Increased corticosterone levels in mice subjected to the rat exposure test

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Planejamento, síntese e avaliação farmacológica de compostos híbridos potencialmente ativos para o tratamento da anemia falciforme

Sickle cell disease (SCD) is a hereditary hemolytic anemia caused by the inheritance of one S hemoglobin gene from each ancestor. Patients with SCD present increased circulating levels of cytokines, including TNF-alpha (TNF-α). Hydroxyurea (HU) is the available therapeutically strategy for treatment; it acts as a source of nitric oxide and benefits patients by increasing the levels of fetal hemoglobin (HbF). Thus, within one research line that aims at finding new drugs, a series of compounds with TNF-α inhibition and nitric oxide donation properties have been synthesized in order to explore possible synergism of actions beneficial in the treatment of the disease. Six compounds were synthesized: five derivatives of organic nitrates and one of sulfonamide. The compounds, (1,3-dioxo-1,3-dihydro-2Hisoindol-2-yl) methyl nitrate (compound I); (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl nitrate (compound II); 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzyl nitrate (compound III);4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxybenzenesulfonamide (compound IV); 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzyl nitrate (compound V) and 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) phenyl]ethyl nitrate (compound VI), were synthesized using linear synthetic methodology, with excellent overall yields. All compounds showed anti-inflammatory and analgesic effects with a reduction in 43%-65% of ear edema in mice and a reduction of 25%-42% of writhing induced by acetic acid. All compounds showed comparable reductions in the leukocyte infiltration capacity and ability to generate nitric oxide. The aryl compounds (III, IV and V) presented less mutagenic activity compared to compounds I, II and VI according to the salmonella mutagenicity assay (Ames test). Compounds IV and VI showed activity in K562 culture cells, with increases in gamma globin gene expression to levels higher than with hydroxyurea suggesting a potential to increase fetal hemoglobin. This data set characterizes new potentially useful drug candidates for the treatment of symptoms of sickle cell anemia.

Effects of NAMPT polymorphisms and haplotypes on circulating visfatin/NAMPT levels in hypertensive disorders of pregnancy

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Administration of physiologic levels of triiodothyronine increases leptin expression in calorie-restricted obese rats, but does not influence weight loss

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Circulating thyroid hormone levels in young pregnant rats and their fetuses: Effect of malnutrition

In order to evaluate some factors likely to be involved in the maternal and fetal growth impairment due to alimentary protein deficiency, the circulating levels of triiodothyronine (T 3) and thyroxine (T 4) were studied in 4 young (45-day-old) female rat groups: control and malnourished, both nonpregnant and pregnant; similarly schedules groups were studied using adult (100-day-old) rats. Circulating levels of T 4 were higher in nonpregnant, malnourished young rats in their corresponding controls. T 3 levels were higher in young malnourished animals and lower in adult malnourished animals, nonpregnant or pregnant, as compared to controls. Pups from young malnourished mothers showed significantly lower birth weights than those from controls. The present results suggest that there are age differences in thyroid function, as affected by protein-calorie malnutrition in pregnant and non-pregnant rats. On the other hand, the circulating thyroid hormone levels were not importantly affected by the mother dietary protein restriction under our experimental conditions.

Dissociation between the circulating renin-angiotensin system and angiotensin II receptors in central losartan-induced hypertension

