Organising metabolic networks: cycles in flux distributions

Metabolic networks are among the most widely studied biological systems. The topology and interconnections of metabolic reactions have been well described for many species, but are not sufficient to understand how their activity is regulated in living organisms. The principles directing the dynamic organisation of reaction fluxes remain poorly understood. Cyclic structures are thought to play a central role in the homeostasis of biological systems and in their resilience to a changing environment. In this work, we investigate the role of fluxes of matter cycling in metabolic networks. First, we introduce a methodology for the computation of cyclic and acyclic fluxes in metabolic networks, adapted from an algorithm initially developed to study cyclic fluxes in trophic networks. Subsequently, we apply this methodology to the analysis of three metabolic systems, including the central metabolism of wild type and a deletion mutant of Escherichia coli, erythrocyte metabolism and the central metabolism of the bacterium Methylobacterium extorquens. The role of cycles in driving and maintaining the performance of metabolic functions upon perturbations is unveiled through these examples. This methodology may be used to further investigate the role of cycles in living organisms, their pro-activity and organisational invariance, leading to a better understanding of biological entailment and information processing

3-Hydroxy-2-phenyl-2,3,3a,7a-tetrahydro-1H,5H-pyrano[3,2-b]pyrrol-5-one: crystal structure and Hirshfeld surface analysis

The title isoaltholactone derivative, C13H13NO3, has an NH group in place of the ether-O atom in the five-membered ring of the natural product. The five-membered ring is twisted about the N—C bond linking it to the six-membered ring, which has a half-chair conformation with the O atom connected to the ether-O atom lying above the plane defined by the remaining atoms. The dihedral angle between the mean planes of the rings comprising the fused-ring system is 75.10 (8)°. In the crystal, hydroxy-O—H...N(amine) hydrogen bonding sustains linear supramolecular chains along the a axis. Chains are linked into a three-dimensional architecture via amine-N—H...π(phenyl) and phenyl-C—H...O(hydroxy) interactions. The influence of the amine-N—H...π(phenyl) contact on the molecular packing is revealed by an analysis of the Hirshfeld surface

Chemical Chaperones Curcumin and 4-Phenylbutyric Acid Improve Secretion of Mutant Factor H R127H by Fibroblasts from a Factor H-Deficient Patient

Factor H (FH) is one of the most important regulatory proteins of the alternative pathway of the complement system. Patients with FH deficiency have a higher risk for development of infections and kidney diseases because of the uncontrolled activation and subsequent depletion of the central regulatory component C3 of the complement system. In this study, we investigated the consequences of the Arg(127)His mutation in FH (FHR127H) previously described in an FH-deficient patient, on the secretion of this protein by skin fibroblasts in vitro. We observed that, although the patient cells stimulated with IFN-gamma were able to synthesize FHR127H, the mutant protein was largely retained within the endoplasmic reticulum (ER), whereas normal human fibroblasts stimulated with IFN-gamma secrete FH without retention in the ER. Moreover, the retention of FHR127H provoked enlargement of ER cisterns after treatment with IFN-gamma. A similar ER retention was observed in Cos-7 cells expressing the mutant FHR127H protein. Despite this deficiency in secretion, we show that the FHR127H mutant is capable of functioning as a cofactor in the Factor I-mediated cleavage of C3. We then evaluated whether a treatment could increase the secretion of FH, and observed that the patient's fibroblasts treated with the chemical chaperones 4-phenylbutiric acid or curcumin increased the secretion rate of FH. We propose that these chemical chaperones could be used as alternative therapeutic agents to increase FH plasma levels in FH-deficient patients caused by secretion delay of this regulatory protein. The Journal of Immunology, 2012, 189: 3242-3248.Fundacao de Amparo a Pesquisa do Estado de Sao PauloFundacao de Amparo a Pesquisa do Estado de Sao PauloConselho Nacional de Pesquisa e Desenvolvimento Cientifico, BrazilConselho Nacional de Pesquisa e Desenvolvimento Cientifico, Brazi

Antiproliferative Activity Of Flavonoids From Croton Sphaerogynus Baill. (euphorbiaceae)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Croton sphaerogynus is a shrub from the Atlantic Rain Forest in southeastern Brazil. A lyophilized crude EtOH extract from leaves of C. sphaerogynus, obtained by maceration at room temperature (seven days), was suspended in methanol and partitioned with hexane. The purified MeOH phase was fractionated over Sephadex LH-20 yielding five fractions (F1-F5) containing flavonoids, as characterized by HPLC-DAD and HPLC-MS analyses. The antiproliferative activity of the crude EtOH extract, MeOH and hexane phases, and fractions F1-F5 was evaluated on in vitro cell lines NCI-H460 (nonsmall cell lung), MCF-7 (breast cancer), and U251 (glioma). The MeOH phase showed activity (mean log GI(50) 0.54) higher than the hexane phase and EtOH extract (mean log GI(50) 1.13 and 1.19, resp.). F1 exhibited activity against NCI-H460 (nonsmall cell lung) (GI(50) 1.2 mu g/mL), which could be accounted for the presence of flavonoids and/or diterpenes. F4 showed moderate activity (mean log GI(50) 1.05), while F5 showed weak activity (mean log GI(50) 1.36). It is suggested that the antiproliferative activity of the crude EtOH extract and MeOH phase is accounted for a synergistic combination of flavonoids and diterpenes.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)FAPESP [FAPESP 2012/10079-0

Antiproliferative Activity Of Flavonoids From Croton Sphaerogynus Baill. (euphorbiaceae).

