Carme Perez-Quilis

Irisin: A new potential hormonal target for the treatment of obesity and type 2 diabetes.

Type 2 diabetes (T2D) is a pandemic disease that shows little sign of decline. Rates of obesity are increasing worldwide. It is now clear that obesity is associated with an increased risk of developing insulin resistance and T2D. A novel peptide was recently identified by Boström et al. and has been named ‘irisin’ by the researchers after the Greek messenger goddess Iris. Irisin acts on the cells of white adipose tissue. Interestingly, concentrations of irisin increase significantly after endurance exercise training in both mice and humans. Moreover, irisin levels in the blood are correlated with irisin mRNA levels in muscle tissue. Irisin increases total energy expenditure and, in certain animal models, prolongs life expectancy, reduces body weight, and mitigates diet-induced insulin resistance, thus reducing obesity and insulin resistance. It has been postulated that irisin could serve as an injectable treatment for metabolic disease and other disorders for which physical exercise may lead to improvements, such as obesity and T2D. Several compounds that may act to improve such disorders have been discovered and evaluated. A few years ago, exercise-mimetic drugs such as 5¢-aminoimidazole-4-carboxamide-1-b-d-ribofuranoside (AICAR) and GW1516 (a modulator of peroxisome proliferator-activated receptor d) were suggested as potential treatments for obesity. This suggestion led to questionable announcements about these drugs in the media, such as ‘exercise in a pill’. However, the side effects of AICAR are contentious (see http://www.outsideonline.com/ outdoor-adventure/natural-intelligence/faster–higher– squeakier-.html?page=all, accessed 10 February 2012) and a specific disease application for this compound has not been identified so far. Because the US Food and Drug Administration (FDA) will not approve any drug without proven clinical application, such treatments remain at the development stage. Nevertheless, it is imperative to develop pioneering and suitable formulations to guarantee that patients with conditions such as obesity have access to appropriate medication. Although optimism should be guarded, the identification of irisin opens new possibilities because it is an endogenous hormone that can be cloned easily using recombinant DNA technology. Recombinant human proteins (e.g. insulin, growth hormone, erythropoietin) are used widely in modern therapeutics. Although much work is still needed, the application of irisin may prove beneficial not only in the treatment of obesity and diabetes, but also for a wide range of pathological conditions that are characterized by a variable imbalance of energy demand and expenditure.

Epidemiology of coronary heart disease and acute coronary syndrome

The aim of this review is to summarize the incidence, prevalence, trend in mortality, and general prognosis of coronary heart disease (CHD) and a related condition, acute coronary syndrome (ACS). Although CHD mortality has gradually declined over the last decades in western countries, this condition still causes about one-third of all deaths in people older than 35 years. This evidence, along with the fact that mortality from CHD is expected to continue increasing in developing countries, illustrates the need for implementing effective primary prevention approaches worldwide and identifying risk groups and areas for possible improvement.

Physical Exercise as an Epigenetic Modulator: Eustress, the Positive Stress as an Effector of Gene Expression

Physical exercise positively influences epigenetic mechanisms and improves health. Several issues remain unclear concerning the links between physical exercise and epigenetics. There is growing concern about the negative influence of excessive and persistent physical exercise on health. How an individual physically adapts to the prevailing environmental conditions might influence epigenetic mechanisms and modulate gene expression. In this article, we put forward the idea that physical exercise, especially long-term repetitive strenuous exercise, positively affects health, reduces the aging process, and decreases the incidence of cancer through induced stress and epigenetic mechanisms. We propose herein that stress may stimulate genetic adaptations through epigenetics that, in turn, modulate the link between the environment, human lifestyle factors, and genes.

Inconsistency in circulating irisin levels: what is really happening?

