Physical Activity Plays an Important Role in Body Weight Regulation

Emerging literature highlights the need to incorporate physical activity into every strategy intended to prevent weight gain as well as to maintain weight loss over time. Furthermore, physical activity should be part of any plan to lose weight. The stimulus of exercise provides valuable metabolic adaptations that improve energy and macronutrient balance regulation. A tight coupling between energy intake and energy expenditure has been documented at high levels of physical exercise, suggesting that exercise may improve appetite control. The regular practice of physical activity has also been reported to reduce the risk of stress-induced weight gain. A more personalized approach is recommended when planning exercise programs in a clinical weight loss setting in order to limit the compensatory changes associated to exercise-induced weight loss. With modern environment promoting overeating and sedentary behavior, there is an urgent need for a concerted action including legislative measures to promote healthy active living in order to curb the current epidemic of chronic diseases

Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher selectivity in its binding to US28 versus CX3CR1, the endogenous receptor for CX3CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate for HCMV treatment. Many viruses encode internalizing receptors suggesting that not only HCMV but also, for instance, Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus may be targeted by FTPs

Pharmacokinetics of oral and intravenous melatonin in healthy volunteers

BACKGROUND: The aim was to investigate the pharmacokinetics of oral and iv melatonin in healthy volunteers. METHODS: The study was performed as a cohort crossover study. The volunteers received either 10 mg oral melatonin or 10 mg intravenous melatonin on two separate study days. Blood samples were collected at different time points following oral administration and short iv infusion, respectively. Plasma melatonin concentrations were determined by RIA technique. Pharmacokinetic analyses were performed by “the method of residuals” and compartmental analysis. The pharmacokinetic variables: k(a), t(1/2 absorption), t(max), C(max), t(1/2 elimination,)AUC(0-∞), and bioavailability were determined for oral melatonin. C(max), t(1/2 elimination), V(d), CL and AUC(0-∞) were determined for intravenous melatonin. RESULTS: Twelve male volunteers completed the study. Baseline melatonin plasma levels did not differ significantly between the study days (P = 0.067). Mean (SD) t(1/2 absorption) of oral melatonin was 6.0 (3.1) min. Mean t(max) was 40.8 (17.8) min with a median (IQR) C(max) of 3550.5 (2500.5–8057.5) pg ml(-1). Mean t(1/2 elimination) was 53.7 (7.0) min. Median absolute bioavailability was 2.5 (1.7–4.7) %. Median C(max) after short iv infusion of melatonin was 389,875.0 (174,775.0–440,362.5) pg ml(-1). Mean t(1/2 elimination) was 39.4 (3.6) min, mean V(d) 1.2 (0.6) l kg(-1) and mean CL 0.0218 (0.0102) l min(-1) kg(-1). CONCLUSIONS: This cohort crossover study estimated pharmacokinetics of oral and iv melatonin, respectively in healthy volunteers. Bioavailability of oral melatonin was only 3 %. TRIAL REGISTRATION: Eudra-CT number: 2013-000205-23 (initial registration 27.03.2013). Clinicaltrials.gov Identifier: NCT01923974 (initial registration 08.08.2013)

Alcohol consumption and mortality in patients undergoing coronary artery bypass graft (CABG):a register-based cohort study

BACKGROUND: Previous studies have shown that compared with abstinence and heavy drinking, moderate alcohol consumption is associated with a reduced risk of mortality among the general population and patients with heart failure and myocardial infarction. We examined the association between alcohol consumption and mortality in coronary artery bypass graft (CABG) patients. METHOD: We studied 1,919 first-time CABG patients using data on alcohol consumption and mortality obtained from Danish national registers from March 2006 to October 2011. Alcohol consumption was divided into the following groups: abstainers (0 units/week), moderate consumers (1–14 units/week), moderate-heavy drinkers (15–21 units/week) and heavy drinkers (>21 units/week). Hazard ratios (HR) of all-cause mortality were calculated using Cox proportional hazard regression analysis. RESULTS: The median follow-up was 2.2 years [IQR 2.0]. There were 112 deaths, of which 96 (86 %) were classified as cardiovascular. Adjustments for age and sex showed no increased risk of all-cause mortality for the abstainers (HR 1.61, 95 % CI, 1.00–2.58) and moderate-heavy drinkers (HR 1.40, 95 % CI, 0.73–2.67) compared with moderate consumers. However, heavy drinkers had a high risk of all-cause mortality compared with moderate consumers (HR 2.44, 95 % CI, 1.47–4.04). A full adjustment showed no increase in mortality for the abstainers (HR 1.59, 95 % CI, 0.98–2.57) and moderate-heavy drinkers (HR 1.68, 95 % CI, 0.86–3.29), while heavy drinkers were associated with an increased mortality rate (HR 1.88, 95 % CI, 1.10–3.21). There was no increased risk of 30-day mortality for the abstainers (HR 0.74, 95 % CI, 0.23–2.32), moderate-heavy drinkers (HR 0.36, 95 % CI, 0.07–1.93) and heavy drinkers (HR 2.20, 95 % CI, 0.65–7.36). CONCLUSION: There was no increased risk of mortality for abstainers (0 units/week) or moderate-heavy drinkers (15–21 units/week) following a CABG. Only heavy drinking (>21 units/week) were significantly associated with an increased mortality rate. These results suggest that only heavy drinking present a risk factor among CABG patients

Rationally designed chemokine-based toxin targeting the viral G protein-coupled receptor US28 potently inhibits cytomegalovirus infection in vivo

The use of receptor–ligand interactions to direct toxins to kill diseased cells selectively has shown considerable promise for treatment of a number of cancers and, more recently, autoimmune disease. Here we move the fusion toxin protein (FTP) technology beyond cancer/autoimmune therapeutics to target the human viral pathogen, human cytomegalovirus (HCMV), on the basis of its expression of the 7TM G protein-coupled chemokine receptor US28. The virus origin of US28 provides an exceptional chemokine-binding profile with high selectivity and improved binding for the CX3C chemokine, CX(3)CL1. Moreover, US28 is constitutively internalizing by nature, providing highly effective FTP delivery. We designed a synthetic CX(3)CL1 variant engineered to have ultra-high affinity for US28 and greater specificity for US28 than the natural sole receptor for CX(3)CL1, CX(3)CR1, and we fused the synthetic variant with the cytotoxic domain of Pseudomonas Exotoxin A. This novel strategy of a rationally designed FTP provided unparalleled anti-HCMV efficacy and potency in vitro and in vivo

Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production

Glucagon is secreted from pancreatic a cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in b cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion