Metformin Improves Autonomic Nervous System Imbalance and Metabolic Dysfunction in Monosodium L-Glutamate-Treated Rats.

Metformin is an antidiabetic drug used for the treatment of diabetes and metabolic diseases. Imbalance in the autonomic nervous system (ANS) is associated with metabolic diseases. This study aimed to test whether metformin could improve ANS function in obese rats. Obesity was induced by neonatal treatment with monosodium L-glutamate (MSG). During 21-100 days of age, MSG-rats were treated with metformin 250 mg/kg body weight/day or saline solution. Rats were euthanized to evaluate biometric and biochemical parameters. ANS electrical activity was recorded and analyzed. Metformin normalized the hypervagal response in MSG-rats. Glucose-stimulated insulin secretion in isolated pancreatic islets increased in MSG-rats, while the cholinergic response decreased. Metformin treatment normalized the cholinergic response, which involved mostly the M3 muscarinic acetylcholine receptor (M3 mAChR) in pancreatic beta-cells. Protein expression of M3 mAChRs increased in MSG-obesity rats, while metformin treatment decreased the protein expression by 25%. In conclusion, chronic metformin treatment was effective in normalizing ANS activity and alleviating obesity in MSG-rats.

Moderate exercise training since adolescence reduces Walker 256 tumour growth in adult rats.

KEY POINTS: Cancer growth, cell proliferation and cachexia index can be attenuated by the beneficial programming effect of moderate exercise training, especially if it begins in adolescence. Walker 256 tumour-bearing rats who started exercise training during adolescence did not revert the basal low glycaemia and insulinaemia observed before tumour cell inoculation. The moderate exercise training improved glucose tolerance and peripheral insulin sensitivity only in rats exercised early in adolescence. The chronic effects of our exercise protocol are be beneficial to prevent cancer cachexia and hold clear potential as a nonpharmacological therapy of insulin sensitization. ABSTRACT: We tested the hypothesis that moderate exercise training, performed early, starting during adolescence or later in life during adulthood, can inhibit tumour cell growth as a result of changes in biometric and metabolic markers. Male rats that were 30 and 70 days old performed a treadmill running protocol over 8 weeks for 3 days week-1 , 44 min day-1 and at 55-65% V̇O2max . After the end of training, a batch of rats was inoculated with Walker 256 carcinoma cells. At 15 days after carcinoma cell inoculation, the tumour was weighed and certain metabolic parameters were evaluated. The data demonstrated that physical performance was better in rats that started exercise training during adolescence according to the final workload and V̇O2max . Early or later moderate exercise training decreased the cachexia index, cell proliferation and tumour growth; however, the effects were more pronounced in rats that exercised during adolescence. Low glycaemia, insulinaemia and tissue insulin sensitivity was not reverted in Walker 256 tumour-bearing rats who trained during adolescence. Cancer growth can be attenuated by the beneficial programming effect of moderate exercise training, especially if it begins during adolescence. In addition, improvement in glucose-insulin homeostasis might be involved in this process.

Environmental monitoring and the developmental origins of health and disease.

Early-life chronic exposure to environmental contaminants, such as bisphenol-A, particulate matter air pollution, organophosphorus pesticides, and pharmaceutical drugs, among others, may affect central tissues, such as the hypothalamus, and peripheral tissues, such as the endocrine pancreas, causing inflammation and apoptosis with severe implications to the metabolism. The Developmental Origins of Health and Disease (DOHaD) concept articulates events in developmental phases of life, such as intrauterine, lactation, and adolescence, to later-life metabolism and health. These developmental phases are more susceptible to environmental changes, such as those caused by environmental contaminants, which may predispose individuals to obesity, metabolic syndrome, and chronic noncommunicable diseases later in life. Alterations in the epigenome are explored as an underlying mechanism to the programming effects on metabolism, as the expression of key genes related with central and peripheral metabolic functions may be altered in response to environmental disturbances. Studies show that environmental contaminants may affect gene expressions in mammals, especially when exposed to during the developmental phases of life, leading to metabolic disorders in adulthood. In this review, we discuss the current obesity epidemics, the DOHaD concept, pollutants' toxicology, environmental control, and the role of environmental contaminants in the central and peripheral programming of obesity and metabolic syndrome. Improving environmental monitoring may directly affect the quality of life of the population and help protect the future generations from metabolic diseases.

Assessment of in vivo and in vitro genotoxicity of glibenclamide in eukaryotic cells.

Glibenclamide is an oral hypoglycemic drug commonly prescribed for the treatment of type 2 diabetes mellitus, whose anti-tumor activity has been recently described in several human cancer cells. The mutagenic potential of such an antidiabetic drug and its recombinogenic activity in eukaryotic cells were evaluated, the latter for the first time. The mutagenic potential of glibenclamide in therapeutically plasma (0.6 µM) and higher concentrations (10 µM, 100 µM, 240 µM and 480 µM) was assessed by the in vitro mammalian cell micronucleus test in human lymphocytes. Since the loss of heterozygosity arising from allelic recombination is an important biologically significant consequence of oxidative damage, the glibenclamide recombinogenic activity at 1 µM, 10 µM and 100 µM concentrations was evaluated by the in vivo homozygotization assay. Glibenclamide failed to alter the frequency of micronuclei between 0.6 µM and 480 µM concentrations and the cytokinesis block proliferation index between 0.6 µM and 240 µM concentrations. On the other hand, glibenclamide changed the cell-proliferation kinetics when used at 480 µM. In the homozygotization assay, the homozygotization indices for the analyzed markers were lower than 2.0 and demonstrated the lack of recombinogenic activity of glibenclamide. Data in the current study demonstrate that glibenclamide, in current experimental conditions, is devoid of significant genotoxic effects. This fact encourages further investigations on the use of this antidiabetic agent as a chemotherapeutic drug.

Protective effect of metformin against walker 256 tumor growth is not dependent on metabolism improvement.

BACKGROUND/AIMS: The objective of the current work was to test the effect of metformin on the tumor growth in rats with metabolic syndrome. METHODS: We obtained pre-diabetic hyperinsulinemic rats by neonatal treatment with monosodium L-glutamate (MSG), which were chronically treated every day, from weaning to 100 day old, with dose of metformin (250 mg/kg body weight). After the end of metformin treatment, the control and MSG rats, treated or untreated with metformin, were grafted with Walker 256 carcinoma cells. Tumor weight was evaluated 14 days after cancer cell inoculation. The blood insulin, glucose levels and glucose-induced insulin secretion were evaluated. RESULTS: Chronic metformin treatment improved the glycemic homeostasis in pre-diabetic MSG-rats, glucose intolerance, tissue insulin resistance, hyperinsulinemia and decreased the fat tissue accretion. Meanwhile, the metformin treatment did not interfere with the glucose insulinotropic effect on isolated pancreatic islets. Chronic treatment with metformin was able to decrease the Walker 256 tumor weight by 37% in control and MSG rats. The data demonstrated that the anticancer effect of metformin is not related to its role in correcting metabolism imbalances, such as hyperinsulinemia. However, in morphological assay to apoptosis, metformin treatment increased programmed cell death. CONCLUSION: Metformin may have a direct effect on cancer growth, and it may programs the rat organism to attenuate the growth of Walker 256 carcinoma.

Genetic and molecular characterization of pathogenic isolates of Pyricularia grisea from wheat (Triticum aestivum Lam.) and triticale (x Triticosecale Wittmack) in the state of Paraná, Brazil.

Isolates of Pyricularia grisea from wheat (Triticum aestivum Lam.) and triticale (x Triticosecale Wittmack) spikes with blast symptoms were analyzed by classical (VCG) and molecular (RAPD) techniques. P. grisea mutants, unable to use sodium nitrate (nit) as nitrogen source, were obtained with potassium chlorate. For vegetative compatibility (VCG) tests, genetically complementary nit mutant pairs were inoculated in a medium with sodium nitrate as a single nitrogen source. P. grisea isolates were divided into two vegetative compatibility groups and two RAPD groups. Since vegetative compatible strains may mutually exchange genetic and cytoplasmatic material, the contribution of the parasexual cycle in the genetic variability of Brazilian P. grisea isolates is discussed.

