugs Potentially Able to Modulate Sirtuin Expression

Sirtuins comprise a unique class of NAD(+)-dependent deacetylases that are key regulators of many physiological processes. They appear to be a potential target set of enzymes for treatment of age-associated diseases and have attracted interest in many research areas involving chemical and cellular investigations to understand them and discover potential ligands. For molecular screening, a cost-effective, easily manipulated, and consolidated model organism is needed, and the zebrafish fits these requirements perfectly. Here, we report the identification of sirtuin-related genes and their expression patterns in nine tissues of adult zebrafish. The investigation identified eight sirtuin-related genes, and their phylogenetic analysis resulted in seven well-resolved terminal clades, corresponding to each sirtuin (SIRT1, 2, 4-7) and two SIRT3 paralogs. Each gene showed a unique expression profile, illustrating a wide tissue distribution of sirtuins in zebrafish. SIRT1, SIRT3, SIRT5, and SIRT6 genes were expressed in all tissues, and SIRT1 exhibited the highest level of expression in all organs. A modulation experiment was performed using resveratrol, and results confirmed to the predicted scenario: altered sirtuin expression levels. Drugs based on sirtuin modulators may be tested using this system and could lead us to more selective and powerful therapies for age-related disorders.

The role of calcium channel blockers and resveratrol in the prevention of paraquat-induced parkinsonism in Drosophila melanogaster: a locomotor analysis.

Studies have suggested that neuronal loss in Parkinson’s disease (PD) could be related to the pacemaker activity of the substantia nigra pars compacta generated by L-type Cav 1.3 calcium channels, which progressively substitute voltage-dependent sodium channels in this region during aging. Besides this mechanism, which leads to increases in intracellular calcium, other factors are also known to play a role in dopaminergic cell death due to overproduction of reactive oxygen species. Thus, dihydropyridines, a class of calcium channel blockers, and resveratrol, a polyphenol that presents antioxidant properties, may represent therapeutic alternatives for the prevention of PD. In the present study, we tested the effects of the dihydropyridines, isradipine, nifedipine, and nimodipine and of resveratrol upon locomotor behavior in Drosophila melanogaster. As previously described, paraquat induced parkinsonian-like motor deficits. Moreover, none of the drugs tested were able to prevent the motor deficits produced by paraquat. Additionally, isradipine, nifedipine, resveratrol, and ethanol (vehicle), when used in isolation, induced motor deficits in flies. This study is the first demonstration that dyhidropyridines and resveratrol are unable to reverse the locomotor impairments induced by paraquat in Drosophila melanogaster.

Degree of conversion and hardness of an orthodontic resin cured with a light-emitting diode and a quartz - tungsten - halogen light

The purpose of this study was to assess the influence of two light units, a quartz-tungsten-halogen (QTH) and a light-emitting diode (LED), on the hardness and degree of conversion of an orthodontic composite resin. Sixty specimen disks were prepared from Transbond XT composite resin (3M Unitek) and light cured for 10, 20, and 30 seconds with a QTH (Curing Light XL 3000, 3M Unitek) or a LED (Ortholux, 3M Unitek) light-curing unit for 5, 10, and 15 seconds. Composite resin polymerization was evaluated by Fourier-transform infrared (FTIR) spectrophotometry and Knoop hardness number (KHN). The results were statistically analysed using analysis of variance and Tukeys multiple comparisons test (alpha = 0.05). The highest KHN was obtained with the QTH at 30 (25.19 KHN) and 20 (24.01) seconds, which did not differ statistically, and in the LED 15 second (21.86) group. The QTH 10 second group (20.53) did not differ statistically from the QTH 20 second or the LED 5 (19.96) and 15, or 10 second (18.95) groups. According to FTIR, there was no statistical difference for the degree of conversion among the groups, QTH 10 (43.42 per cent), QTH 20 (46.12 per cent), QTH 30 (45.30 per cent), LED 10 (47.02 per cent), or LED 15 (47.24 per cent) seconds. The lowest degree of conversion was obtained for the LED 5 second group (38.97 per cent), which did not differ statistically from the QTH 10 second group. Light curing with the LED resulted in a reduction of 50 per cent in the time recommended for use of the QTH light with the composite resin, Transbond XT.

Design of Novel Potent Inhibitors of Human Uridine Phosphorylase-1: Synthesis, Inhibition Studies, Thermodynamics, and in Vitro Influence on 5-Fluorouracil Cytotoxicity

Uridine (Urd) is a promising biochemical modulator to reduce host toxicity caused by 5-fluorouracil (5-FU) without impairing its antitumor activity. Elevated doses of Urd are required to achieve a protective effect against 5-FU toxicity, but exogenous administration of Urd is not well-tolerated. Selective inhibitors of human uridine phosphorylase (hUP) have been proposed as a strategy to increase Urd levels. We describe synthesis and characterization of a new class of ligands that inhibit hUP type 1 (hUP1). The design of ligands was based on a possible SN1 catalytic mechanism and as mimics of the carbocation in the transition state of hUP1. The kinetic and thermodynamic profiles showed that the ligands here presented are the most potent in vitro hUP1 inhibitors developed to date. In addition, a lead compound improved the antiproliferative effects of 5-FU on colon cancer cells, accompanied by a reduction of in vitro 5-FU cytotoxicity in aggressive SW-620 cancer cells.