Fat-to-glucose interconversion by hydrodynamic transfer of two glyoxylate cycle enzyme genes

The glyoxylate cycle, which is well characterized in higher plants and some microorganisms but not in vertebrates, is able to bypass the citric acid cycle to achieve fat-to-carbohydrate interconversion. In this context, the hydrodynamic transfer of two glyoxylate cycle enzymes, such as isocytrate lyase (ICL) and malate synthase (MS), could accomplish the shift of using fat for the synthesis of glucose. Therefore, 20 mice weighing 23.37 ± 0.96 g were hydrodinamically gene transferred by administering into the tail vein a bolus with ICL and MS. After 36 hours, body weight, plasma glucose, respiratory quotient and energy expenditure were measured. The respiratory quotient was increased by gene transfer, which suggests that a higher carbohydrate/lipid ratio is oxidized in such animals. This application could help, if adequate protocols are designed, to induce fat utilization for glucose synthesis, which might be eventually useful to reduce body fat depots in situations of obesity and diabetes

Fat-to-glucose interconversion by hydrodynamic transfer of two glyoxylate cycle enzyme genes

The glyoxylate cycle, which is well characterized in higher plants and some microorganisms but not in vertebrates, is able to bypass the citric acid cycle to achieve fat-to-carbohydrate interconversion. In this context, the hydrodynamic transfer of two glyoxylate cycle enzymes, such as isocytrate lyase (ICL) and malate synthase (MS), could accomplish the shift of using fat for the synthesis of glucose. Therefore, 20 mice weighing 23.37 +/- 0.96 g were hydrodinamically gene transferred by administering into the tail vein a bolus with ICL and MS. After 36 hours, body weight, plasma glucose, respiratory quotient and energy expenditure were measured. The respiratory quotient was increased by gene transfer, which suggests that a higher carbohydrate/lipid ratio is oxidized in such animals. This application could help, if adequate protocols are designed, to induce fat utilization for glucose synthesis, which might be eventually useful to reduce body fat depots in situations of obesity and diabete

The Highest Energy Neutrinos

Measurements of the arrival directions of cosmic rays have not revealed their sources. High energy neutrino telescopes attempt to resolve the problem by detecting neutrinos whose directions are not scrambled by magnetic fields. The key issue is whether the neutrino flux produced in cosmic ray accelerators is detectable. It is believed that the answer is affirmative, both for the galactic and extragalactic sources, provided the detector has kilometer-scale dimensions. We revisit the case for kilometer-scale neutrino detectors in a model-independent way by focussing on the energetics of the sources. The real breakthrough though has not been on the theory but on the technology front: the considerable technical hurdles to build such detectors have been overcome. Where extragalactic cosmic rays are concerned an alternative method to probe the accelerators consists in studying the arrival directions of neutrinos produced in interactions with the microwave background near the source, i.e. within a GZK radius. Their flux is calculable within large ambiguities but, in any case, low. It is therefore likely that detectors that are larger yet by several orders of magnitudes are required. These exploit novel techniques, such as detecting the secondary radiation at radio wavelengths emitted by neutrino induced showers.Comment: 16 pages, pdflatex, 7 jpg figures, ICRC style files included. Highlight talk presented at the 30th International Cosmic Ray Conference, Merida, Mexico, 200

Effect of a diet supplemented with sphingomyelin and probiotics on colon cancer development in mice

Previous studies have reported that dietary sphingomyelin could inhibit early stages of colon cancer. Lactic acid–producing bacteria have also been associated with an amelioration of cancer symptoms. However, little is known about the potential beneficial effects of the combined administration of both sphingomyelin and lactic acid–producing bacteria. This article analyzes the effect of a diet supplemented with a combination of the probiotics Lacticaseibacillus casei and Bifidobacterium bifidum (108 CFU/ml) and sphingomyelin (0.05%) on mice with 1,2-dimethylhydrazine (DMH)-induced colon cancer. Thirty-six BALB/c mice were divided into 3 groups: one healthy group (group C) and two groups with DMH-induced cancer, one fed a standard diet (group D) and the other fed a diet supplemented with sphingomyelin and probiotics (DS). The number of aberrant crypt foci, marker of colon cancer development, was lower in the DS. The dietary supplementation with the synbiotic reversed the cancer-induced impairment of galactose uptake in enterocyte brush–border–membrane vesicles. These results confirm the beneficial effects of the synbiotic on the intestinal physiology of colon cancer mice and contribute to the understanding of the possible mechanisms involved.This study was supported by the Government of Spain grant number AGL 2006–1029-C02-01/ALI, CIBER (CB12/03/30002) and the Department of Innovation, Business and Employment of the Government of Navarra (Spain)

Green by design: Convergent synthesis, computational analyses, and activity evaluation of new fxa inhibitors bearing peptide triazole linking units

