Biomedical subjects

Alexandre Benani

Publications and source records attributed to Alexandre Benani.

5 recordsLinked to original sources

PubMed2007

Role for mitochondrial reactive oxygen species in brain lipid sensing: redox regulation of food intake.

The ability for the brain to sense peripheral fuel availability is mainly accomplished within the hypothalamus, which detects ongoing systemic nutrients and adjusts food intake and peripheral metabolism as needed. Here, we hypothesized that mitochondrial reactive oxygen species (ROS) could trigger sensing of nutrients within the hypothalamus. For this purpose, we induced acute hypertriglyceridemia in rats and examined the function of mitochondria in the hypothalamus. Hypertriglyceridemia led to a rapid increase in the mitochondrial respiration in the ventral hypothalamus together with a transient production of ROS. Cerebral inhibition of fatty acids-CoA mitochondrial uptake prevented the hypertriglyceridemia-stimulated ROS production, indicating that ROS derived from mitochondrial metabolism. The hypertriglyceridemia-stimulated ROS production was associated with change in the intracellular redox state without any noxious cytotoxic effects, suggesting that ROS function acutely as signaling molecules. Moreover, cerebral inhibition of hypertriglyceridemia-stimulated ROS production fully abolished the satiety related to the hypertriglyceridemia, suggesting that hypothalamic ROS production was required to restrain food intake during hypertriglyceridemia. Finally, we found that fasting disrupted the hypertriglyceridemia-stimulated ROS production, indicating that the redox mechanism of brain nutrient sensing could be modulated under physiological conditions. Altogether, these findings support the role of mitochondrial ROS as molecular actors implied in brain nutrient sensing.

Animals↗

PubMed2006

Brain glucose sensing: a subtle mechanism.

PURPOSE OF REVIEW: Brain nutrient sensing allows a fine regulation of different physiological functions, such as food intake and blood glucose, related to energy homeostasis. Glucose sensing is the most studied function and a parallel has been made between the cellular mechanisms involved in pancreatic beta cells and neurons. RECENT FINDINGS: Two types of glucosensing neurons have been characterized--those for which the activity is proportional to changes in glucose concentration and those for which the activity is inversely proportional to these changes. A new level of complexity has recently been demonstrated, as the response and the mechanism appear to vary in function according to the level of the glucose change. For some of the responses, the detection is probably not at the level of the neuron itself, but astrocytes also appear to be involved, indicating a coupling between the two types of cells. Finally, numerous data have demonstrated the modulation of glucose sensing by other nutrients, in particular fatty acids, hormones (insulin, leptin and ghrelin) and peptides (neuropeptide Y). This implies a common pathway in which AMPkinase may play a crucial role. SUMMARY: Recent observations in brain nutrient sensing indicate subtle mechanisms, with different cellular and molecular mechanisms involved. This fact would explain the discrepancies reported in the expression of different proteins (glucose transporters, hexokinases, channels). Astrocytes may be involved in one type of response, thus adding a new level of complexity.

Adenylate Kinase↗

PubMed2006

Mitochondrial reactive oxygen species are required for hypothalamic glucose sensing.

The physiological signaling mechanisms that link glucose sensing to the electrical activity in metabolism-regulating hypothalamus are still controversial. Although ATP production was considered the main metabolic signal, recent studies show that the glucose-stimulated signaling in neurons is not totally dependent on this production. Here, we examined whether mitochondrial reactive oxygen species (mROS), which are physiologically generated depending on glucose metabolism, may act as physiological sensors to monitor the glucose-sensing response. Transient increase from 5 to 20 mmol/l glucose stimulates reactive oxygen species (ROS) generation on hypothalamic slices ex vivo, which is reversed by adding antioxidants, suggesting that hypothalamic cells generate ROS to rapidly increase glucose level. Furthermore, in vivo, data demonstrate that both the glucose-induced increased neuronal activity in arcuate nucleus and the subsequent nervous-mediated insulin release might be mimicked by the mitochondrial complex blockers antimycin and rotenone, which generate mROS. Adding antioxidants such as trolox and catalase or the uncoupler carbonyl cyanide m-chlorophenylhydrazone in order to lower mROS during glucose stimulation completely reverses both parameters. In conclusion, the results presented here clearly show that the brain glucose-sensing mechanism involved mROS signaling. We propose that this mROS production plays a key role in brain metabolic signaling.

Animals↗

PubMed2005

Uncoupling of oxidative phosphorylation and Smac/DIABLO release are not sufficient to account for induction of apoptosis by sulindac sulfide in human colorectal cancer cells.

Non-steroidal anti-inflammatory drugs (NSAIDs) have shown chemopreventive properties in colorectal cancer, involving both cyclooxygenase (COX)-dependent and -independent mechanisms. Apart from their selectivity for COX isoenzymes, NSAIDs differ in their acidic character which supports ability to uncouple oxidative phosphorylation. To assess the possible contribution of uncoupling to their antineoplastic properties, we compared the effect of sulindac sulfide (SS), an acidic NSAID and NS-398, a non-acidic tricyclic, on mitochondrial function and apoptosis in colorectal cancer cell lines (HT29, Caco-2, HCT15 and HCT116). Although cell lines displayed a different COX status, SS and NS-398 caused growth arrest in a dose-related manner. High dose (10(-4)M) of SS but not of NS-398, increased the percentage of subG1 cell population while reducing mitochondrial transmembrane potential (DeltaPsim). Cyclosporin A (CsA, 1 microM) prevented collapse of DeltaPsim induced by 10(-4)M SS but not by 7.5 microM FCCP used as a protonophoric control. SS and FCCP increased the cytosolic release of Smac/DIABLO which was differently affected by CsA pretreatment depending on the uncoupler. Finally, 7.5 microM FCCP failed to induce apoptosis whereas CsA prevented apoptosis induced by SS from 16% in HCT15 to 41% in HCT116. The present study shows that despite the ability of sulindac sulfide to behave as a protonophoric uncoupler, CsA-sensitive opening of mitochondrial permeability transition pore contributes little to its pro-apoptotic effect in colorectal cancer cells.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2004

[Pharmacology and classification of cyclooxygenase inhibitors].

The discovery of at least two cyclooxygenase (COX) isoenzymes had two major consequences: i) to give a new impetus to the research on lipid metabolism, giving rise to the crystallization of these peculiar membrane enzymes, the characterization of their active sites and their gene regulation, and the identification of new metabolic pathways; ii) the development of new NSAIDs aimed to have an improved safety profile, the coxibs. These drugs are defined by their COX-2 selectivity which is supported by a negligible inhibitory potency on platelet COX-1 in vitro and ex vivo after oral intake of maximal therapeutic doses. However, the coxibs marketed in France (celecoxib, rofecoxib, parecoxib) are not equivalent in terms of selectivity and some drugs developed by pharmaceutical companies (etoricoxib, lumiracoxib) will be even more selective for COX-2. These "new" coxibs are the final step in the theory of COX-2 selectivity and they will probably be helpful to better define the limitations of the therapeutic concept based on a selective inhibition of this iso-enzyme.

Anti-Inflammatory Agents, Non-Steroidal↗