Losartan, an AT1 angiotensin II (ANG II) receptor non-peptide antagonist, induces an increase in mean arterial pressure (MAP) when injected intracerebroventricularly (icv) into rats. The present study investigated possible effector mechanisms of the increase in MAP induced by icv losartan in unanesthetized rats. Male Holtzman rats (280-300 g, N = 6/group) with a cannula implanted into the anterior ventral third ventricle received an icv injection of losartan (90 µg/2 µl) that induced a typical peak pressor response within 5 min. In one group of animals, this response to icv losartan was completely reduced from 18 ± 1 to 4 ± 2 mmHg by intravenous (iv) injection of losartan (2.5-10 mg/kg), and in another group, it was partially reduced from 18 ± 3 to 11 ± 2 mmHg by iv prazosin (0.1-1.0 mg/kg), an alpha1-adrenergic antagonist (P<0.05). Captopril (10 mg/kg), a converting enzyme inhibitor, injected iv in a third group inhibited the pressor response to icv losartan from 24 ± 3 to 7 ± 2 mmHg (P<0.05). Propranolol (10 mg/kg), a ß-adrenoceptor antagonist, injected iv in a fourth group did not alter the pressor response to icv losartan. Plasma renin activity and serum angiotensin-converting enzyme activity were not altered by icv losartan in other animals. The results suggest that the pressor effect of icv losartan depends on angiotensinergic and alpha1-adrenoceptor activation, but not on increased circulating ANG II.

Morphofunctional Alterations in Endocrine Pancreas of Short- and Long-term Dexamethasone-treated Rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Oxidative stress markers and apoptosis in the prostate of diabetic rats and the influence of vitamin C treatment

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Time-dependent effects of lead on rat reproductive functions

The effects of exposure to lead on endocrine function and the reproductive parameters were studied in pubertal rats treated with 1.0 g l(-1) lead acetate in drinking water for 20 days (subacute group) or 9 months (chronic group) in addition to i.v. injections of lead acetate (0.1 mg 100 g(-1) body wt.) every 10 (subacute group) or 15 days (chronic group). Although basal levels of testosterone were higher both in plasma and in testes of acutely intoxicated animals, the circulating levels of luteinizing hormone (LH) were not affected in either group, nor was the LH-releasing hormone content of the median eminence. The density of [I-125]LH/human chorionic gonadotrophin (hCG) binding sites in testicular homogenates was reduced by saturnism in both groups, concomitant with a significantly increased apparent affinity constant of the hormone-receptor complex. These data can be viewed as the result of a mixture of specific lead toxicity (e.g. at the enzyme level) with other more general actions (e.g. at the level of the hypothalamus-pituitary-testicular axis).

Ionotropic Glutamate Receptors in Hypothalamic Paraventricular and Supraoptic Nuclei Mediate Vasopressin and Oxytocin Release in Unanesthetized Rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Free diet selection by broilers as influenced by dietary macronutrient ratio and corticosterone supplementation. 1. Diet selection, organ weights, and plasma metabolites

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Biochemical evaluation of glycemic levels of long-term tacrolimus therapy in rats

One of the more serious complications following transplantation is the development of post-transplantation diabetes mellitus (PTDM), which has a major impact on the quality of life, with effects ranging from the control of glycemia times to increased susceptibility to infections and cardiovascular complications. It has been suggested that immunosuppressive therapy, mainly tacrolimus therapy, may be an important factor in the development of PTDM. There is a lack of studies that explore the effects of long-term tacrolimus on PTDM in animal protocols. The objective of this study was therefore to evaluate the effects of long-term therapy with tacrolimus in rats. One group was treated with tacrolimus, injected subcutaneously, in a daily dose of 1 mg/kg of body weight. The chosen dose was sufficient to achieve therapeutic tacrolimus serum levels. The experimental periods were 60, 120, 180 and 240 days. One group was used as control and received daily subcutaneous injections of saline solution during all periods. A tendency towards increased glycemia levels during the initial periods (60 and 120 days) was observed. However, at 180 and 240 days, the glycemia levels were not statistically different from that of the control group of the same period. It may thus be concluded that the deleterious effects of tacrolimus therapy on glycemia may be a time-related side effect.

