Sirtuin modulators: mechanisms and potential clinical implications

In the last years, studies about longevity have highlighted that caloric restriction can be linked with a less normal agingassociated damage, and in the same way, with the activity of the Silent Information Regulator 2 (SIR2) gene. Sir2-like genes, known as sirtuins (SIRTs), have been found in organisms ranging from bacteria to mammals promoting health and survival. At the moment, it has been identified seven classes of SIRTs in mammalian and the understanding of many of them remains still rudimentary. However, they are in the spotlight by their potential protection against aging-associated diseases and have emerged as key mediators of longevity in evolutionarily distant organisms models. SIRTs are proteins found in numerous compartments within the cell, which are NAD(+)-dependent protein deacetylases and adenosine diphosphate (ADP)-ribosyltransferases. They catalyse a reaction in which NAD(+) and an acetylated substrate are converted into a deacetylated substrate, nicotinamide and a novel metabolite O-acetyl ADP ribose. Therefore, its enzymatic activity requires NAD(+), which is a crucial molecule intermediary of many metabolic reactions in cells. Basically, SIRTs are mediators of aging process, they have the potential of ameliorating and taking part in important cellular processes associated, such as metabolic homeostasis, tumorigenesis and cancer cell proliferation, inflammatory disorders, cardiovascular diseases and neurodegeneration. This background opens up new lines of investigation into the modulation of SIRTs activity in order to develop novel therapeutic targets to these age-related diseases. Current experiments using molecule activators or inhibitors and genetically engineered animals have facilitated new insights into the role of these enzymes and contributed to highlight some of the potentially relevant targets. This review is intended to provide an appreciation of the possible protection against aging-associated diseases by these enzymes, summarize novel underlying mechanisms and evaluate potential clinical applications.     

Body fat distribution and organ weights of 14 common strains and a 22-strain consomic panel of rats

The goal of this study was to determine the adiposity of a range of rat strains, including a panel of consomics, to estimate heritability. To that end, we assessed the body fat distribution and organ weights of groups of adult male rats from 3 outbred strains, 11 inbred strains and 22 consomic strains. We measured the weights of the gonadal, retroperitoneal, mesenteric, femoral, subscapular and pericardial white fat depots, the subscapular brown fat depot, the kidneys, liver, heart, spleen, and brain. Strains were compared for the measured weight of each of these adipose depots and organs, and also for these weights adjusted statistically for body size. All individual adipose depot and organ weights were highly heritable, in most cases h² > 0.50. The fourteen inbred and outbred rat strains were not very different in body length but there was a three-fold difference in body weight, and up to a twenty-fold difference in the weight of some adipose depots. Comparison of the FHH-Chr n^BN consomic strains with the FHH host strain revealed 98 quantitative trait loci (QTLs) for body composition and organ weight, with the introgressed chromosome reducing weight or adiposity in most cases. These results can be used to guide the choice of appropriate rat strains for future studies of the genetic architecture of obesity and body size.     

Structural basis of NR2B-selective antagonist recognition by N-methyl-D-aspartate receptors

N-Methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors endowed with unique pharmacological and functional properties. In particular, their high permeability to calcium ions confers on NMDARs a central role in triggering long term changes in synaptic strength. Under excitotoxic pathological conditions, such as those occurring during brain trauma, stroke, or Parkinson's or Huntington's diseases, calcium influx through NMDAR channels can also lead to neuronal injury. This argues for the use of NMDAR antagonists as potential therapeutic agents. To date, the most promising NMDAR antagonists are ifenprodil and derivatives, compounds that act as noncompetitive inhibitors selective for NMDARs containing the NR2B subunit. Recent studies have identified the large N-terminal domain (NTD) of NR2B as the region controlling ifenprodil sensitivity of NMDARs. We present here a detailed characterization of the ifenprodil binding site using both experimental and computational approaches. 3D homology modeling reveals that ifenprodil fits well in a closed cleft conformation of the NRB NTD; however, ifenprodil can adopt either of two possible binding orientations of opposite direction. By studying the effects of cleft mutations, we show that only the orientation in which the phenyl moiety points deep toward the NTD hinge is functionally relevant. Moreover, based on our model, we identify novel NTD NR2B residues that are crucial for conferring ifenprodil sensitivity and provide functional evidence that these residues directly interact with the ifenprodil molecule. This work provides a general insight into the origin of the subunit-selectivity of NMDAR noncompetitive antagonists and offer clues for the discovery of novel NR2B-selective antagonists.     