The discovery of irisin as a novel and promising peptidic hormone for the treatment of obesity and diabetes has recently been reported. As a result, great hopes have been raised based on this finding, hypothesizing that irisin might provide additional benefits, not only for obesity and diabetes, but also for a wide range of pathological conditions requiring therapeutical and clinical attention. However, controversial results and conclusions on circulating irisin concentrations and correlations with other variables, including its role in metabolism, have recently been reported. Although laboratory assessment of irisin by ELISA is easily available and may provide interesting information for therapeutics and clinical practice, the heterogeneous and often discrepant results published so far, raise serious concerns about its measurement, indicating that it may still not be ready for use or whether irisin really exists. We highlight here some aspects on these discrepancies and contradictions, and put forward their implications.

Histone H3 Glutathionylation in Proliferating Mammalian Cells Destabilizes Nucleosomal Structure

AIMS Here we report that chromatin, the complex and dynamic eukaryotic DNA packaging structure, is able to sense cellular redox changes. Histone H3, the only nucleosomal protein that possesses cysteine(s), can be modified by glutathione (GSH). RESULTS Using Biotin labeled glutathione ethyl ester (BioGEE) treatment of nucleosomes in vitro, we show that GSH, the most abundant antioxidant in mammals, binds to histone H3. BioGEE treatment of NIH3T3 cells indicates that glutathionylation of H3 is maximal in fast proliferating cells, correlating well with enhanced levels of H3 glutathionylation in different tumor cell lines. Furthermore, glutathionylation of H3 in vivo decreases in livers from aged SAMP8 and C57BL/6J mice. We demonstrate biochemically and by mass spectrometry that histone variants H3.2/H3.3 are glutathionylated on their cysteine residue 110. Furthermore, circular dichroism, thermal denaturation of reconstituted nucleosomes, and molecular modeling indicate that glutathionylation of histone H3 produces structural changes affecting nucleosomal stability. INNOVATION We characterize the implications of histone H3 glutathionylation in cell physiology and the modulation of core histone proteins structure affected by this modification. CONCLUSION Histone H3 senses cellular redox changes through glutathionylation of Cys, which increases during cell proliferation and decreases during aging. Glutathionylation of histone H3 affects nucleosome stability structure leading to a more open chromatin structure.

Erythropoietin and the heart: Physiological effects and the therapeutic perspective

Erythropoietin (Epo) has been thought to act exclusively on erythroid progenitor cells. The identification of Epo receptor (EpoR) in non-haematopoietic cells and tissues including neurons, astrocytes, microglia, immune cells, cancer cell lines, endothelial cells, bone marrow stromal cells, as well as cells of myocardium, reproductive system, gastrointestinal tract, kidney, pancreas and skeletal muscle indicates that Epo has pleiotropic actions. Epo shows signals through protein kinases, anti-apoptotic proteins and transcription factors. In light of interest of administering recombinant human erythropoietin (rhEpo) and its analogues for limiting infarct size and left ventricular (LV) remodelling after acute myocardial infarction (AMI) in humans, the foremost studies utilising rhEpo are reviewed. The putative mechanisms involved in Epo-induced cardioprotection are related to the antiapoptotic, anti-inflammatory and angiogenic effects of Epo. Thus, cardioprotective potentials of rhEpo are reviewed in this article by focusing on clinical applicability. An overview of non-haematopoietic Epo analogues, which are a reliable alternative to the classic EpoR agonists and may prevent undesired side effects, is also provided.

The p38-PGC-1α-irisin-betatrophin axis: Exploring new pathways in insulin resistance.

The discovery of irisin as a novel and promising peptidic hormone has raised hopes regarding the hypothesis that irisin may provide additional benefits, not only for obesity and diabetes, but also for a wide range of pathological conditions since this hormone may prove to be therapeutically and clinically beneficial. In addition, a new hormone, betatrophin, has recently been identified by Yi and coworkers. Both hormones are connected by a new pathway clearly involved in insulin resistance. We hypothesize here how these hormones may be linked and their possible implications in both aged-reduced restricted regenerative capacity and dedifferentiated β cells of diabetic patients.

Desmopresssin and hemodilution: implications in doping.