Pulpal and periodontal diseases increase triglyceride levels in diabetic rats

Objectives: The aim of this study was to evaluate triglyceride and cholesterol levels in diabetic rats and their relationship with pulpal and periodontal diseases. Methods: Eighty male rats (Rattus norvegicus albinus, Wistar) were divided into the following eight groups comprising ten animals each: normal rats (G1), rats with pulpal diseases (G2), rats with periodontal diseases (G3), rats with both pulpal and periodontal diseases (G4), diabetic rats (G5), diabetic rats with pulpal diseases (G6), diabetic rats with periodontal diseases (G7), and diabetic rats with both periodontal and pulpal diseases (G8). Diabetes was induced by injecting streptozotocin, periapical lesions were induced by exposing pulpal tissue to the oral environment, and periodontal diseases were induced by periodontal ligature. The animals were killed after 30 days, and lipid profile was enzymatically measured using Trinder's method. The total assessed values were statistically analyzed by analysis of variance and Tukey test (p < 0.05). Results: The triglyceride levels of diabetic rats with periodontal disease and of diabetic rats with both periodontal and pulpal diseases were significantly higher than those of normal rats and nondiabetic group rats, respectively. The differences in the cholesterol levels among the groups were not significant. Conclusions: We found that the association of pulpal and periodontal diseases with diabetes increased triglyceride levels in rats. Clinical significance: Changes in lipid profile may be related to the presence of oral infections and diabetes. © 2012 Springer-Verlag Berlin Heidelberg.

Acid and alkaline phosphatase activity in broiler chicks fed with different levels of phytase and non-phytate phosphorus

Tartrate-resistant acid (ACP) and alkaline phosphatase (ALP) activities were evaluated in the serum and bone of broiler chicks fed with various amounts of non-phytate phosphorus (NPP) or phytase. Data were analysed using a 4×3 factorial design containing four NPP levels per period. Analyses were performed in chicks aged 1-21 days (0.21; 0.29; 0.37; 0.45 ppm) and 36-42 days (0.13; 0.21; 0.29; 0.37 ppm) and under three different phytase level treatments (0, 500 and 1000 FTU/kg) for each period. In 42-day-old animals, the serum ACP and ALP activities did not differ in response to NPP and phytase levels and bone ACP activity decreased with increased phosphorus levels. We observed effects on ALP activity by approximately 70% in lower phosphorus (0.13 and 0.21) levels without phytase. The phytase addition decreased (P<0.05) ALP values in lower phosphorus levels. The bone ALP and ACP levels of 21-day-old animals were not affected by phosphorus or phytase. Pi depletion induces a significant increase in alkaline phosphatase synthesis, suggesting that the function of this enzyme is downregulated by phosphorus. © 2013 Copyright Taylor and Francis Group, LLC.

Stimulation of MMP-1 and CCL2 by NAMPT in PDL cells

Periodontitis is an inflammatory disease caused by pathogenic microorganisms and characterized by the destruction of the periodontium. Obese individuals have an increased risk of periodontitis, and elevated circulating levels of adipokines, such as nicotinamide phosphoribosyltransferase (NAMPT), may be a pathomechanistic link between both diseases. The aim of this in vitro study was to examine the regulation of periodontal ligament (PDL) cells by NAMPT and its production under inflammatory and infectious conditions. NAMPT caused a significant upregulation of 9 genes and downregulation of 3 genes, as analyzed by microarray analysis. Eight of these genes could be confirmed by real-time PCR: NAMPT induced a significant upregulation of EGR1, MMP-1, SYT7, ITPKA, CCL2, NTM, IGF2BP3, and NRP1. NAMPT also increased significantly the MMP-1 and CCL2 protein synthesis. NAMPT was significantly induced by interleukin-1β and the periodontal microorganism P. gingivalis. NAMPT may contribute to periodontitis through upregulation of MMP-1 and CCL2 in PDL cells. Increased NAMPT levels, as found in obesity, may therefore represent a mechanism whereby obesity could confer an increased risk of periodontitis. Furthermore, microbial and inflammatory signals may enhance the NAMPT synthesis in PDL cells and thereby contribute to the increased gingival and serum levels of this adipokine, as found in periodontitis. © 2013 Marjan Nokhbehsaim et al.