Therapeutic action and underlying mechanisms of a combination of two pentacyclic triterpenes, α- and β-amyrin,in a mouse model of colitis

Background and purpose:

α- and β-amyrin are pentacyclic triterpenes found in plants and are known to exhibit pronounced anti-inflammatory effects. Here, we evaluated the effects of a 1:1 mixture of α- and β-amyrin (α,β-amyrin) on an experimental model of colitis in mice.

Experimental approach:

Colitis was induced in Swiss male mice by trinitrobenzene sulphonic acid (TNBS) and followed up to 72 h; animals were treated systemically with α,β-amyrin, dexamethasone or vehicle. Macro- and microscopic damage, myeloperoxidase activity and cytokine levels were assessed in colons. Histological sections were immunostained for cyclooxygenase-2 (COX-2), vascular endothelial growth factor, phospho-p65 nuclear factor-κB (NF-κB) and phospho-cyclic AMP response element-binding protein (CREB)

Key results:

TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of inflammatory mediators. Treatment with α,β-amyrin (3 mg·kg⁻¹, i.p.) or dexamethasone (1 mg·kg⁻¹, s.c.) consistently improved tissue damage scores and abolished polymorphonuclear cell infiltration. α,β-Amyrin, like dexamethasone, significantly diminished interleukin (IL)-1β levels and partially restored IL-10 levels in colon tissues 72 h after colitis induction, but only α,β-amyrin reduced vascular endothelial growth factor expression by immunohistochemistry. The colonic expression of COX-2 at 24 h and that of phospho-NF-κB and phospho-CREB (peaking at 6 h) after colitis induction were consistently inhibited by both α,β-amyrin and dexamethasone.

Conclusions and implications:

Systemic administration of α,β-amyrin exerted a marked and rapid inhibition of TNBS-induced colitis, related to the local suppression of inflammatory cytokines and COX-2 levels, possibly via inhibition of NF-κB and CREB-signalling pathways. Taken together, our data suggest a potential use of α,β-amyrin to control inflammatory responses in bowel disease.     

Evaluation of a 15-year experience with splenic injuries in a state trauma system

BACKGROUND: The management of splenic injuries has evolved with a greater emphasis on nonoperative management. Although several institutions have demonstrated that nonoperative management of splenic injuries can be performed with an increasing degree of success, the impact of this treatment shift on outcome for all patients with splenic injuries remains unknown. We hypothesized that outcomes for patients with splenic injuries have improved as the paradigm for splenic injury treatment has shifted. METHODS: Consecutive patients from 1987 to 2001 with splenic injuries who were entered into a state trauma registry were reviewed. Demographic variables, injury characteristics, and outcome data were collected. RESULTS: The number of patients who were diagnosed with splenic injuries increased from 1987 through 2001, despite a stable number of institutions submitting data to the registry. The number of minor injuries and severe splenic injuries remained stable, and the number of moderately severe injuries significantly increased over time. Overall mortality rate improved but primarily reflected the decreased mortality rates of moderately severe injuries; the mortality rate for severe splenic injuries was unchanged. CONCLUSION: Trauma centers are seeing increasing numbers of splenic injuries that are less severe in magnitude, although the number of the most severe splenic injuries is stable. The increased proportion of patients with less severe splenic injuries who are being admitted to trauma centers is a significant factor in the increased use and success rate of nonoperative management.     

Could a rural lifestyle decrease the prevalence of erectile dysfunction?

OBJECTIVE: To determine the prevalence of erectile dysfunction (ED) in a specific population and explore potential correlates with lifestyle. SUBJECTS AND METHODS: This prospective observational study, covering a population of a very small rural town, included 2000 men aged > or = 20 years from a total population of 121 831 (51% female and 49% male). The International Index of Erectile Function was completed by each of the 2000 men at their homes over a 1-year period. Another questionnaire assessing socio-economic status and health-related determinants of ED were also completed. RESULTS: All 2000 men completed the questionnaires; overall, only 34 reported ED (1.7%). The frequency of mild, mild to moderate, moderate and severe ED was 12%, 29%, 20% and 38%, respectively. Significantly more men aged > 51 years had ED than those aged <41 years (0.05% and 0.45%, respectively; P < 0.001). There was no difference in ED with salary levels. CONCLUSION: The prevalence of ED in this particular rural population of Brazil was very low, at only 1.7%. Although ED increases with age, this association was not apparent for all age groups. It seems that several others factors, e.g. lifestyle, culture and diet, could be important for the onset of ED.