Blood doping improves physical performance in sport. This is the reason why the antidoping authorities subject athletes to blood tests. Plasma volume expanders are prohibited agents used to reduce an artificial increase in hematological values using different illegal practices. The aim of our study was to test whether desmopressin (DDAVP)-induced hemodilution would alter the concentration of hematological parameters used to detect blood doping in sports. This was an intra-subject crossover study. Venous blood samples were obtained from eight physically active males on two occasions. On the first occasion the subjects ingested 1.5 L of mineral water and 4.3 microg/kg of DDAVP. On the second occasion the subjects ingested 1.5 L of mineral water. The samples were analyzed for hematocrit, hemoglobin, reticulocytes, OFF Hr-Score, glucose, albumin, creatinine and total proteins. After treatment with DDAVP we found a significant decrease in the hematocrit, hemoglobin and in the OFF Hr-Score values. We also found a significant decrease in glucose, albumin, creatinine and total proteins concentration; however, in this case, all the values were significantly below the physiological levels. Treatment with DDAVP has a very effective hemodilution effect. We consider that this substance should be included in the WADAs prohibited list.

New molecular targets and lifestyle interventions to delay aging sarcopenia

The term sarcopenia was originally created to refer age-related loss of muscle mass with consequent loss of strength (Morley et al., 2001). There are now four international definitions of sarcopenia (Cruz-Jentoft et al., 2010; Muscaritoli et al., 2010; Morley et al., 2011). In essence they all agree, requiring a measure of walking capability [either low gait speed or a limited endurance (distance) in a 6-min walk], together with an appendicular lean mass of <2 SDs of a sex and ethnically corrected normal level for individuals 20–30 years old. Sarcopenia is a prevalent health problem among the elderly. On average, 5–13 and 11–50% of people aged 60−70 years and ≥80 years, respectively suffer sarcopenia with higher prevalences (68%) been reported in nursing home residents ≥70 years (Landi et al., 2012). Sarcopenia needs to be differentiated from cachexia, which is a combination of both muscle and fat loss and is usually attributable to an excess of catabolic cytokines associated with a disease process (Argiles et al., 2010). Sarcopenia is a prime component of the frailty syndrome, and both sarcopenia and frailty are associated with increased disability, falls, hospitalization, nursing home admission, and mortality (Cesari and Vellas, 2012; Landi et al., 2012). Medical efforts to develop treatments aiming at preventing aging sarcopenia as well as acute muscle atrophy and frailty in critical patients are considered a step forward in public health. Several hormonal therapies have been proposed for this purpose, such as those based on human growth hormone (hGH), IGF-1, testosterone, and stanozolol. However, the secondary effects associated with these therapies make it necessary to find novel non-toxic and non-hormonal therapies. In this way, elderly or bedridden patients may improve muscle function and decrease the degree of dependence associated with these populations. New drugs such as allopurinol or losartan (Sanchis-Gomar et al., 2011), all of them approved by the Food and Drugs Administration (FDA) and actually prescribed for the treatment of other diseases, could be useful in preventing loss of muscle mass in the described susceptible populations yet new pharmacological targets are needed.

Erythropoietin Receptor (EpoR) Agonism Is Used to Treat a Wide Range of Disease

The erythropoietin receptor (EpoR) was discovered and described in red blood cells (RBCs), stimulating its proliferation and survival. The target in humans for EpoR agonists drugs appears clear—to treat anemia. However, there is evidence of the pleitropic actions of erythropoietin (Epo). For that reason, rhEpo therapy was suggested as a reliable approach for treating a broad range of pathologies, including heart and cardiovascular diseases, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), spinal cord injury, stroke, diabetic retinopathy and rare diseases (Friedreich ataxia). Unfortunately, the side effects of rhEpo are also evident. A new generation of nonhematopoietic EpoR agonists drugs (asialoEpo, Cepo and ARA 290) have been investigated and further developed. These EpoR agonists, without the erythropoietic activity of Epo, while preserving its tissue-protective properties, will provide better outcomes in ongoing clinical trials. Nonhematopoietic EpoR agonists represent safer and more effective surrogates for the treatment of several diseases such as brain and peripheral nerve injury, diabetic complications, renal ischemia, rare diseases, myocardial infarction, chronic heart disease and others.