Green chemistry implementation has led to promising results in waste reduction in the pharmaceutical industry. However, the early sustainable development of pharmaceutically active compounds and ingredients remains a considerable challenge. Herein, we wish to report a green synthesis of new pharmaceutically active peptide triazoles as potent factor Xa inhibitors, an important drug target associated with the treatment of diverse cardiovascular diseases. The new inhibitors were synthesized in three steps, featuring cycloaddition reactions (high atom economy), microwave-assisted organic synthesis (energy efficiency), and copper nanoparticle catalysis, thus featuring Earth-abundant metals. The molecules obtained showed FXa inhibition, with IC50-values as low as 17.2 μM and no associated cytotoxicity in HEK293 and HeLa cells. These results showcase the environmental potential and chemical implications of the applied methodologies for the development of new molecules with pharmacological potential.Fil: Rodríguez, Diego F.. Pontificia Universidad Católica de Chile; ChileFil: Durán Osorio, Francisca. Pontificia Universidad Católica de Chile; ChileFil: Duarte, Yorley. Universidad Andrés Bello; ChileFil: Olivares, Pedro. Universidad Andrés Bello; ChileFil: Moglie, Yanina Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: kamal, Dua. University of Sydney; AustraliaFil: Zacconi, Flavia Cristina Milagro. Pontificia Universidad Católica de Chile; Chile. Pontificia Universidad Catolica de Chile. Facultad de Ciencias Biológicas; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73–93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (μ), chemical hardness (η), and electrophilicity (ω) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29–31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.Fil: Santana Romo, Fabián. Pontificia Universidad Católica de Chile; ChileFil: Lagos, Carlos F.. Universidad San Sebastián; ChileFil: Duarte, Yorley. Universidad Andrés Bello; ChileFil: Castillo, Francisco. Pontificia Universidad Católica de Chile; ChileFil: Moglie, Yanina Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Maestro, Miguel A.. University of A Coruña; EspañaFil: Charbe, Nitin. Pontificia Universidad Católica de Chile; ChileFil: Zacconi, Flavia Cristina Milagro. Pontificia Universidad Católica de Chile; Chil

Obesity induced by a pair-fed high fat sucrose diet: methylation and expression pattern of genes related to energy homeostasis.

BACKGROUND: The expression of some genes controlling energy homeostasis could be regulated by epigenetic mechanisms that may play a role in body weight regulation. Thus, it is known that various nutritional factors affect DNA methylation. In order to assess whether the macronutrient composition of the diet could be related to the epigenetic regulation of gene expression and with obesity development, we investigated the effects on methylation and expression patterns of two pair-fed isocaloric diets in rats: control (rich in starch) and HFS (rich in fat and sucrose). RESULTS: The pair-fed HFS diet induced higher weight gain and adiposity as compared to the controls as well as liver triglyceride accumulation and oxidative stress. Feeding the HFS diet impaired glucose tolerance and serum triglycerides and cholesterol. Liver glucokinase expression, a key glycolytic gene, remained unaltered, as well as the mRNA values of fatty acid synthase and NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6 (NDUFB6) in liver and visceral adipocytes, which regulate lipogenesis and mitochondrial oxidative metabolism, respectively. Liver expression of hydroxyacyl-coenzyme A dehydrogenase (HADHB), a key gene of beta-oxidation pathway, was higher in the HFS-fed animals. However, the methylation status of CpG islands in HADHB and glucokinase genes remained unchanged after feeding the HFS diet. CONCLUSIONS: These results confirm that the distribution and type of macronutrients (starch vs. sucrose, and percent of fat) influence obesity onset and the associated metabolic complications. HFS diets produce obesity independently of total energy intake, although apparently no epigenetic (DNA methylation) changes accompanied the modifications observed in gene expression

A new species of Heliocephala from Vietnam

Heliocephala vietnamensis sp. nov., a hyphomycetous fungus collected on decaying leaves of an unidentified plant, is described and illustrated. It is distinguished by determinate apical cluster of conidiogenous cells and obclavate to sub-navicular, 3-septate, pale brown conidia.UCR::Vicerrectoría de Docencia::Ciencias Agroalimentarias::Facultad de Ciencias Agroalimentarias::Escuela de AgronomíaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Agroalimentarias::Centro de Investigación en Protección de Cultivos (CIPROC

Vitamin C modulates the interaction between adipocytes and macrophages

Scope: Increased adiposity is related with monocyte infiltration into the adipose tissue that accentuates inflammation. Antioxidant treatments emerge as approaches to counteract this phenomenon. Methods and results: Cocultures of differentiated 3T3-L1 adipocytes and RAW264.7 macrophages were incubated for 24-72 h with/without 100 nM insulin and/or 200 μM vitamin C (VC). Nitric oxide (NO) secretion (24 h) was measured. Also, expression (24 h) and secretion (72 h) of MCP-1, leptin and apelin were analyzed. NO secretion was significantly inhibited by insulin and VC only in cocultures. MCP-1 expression/secretion was enhanced in cocultures. Insulin incubation reduced MCP-1 expression in both cultures and VC only in controls. Both treatments inhibited MCP-1 secretion in cocultures. Apelin gene expression was induced in cocultures. Insulin induced apelin mRNA expression, but VC inhibited its expression in cocultures under insulin treatment. Apelin secretion was notably induced by insulin and inhibited by VC in cocultures. Leptin expression was decreased in coculture, while presented no effects by VC. Conclusion: VC importantly modulates the established pro-inflammatory state in the interaction between adipocytes and macrophages