Croton sphaerogynus is a shrub from the Atlantic Rain Forest in southeastern Brazil. A lyophilized crude EtOH extract from leaves of C. sphaerogynus, obtained by maceration at room temperature (seven days), was suspended in methanol and partitioned with hexane. The purified MeOH phase was fractionated over Sephadex LH-20 yielding five fractions (F1-F5) containing flavonoids, as characterized by HPLC-DAD and HPLC-MS analyses. The antiproliferative activity of the crude EtOH extract, MeOH and hexane phases, and fractions F1-F5 was evaluated on in vitro cell lines NCI-H460 (nonsmall cell lung), MCF-7 (breast cancer), and U251 (glioma). The MeOH phase showed activity (mean log GI50 0.54) higher than the hexane phase and EtOH extract (mean log GI50 1.13 and 1.19, resp.). F1 exhibited activity against NCI-H460 (nonsmall cell lung) (GI50 1.2 μg/mL), which could be accounted for the presence of flavonoids and/or diterpenes. F4 showed moderate activity (mean log GI50 1.05), while F5 showed weak activity (mean log GI50 1.36). It is suggested that the antiproliferative activity of the crude EtOH extract and MeOH phase is accounted for a synergistic combination of flavonoids and diterpenes.201521280

Antiproliferative activity of flavonoids from croton Sphaerogynus baill. (euphorbiaceae)

Croton sphaerogynus is a shrub from the Atlantic Rain Forest in southeastern Brazil. A lyophilized crude EtOH extract from leaves of C. sphaerogynus, obtained by maceration at room temperature (seven days), was suspended in methanol and partitioned with hexane. The purified MeOH phase was fractionated over Sephadex LH-20 yielding five fractions (F1-F5) containing flavonoids, as characterized by HPLC-DAD and HPLC-MS analyses. The antiproliferative activity of the crude EtOH extract, MeOH and hexane phases, and fractions F1-F5 was evaluated on in vitro cell lines NCI-H460 (nonsmall cell lung), MCF-7 (breast cancer), and U251 (glioma). The MeOH phase showed activity (mean log GI(50) 0.54) higher than the hexane phase and EtOH extract (mean log GI(50) 1.13 and 1.19, resp.). F1 exhibited activity against NCI-H460 (nonsmall cell lung) (GI(50) 1.2 mu g/mL), which could be accounted for the presence of flavonoids and/or diterpenes. F4 showed moderate activity (mean log GI(50) 1.05), while F5 showed weak activity (mean log GI(50) 1.36). It is suggested that the antiproliferative activity of the crude EtOH extract and MeOH phase is accounted for a synergistic combination of flavonoids and diterpenes2015COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informação2012/10079-

Use of ergogenic aids among Brazilian athletes: a cross-sectional study exploring competitive level, sex and sports

Was investigated ergogenic aids (EAs) used by Brazilian athletes and their association with performance, sex, sports classification, and modality. It identified the main purposes of EAs and their prescription.Methods239 athletes of 15 modalities, ranging from regional to international level, answered a survey online.ResultsHighly competitive athletes consumed nutritional and mechanical aids more (OR = 1.96 CI 95% [1.28–2.9]; OR = 1.79 CI 95% [1.29–2.47]), while the use of psychological EAs decreased [OR = 1.66 95% CI (1.18–2.94); p = 0.001]. Male athletes [OR = 1.44 CI 95% (1.11–2.88)] and individual sports practitioners [OR = 1.78 CI 95% (1.02–3.11)] used nutritional aids more. Triathlon athletes had higher nutritional EA use, while soccer athletes had lower. Combat sports athletes had higher pharmacological EA use.ConclusionAthletes use nutritional and pharmacological aids more to improve performance and gain lean body mass. Mechanical aids were used for recovery and psychological aids for motivation. Self-prescription is common, especially for pharmacological aids

Natural polyprenylated benzophenones: keto-enol tautomerism and stereochemistry

The keto-enol tautomerism and stereochemistry study of a HIV-inhibitory natural benzophenone, (1R,5R,7R,8S)-(+)-3-(10-(3,4-dihydroxyphenyl)-10-hydroxymethylene)-8-methyl -1,5,7-tris(3-methyl-2-butenyl)-8-(4-methyl-3-pentenyl)-bicyclo[3.3.1]nonane-2,4,9-trione (a), isolated from Garcinia brasiliensis seeds is presented. The crystal structure of (a), which is also know as guttiferona A, was determined by X-ray diffraction and its intra and inter-molecular geometries discussed and compared with two analogue natural benzophenones: clusianone and epiclusianone. In (a), the hydroxyl H atom from enolizable 2,4,10-trione moiety is linked in the oxygen atom bonded to 10-(3,4-dihydroxyphenyl)methylene group, in opposition to the related natural benzophenones, where this analogue H-atom is placed in different O-atoms from bicyclo[3.3.1]nonane ring system. Such behaviour can be explained by the presence of aromatic OH6 group in (a) that origins a further delocalized resonance path along of 3,4-dihydroxyphenyl-C10-OH2 group. In addition, the (a) stereochemistry around C7 atom is compared with known structures of clusianone and epiclusianone and the influence from configuration in this chiral C-atom to structural features found in the enolizable system is proposed