Mitochondrial dysfunctions accompany several neurodegenerative disorders and contribute to disease pathogenesis among others in Parkinson’s disease (PD). Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a major regulator of mitochondrial functions and biogenesis, and was suggested as a therapeutic target in PD. PGC-1α is regulated by both transcriptional and posttranslational events involving also the action of growth factors. Fibroblast growth factor-21 (FGF21) is a regulator of glucose and fatty acid metabolism in the body but little is known about its action in the brain. We show here that FGF21 increased the levels and activity of PGC-1α and elevated mitochondrial antioxidants in human dopaminergic cells in culture. The activation of PGC-1α by FGF21 occurred via the NAD+-dependent deacetylase Sirtuin-1 (SIRT1) subsequent to an increase in the enzyme, nicotinamide phosphoribosyltransferase (Nampt). FGF21 also enhanced mitochondrial respiratory capacity in human dopaminergic neurons as shown in real-time analyses of living cells. FGF21 is present in the brain including midbrain and is expressed by glial cells in culture. These results show that FGF21 activates PGC-1α and increases mitochondrial efficacy in human dopaminergic neurons suggesting that FGF21 could potentially play a role in dopaminergic neuron viability and in PD.

The aim of the present study was to evaluate if guanine-based purines may affect the gastric motor function in mouse. Thus, the influence of guanosine on the gastric emptying rate in vivo was determined and its effects on spontaneous gastric mechanical activity, detected as changes of the intraluminal pressure, were analyzed in vitro before and after different treatments. Gastric gavage of guanosine (1.75-10 mg/kg) delayed the gastric emptying. Guanosine (30 μM-1 mM) induced a concentration-dependent relaxation of isolated stomach, which was not affected by the inhibition of the purine nucleoside phosphorylase enzyme by 4′-deaza-1′-aza-2′-deoxy-1′-(9-methylene)-immucillin-H. The inhibitory response was antagonized by S-(4-nitrobenzyl)-6-thioinosine, a membrane nucleoside transporter inhibitor, but not affected by 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine, a nonselective adenosine receptor antagonist, or by tetrodotoxin, a blocker of neuronal voltagedependent Na + channels. Moreover, guanosine-induced effects persisted in the presence of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylyl cyclase or tetraethylammonium, a nonselective potassium channel blocker, but they were progressively reduced by increasing concentrations of 2′5′dideoxyadenosine, an adenylyl cyclase inhibitor. Lastly, the levels of cyclic adenosine monophosphate (cAMP), measured by ELISA, in gastric full thickness preparations were increased by guanosine. In conclusion, our data indicate that, in mouse, guanosine is able to modulate negatively the gastric motor function, reducing gastric emptying and inducing muscular relaxation. The latter is dependent by its cellular uptake and involves adenylyl cyclase activation and increase in cAMP intracellular levels, while it is independent on neural action potentials, adenosine receptors, and K + channel activation.

BackgroundFunctional dyspepsia (FD) is a multifactorial disorder. Helicobacter pylori (H. pylori)‐related dyspepsia (HpD) may be considered a separate entity. Duodenal eosinophilia is a potential pathogenic mechanism in FD. However, the impact of duodenal eosinophilia and host genetic polymorphism of innate and pro‐inflammatory cascade, nucleotide‐binding oligomerization domain 1 (NOD‐1), and interleukin‐1 beta (IL‐1β) in HpD was not explored.AimTo evaluate the association of NOD1‐796G>A and IL‐1B‐511C>T gene variants and low‐grade duodenal eosinophilia in HpD.MethodsA multicenter cross‐sectional study was conducted. A total of 253 patients who met Rome‐IV criteria were selected before upper endoscopy and 98 patients were included after unremarkable upper endoscopy and positive H. pylori in gastric biopsies were assessed. Clinical parameters, H. pylori cagA and duodenal histology, were evaluated.ResultsSixty‐four (65%) patients had epigastric pain syndrome (EPS), 24 (25%) postprandial distress syndrome (PDS), and 10 (10%) EPS/PDS overlap. FD subtypes were not associated with NOD1‐796G>A and IL‐1B‐511C>T gene variants. Low‐grade duodenal eosinophilia was significantly increased in NOD1‐796 GG versus single A‐allele, but not in IL‐1B‐511 single T‐allele or CC‐allele. This association is dependent of cagA infection, since harboring cagA strain was significantly associated with low‐grade duodenal eosinophilia with isolated variants NOD1‐796 GG and IL‐1B‐511 single T‐allele, but not without cagA. When we performed combined polymorphism analysis with NOD1‐796 GG/IL‐1B‐511 single T‐allele, a synergistic effect on low‐grade duodenal eosinophilia was found between these two loci irrespective of cagA strain status in HpD.ConclusionOur findings suggest that low‐grade duodenal eosinophilia is significantly associated with NOD1‐796 GG allele specially in cagA strain and with allelic combination NOD1‐796 GG/IL‐1B‐511 single T‐allele independent of cagA strain infection in HpD patients.