The wonder exerkines-novel insights: a critical state-of-the-art review.

Several benefits can be acquired through physical exercise. Different classes of biomolecules are responsible for the cross-talk between distant organs. The secretome of skeletal muscles, and more widely the field of organokines, is ever-expanding. "Exerkine" has emerged as the umbrella term covering any humoral factors secreted into circulation by tissues in response to exercise. This review aims at describing the most interesting exerkines discovered in the last 3 years, which are paving the way for both physiological novel insights and potential medical strategies. The five exerkines identified all play a significant role in the healthy effect of exercise. Specifically: miR-1192, released by muscles and myocardium into circulation, by modulating cardioprotective effect in trained mice; miR-342-5p, located into exosomes from vascular endothelial cells, also a cardioprotective miRNA in trained young humans; apelin, released by muscles into circulation, involved in anti-inflammatory pathways and muscle regenerative capacity in rats; GDF-15, released into circulation from yet unknown source, whose effects can be observed on multiple organs in young men after a single bout of exercise; oxytocin, released by myoblasts and myotubes, with autocrine and paracrine functions in myotubes. The systemic transport by vesicles and the crosstalk between distant organs deserve a deep investigation. Sources, targets, transport mechanisms, biological roles, population samples, frequency, intensity, time and type of exercise should be considered for the characterization of existing and novel exerkines. The "exercise is medicine" framework should include exerkines in favor of novel insights for public health.

Do CYP3A and ABCB1 genotypes influence the plasma concentration and clinical outcome of donepezil treatment?

PURPOSE: The aim of our study was to evaluate the impact of CYP3A4, CYP3A5, and ABCB1 polymorphisms on donepezil disposition and clinical outcome. METHODS: Fifty-four Italian patients diagnosed with probable mild to moderate Alzheimer's disease, treated with donepezil (37 patients 5 mg/day, 17 patients 10 mg/day) were genotyped for CYP3A4 (*1B, *3, and *4), CYP3A5 (*2, *3, and *6) and ABCB1 (3435C>T, 2677G>T/A, and 1236C>T) polymorphisms. All patients were evaluated for the degree of cognitive impairment with Mini Mental State Examination (MMSE) screening test at baseline (before treatment) and after at least 3 months of donepezil treatment at stable dose, when the drug plasma levels were measured. RESULTS: Three patients carried one detrimental CYP3A4 allelic variant, and 12 carried one functional CYP3A5*1 allele. No statistically significant association was found between CYP3A4 or CYP3A5 genotypes and plasma donepezil concentrations, or between genotypes and clinical response (as measured by change in MMSE score). Nine ABCB1 haplotypes were observed, the most common being 1236C/2677G/3435C (46%) and 1236T/2677T/3435T (41%). Patients homozygous for the T/T/T haplotype had slightly though not significantly lower plasma donepezil concentration-to-dose ratios than those carrying other genotypes [median (95% CI) 0.18 (0.13-0.45) vs. 0.31 (0.30-0.44) mg/l/mg/kg, respectively]. These patients also showed a slightly better clinical response (as measured by change in MMSE score) than the other genotype groups [median (95% CI) 0 (-1.3 to 3.3) vs. -1.0 (-2.1 to 0.0), respectively]. CONCLUSIONS: Our data suggest that the CYP3A4 and CYP3A5 polymorphisms are unlikely to influence donepezil metabolism and/or clinical outcome. On the other hand, the ABCB1 polymorphisms may play a role in donepezil disposition and clinical outcome.

Serum ferritin and vitamin D evaluation in response to high altitude comparing Italians trekkers vs Nepalese porters.

Altitude hypoxia induces changes in iron homeostasis with serum ferritin (sFER) response being recently linked to erythropoiesis. The main aim of this study was to investigate sFER and Vitamin D (Vit D) response to hypobaric hypoxia, taking into account factors including nutrition and ethnic origin. As part of a "Kanchenjunga Exploration & Physiology" project, 6 Italian trekkers and 6 Nepalese porters took part in a 19-days long altitude trek in the Himalayas self-recording daily food consumption. Blood samples were collected and analyzed before and after the trek for sFER and Vit D. A web-based system calculated the dietary intake, generating reports that were used for later statistical analyses. sFER decreased after the trek (on average by 26% p = 0.013, partial η2 = 0.479) in both groups, whereas Vit D did not change in both groups. Nepalese tended to have lower sFER, but this difference was reduced when corrected for the dietary intake. Mean Cell Volume (MCV) and Hematocrit (HCT), in respect to baseline, remained higher 10 days after the trek (respectively, 87.37-88.85 fL with p = 0.044, and 43.05-44.63% with p = 0.065) in Italian trekkers. The observed reduction of sFER levels was related to altitude per se as inflammation or anemia were medically excluded. sFER, therefore, may act as a primary factor in the examination of hypobaric hypoxia in field studies. The results of this study open a new door into the mechanisms of iron homeostasis in specific tissues related to hypoxia adaptations, taking into account dietary intake and ethnic origin.

Expression of functional GPR35 in human iNKT cells.

The aim of this study was to examine the expression of G protein-coupled receptor (GPR)35 in human invariant natural killer T (iNKT) cells and to determine the functional effects induced by selective activation of this receptor. RT-PCR analysis showed that both human iNKT cells and resting PBMC expressed GPR35; GPR35 protein resulted mostly localized in the plasma membrane, while it internalized in punctate intracellular structures following specific receptor activation (Western blot and immunofluorescence/confocal microscopy analysis). The specific activation of GPR35 by selective receptor agonists [l-kynurenic acid (KYNA)] or 1,4-dihydro-5-(2-propoxyphenyl)-7H-1,2,3-triazolo [4,5-d]pyrimidine-7-one (zaprinast)] functionally correlated with a significant reduction in IL-4 release from alpha-galactosylceramide (alpha-GalCer)-activated human iNKT cells, and this effect resulted mediated by pertussis toxin (PTX)-sensitive Gi/o proteins. In conclusion, our results demonstrate that human iNKT cells express GPR35 functionally active in reducing IL-4 release.

Synthesis and Biological Evaluation of Novel Selenyl and Sulfur-l-Dopa Derivatives as Potential Anti-Parkinson's Disease Agents.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons at level of substantianigrapars compacta. To date, there is no cure for this pathology, except for some drugs able to alleviate the symptoms of PD. In this paper we report the synthesis and biological evaluation of novel sulfur- and selenyl-l-Dopa (LD) derivatives (SP1-6) obtained through the amide junction between the amino group of LD and carboxylic moiety of sulfur- and selenyl-organic compounds, which are commercially available. Biological activity was evaluated on human undifferentiated and retinoic acid/phorbol myristyl acetate (RA/PMA)-differentiated SY-SH5Y neuroblastoma cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Antioxidant activity against oxidative stress was measured using nitroblue tetrazolium (NBT) and 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assays. Finally, physico-chemical characterization and plasma stability studies of SP1-6 were also performed. Biological data revealed that SP6 has a significant protective action against the neurotoxic action of 6-hydroxydopamine (6-OHDA) and H2O2 in a RA/PMA-differentiated SY-SH5Y neuroblastoma cell line that proved to be an effective antioxidant and protective compound. SP6, endowed with a lipophilic nature, low molecular weight, and plasma stability, can easily cross biological membranes via passive diffusion such as through the blood-brain barrier. SP6 has great potential for developing novel pharmacological approach for neurodegenerative diseases, such as PD. Further studies will help define its exact antioxidant mechanism and determine whether the neuroprotective action is mediated or modulated by glutathione peroxidase (GPx).