The castor oil plant detergent (Ricinus communis) inhibits the asexual development of phytopathogenic fungi / Inibição do desenvolvimento de fungos fitopatogênicos por detergente derivado de óleo da mamona (Ricinus communis)

In the present study the fungitoxic effect of the castor oil plant detergent (Ricinus communis) on the development of the phytopathogens Pyricularia grisea, Fusarium graminearum and Colletotrichum lindemuthianum was evaluated. Six concentrations of the detergent (12.5mL L-1 to 300mL L-1) had been, individually, incorporated to the Basal Medium. After fungi inoculations, the radial growth of mycelia were evaluated. Detergent at 50mL L-1 and 200mL L-1 inhibited completely the development of P. grisea and C. lindemuthianum, respectively. On the basis of the mycelial growth of F. graminearum, the fungitoxic activity of the castor oil plant detergent (DOM) determined inhibition in the range of 79.4 and 91% for the F2 race and 80.7 and 90.7% for the F4 race. Detergent at the concentrations of 100mL L-1 to 300mL L-1 inhibited in 100% the F. graminearum germination conidia (races F-4 and F-2). Results demonstrate the fungitoxic activity of the castor oil plant detergent on phytopathogenic fungi.(AU)

No presente estudo avaliou-se o efeito fungitóxico do detergente derivado do óleo da mamona (Ricinus communis) sobre o desenvolvimento dos fitopatógenos: Pyricularia grisea, Fusarium graminearum e Colletotrichum lindemuthianum. Seis concentrações do detergente (12,5mL L-1 a 300mL L-1) foram, individualmente, incorporadas ao Meio Basal; a seguir, após inoculação fúngica, o crescimento radial dos micélios foi avaliado. A inibição total do desenvolvimento de C. lindemuthianum e P. grisea foi observada entre as concentrações de 50mL L-1 e 200mL L-1, respectivamente. Com base no crescimento miceliano das colônias de F. graminearum, a atividade antifúngica do detergente do óleo da mamona (DOM) determinou inibição variável entre 79,4 e 91% para a raça F2 e entre 80,7 e 90,7% para a raça F4. O detergente, nas concentrações de 100 a 300mL L-1, inibiu em 100% a germinação de conídios de F. graminearum (raças F-4 e F-2). Os resultados demonstram nítida atividade antifúngica do detergente derivado do óleo da mamona sobre fitopatógenos.(AU)

uvsZ1 mutation shows epistatic relations with uvsD153 and uvsJ1 mutations without any involvement with checkpoint control in Aspergillus nidulans.

The participation of the recently described uvsZ1 mutation in checkpoint control and the identification of epistatic relations between uvsZ1 mutation and uvsD153 and uvsJ1 mutations are provided. The effect of mutation uvsZ1 in mitotic exchanges into paba-bi (chromosome I) and cho-nic (chromosome VII) genetic intervals has also been evaluated. The mutation uvsZ1 was epistatic with regard to uvsD153 and uvsJ1 mutations, with no involvement with checkpoint control. In contrast to mutations in UvsB and UvsF groups, the uvsZ1 mutation failed to cause any changes in the frequencies of mitotic crossing-over. The distinct phenotypic traits given by mutation uvsZ1 suggest the presence of complex interactions among the different DNA repair pathways. Interaction may be an additional cell strategy of DNA damage response.

Vincristine induces somatic segregation, via mitotic crossing-over, in diploid cells of Aspergillus nidulans.

Vincristine is an alkaloid widely used as an antineoplastic agent. In eukaryotic cells the drug causes blockage in the G2 phase of the cell cycle and an increase in the frequency of sister chromatid exchanges. Due to the fact that germinating Aspergillus nidulans cells spend most of their cycle in G2 phase, they provide an excellent system for the study of mitotic crossing-over. Taking into account that mitotic crossing-over occurs during G2 period, the evaluation of recombinagenic and aneugenic potential of vincristine is provided with regard to two diploid strains of A. nidulans: a wild strain (uvsH+//uvsH+) and a defective one in DNA repair (uvsH//uvsH). Drug toxicity and its effect on the asexual cycle of A. nidulans has been evaluated as well. Treatment of both strains with vincristine did not change colony growth in the culture, however cytological analyses showed aberrant conidiophores. Recombinagenic potential of vincristine was evaluated by induction of gene homozygosis originally present in heterozygosity diploid strains (Homozygotization Index). Results show that vincristine induces mitotic crossing-over and higher frequency of aneuploid mitotic segregants. The results also show the recombinagenic and aneuploidogenic potential of vincristine and suggest its participation in the induction of secondary malignancies.