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1.
Bioorg Med Chem Lett ; 25(17): 3564-8, 2015 09 01.
Article in English | MEDLINE | ID: mdl-26169126

ABSTRACT

The enzyme glycerol-3-phosphate dehydrogenase (G3PDH) from Leishmania species is considered as an attractive target to design new antileishmanial drugs and a previous in silico study reported on the importance of chalcones to achieve its inhibition. Here, we report the identification of a synthetic chalcone in our in vitro assays with promastigote cells from Leishmania amazonensis, its biological activity in animal models, and docking followed by molecular dynamics simulation to investigate the molecular interactions and structural patterns that are crucial to achieve the inhibition complex between this compound and G3PDH. A molecular fragment of this natural product derivative can provide new inhibitors with increased potency and selectivity.


Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Chalcones/chemistry , Chalcones/pharmacology , Glycerolphosphate Dehydrogenase/antagonists & inhibitors , Leishmania/enzymology , Animals , Glycerolphosphate Dehydrogenase/metabolism , Leishmania/drug effects , Leishmaniasis/drug therapy , Leishmaniasis/parasitology , Macrophages/drug effects , Mice , Molecular Docking Simulation
2.
Mem. Inst. Oswaldo Cruz ; 110(1): 75-85, 03/02/2015. graf
Article in English | LILACS | ID: lil-741624

ABSTRACT

In our previous study, we have found that 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-pyrimidin-4-ylamine (BAY 41-2272), a guanylate cyclase agonist, activates human monocytes and the THP-1 cell line to produce the superoxide anion, increasing in vitro microbicidal activity, suggesting that this drug can be used to modulate immune functioning in primary immunodeficiency patients. In the present work, we investigated the potential of the in vivo administration of BAY 41-2272 for the treatment of Candida albicans and Staphylococcus aureus infections introduced via intraperitoneal and subcutaneous inoculation. We found that intraperitoneal treatment with BAY 41-2272 markedly increased macrophage-dependent cell influx to the peritoneum in addition to macrophage functions, such as spreading, zymosan particle phagocytosis and nitric oxide and phorbol myristate acetate-stimulated hydrogen peroxide production. Treatment with BAY 41-2272 was highly effective in reducing the death rate due to intraperitoneal inoculation of C. albicans, but not S. aureus. However, we found that in vitro stimulation of peritoneal macrophages with BAY 41-2272 markedly increased microbicidal activities against both pathogens. Our results show that the prevention of death by the treatment of C. albicans-infected mice with BAY 41-2272 might occur primarily by the modulation of the host immune response through macrophage activation. .


Subject(s)
Animals , Mice , Adipocytes, White/metabolism , Ananas/chemistry , Dietary Supplements , Fruit/chemistry , Hypoglycemic Agents/isolation & purification , Industrial Waste/analysis , Plant Extracts/isolation & purification , Adipogenesis , Adipocytes, White/cytology , Antioxidants/chemistry , Antioxidants/economics , Antioxidants/isolation & purification , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/economics , Enzyme Inhibitors/isolation & purification , Food-Processing Industry/economics , Glycosylation , Glycerolphosphate Dehydrogenase/antagonists & inhibitors , Glycerolphosphate Dehydrogenase/metabolism , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/economics , Glycoside Hydrolase Inhibitors/isolation & purification , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/economics , India , Industrial Waste/economics , Lipotropic Agents/chemistry , Lipotropic Agents/economics , Lipotropic Agents/isolation & purification , Plant Extracts/chemistry , Plant Extracts/economics , Solvents/chemistry , alpha-Amylases/antagonists & inhibitors , alpha-Amylases/metabolism
3.
Horm Metab Res ; 39(12): 867-70, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17973206

ABSTRACT

Leptin modulates the hypothalamus-pituitary-thyroid axis and peripheral metabolism of thyroid hormones (THs). We have studied the effect of acute and chronic leptin treatment upon liver mitochondrial glycerol phosphate dehydrogenase activity (mGPD), whose expression and activity are TH dependent. We performed 2 experiments: 1) acute leptin treatment - LepA: adult rats received a single leptin injection (8 microg/100 g BW); 2) chronic leptin treatment - LepC: adult rats received leptin (8 microg/100 g BW) daily, for 6 days. In both experiments, control groups were saline-treated. All rats were sacrificed 2 hours after the last dose. Liver mGPD activity was determined by colorimetric method. Liver D1 activity was measured by the release of (125)I from (125)I-rT3. Serum hormones were measured by RIA. LepA rats showed higher serum thyroid stimulating hormone (TSH) (+ 64%, p<0.05), free T4 (+ 34%, p<0.05), free T3 (+ 64%, p<0.05), and liver D1 activity (+ 85%, p<0.05), but no change in mGPD activity. Since THs increase mGPD activity, the unchanged level in the acute experiment is suggestive of an inhibitory role of leptin. LepC rats presented lower mGPD activity (-1.7-fold, p<0.05) and higher liver D1 activity (+ 32%, p<0.05), but no alteration in serum TSH and free THs. Our results show that leptin downregulates mGPD activity, mainly when hyperleptinemia is chronic.


Subject(s)
Glycerolphosphate Dehydrogenase/antagonists & inhibitors , Leptin/administration & dosage , Leptin/pharmacology , Mitochondria, Liver/drug effects , Mitochondria, Liver/enzymology , Thyroid Gland/physiology , Animals , Feeding Behavior/drug effects , Male , Rats , Rats, Wistar , Thyroid Hormones/blood
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