Publication informationNeurobiology of Disease, 62 (February 2014): 8-17 Publisher Elsevier Item record/more information http://hdl.handle.net/10197/4791 Publisher's statementThis is the author's version of a work that was accepted for publication in Neurobiology of Disease. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neurobiology of Disease (In press (2013) AbstractChronic intermittent hypoxia (CIH) is an underlying component of obstructive sleep apnoea and has been shown to have deleterious and damaging effects on central neurons and to impair synaptic plasticity in the CA1 region of the rat hippocampus. CIH has previously been shown to impair synaptic plasticity and working memory. CIH is a potent inducer of hypoxia inducible factor (HIF), a key regulator in a cell's adaptation to hypoxia that plays an important role in the fate of neurons during ischemia. Levels of HIF-1α are regulated by the activity of a group of enzymes called HIF-prolyl 4-hydroxylases (PHDs) and these have become potential pharmalogical targets for preconditioning against ischemia. However little is known about the effects of prolyl hydroxylase inhibition and CIH on synaptic transmission and plasticity in sub-regions of the hippocampus. Male Wistar rats were treated for 7-days with either saline, CIH or PHD inhibition (dimethyloxaloylglycine, DMOG; 50mg/kg, i.p.). At the end of treatment all three groups showed no change in synaptic excitability using paired pulse paradigms. However long-term potentiation (LTP) was impaired in the CA1 region of the hippocampus in both CIH and DMOG treated animals. LTP induced in the dentate gyrus was not significantly affected by either CIH or DMOG treatment. We also investigated the effect of 7-day CIH and DMOG treatment on the recovery of synaptic transmission following an acute 30 min hypoxic insult. CIH treated animals showed an improved rate of recovery of synaptic transmission following re-oxygenation in both the CA1 and dentate gyrus. These results suggest that LTP induction in the CA1 region is more sensitive to both CIH and DMOG treatment than the dentate gyrus.

Skeletal muscle is the metabolic powerhouse of the body, however, dysregulation of the mechanisms involved in skeletal muscle mass maintenance can have devastating effects leading to many metabolic and physiological diseases. The lack of effective solutions makes finding a validated nutritional intervention an urgent unmet medical need. In vitro testing in murine skeletal muscle cells and human macrophages was carried out to determine the effect of a hydrolysate derived from vicia faba (PeptiStrong: NPN_1) against phosphorylated S6, atrophy gene expression, and tumour necrosis factor alpha (TNF-α) secretion, respectively. Finally, the efficacy of NPN_1 on attenuating muscle waste in vivo was assessed in an atrophy murine model. Treatment of NPN_1 significantly increased the phosphorylation of S6, downregulated muscle atrophy related genes, and reduced lipopolysaccharide-induced TNF-α release in vitro. In a disuse atrophy murine model, following 18 days of NPN_1 treatment, mice exhibited a significant attenuation of muscle loss in the soleus muscle and increased the integrated expression of Type I and Type IIa fibres. At the RNA level, a significant upregulation of protein synthesis-related genes was observed in the soleus muscle following NPN_1 treatment. In vitro and preclinical results suggest that NPN_1 is an effective bioactive ingredient with great potential to prolong muscle health.

An inadequate supply of oxygen in the brain may lead to the introduction of an inflammatory response through neuronal and glial cells that can result in neuronal damage. Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine that is released during acute hypoxia and can have neurotoxic or neuroprotective effects in the brain. Both TNF-α and interleukin-1β (IL-1β) have been shown by a number of research groups to alter synaptic scaling and also to inhibit long-term potentiation (LTP) in the hippocampus when induced by specific high frequency stimulation protocols. In this study we have examined the effects of TNF-α on synaptic transmission and plasticity in hippocampal slices after acute hypoxia using two high frequency stimulation protocols. Field excitatory postsynaptic potentials were elicited in the medial perforant pathway of the dentate gyrus. Exogenous TNF-α (5 ng/ml) attenuated LTP induced by theta burst stimulation but had no effect on LTP induced by a more prolonged high frequency stimulation (HFS). Pre-treatment with lipopolysaccharide (100 ng/ml) or TNF-α but not IL-1β (4 ng/ml) prior to a 30 min hypoxic insult resulted in a significant enhancement of LTP post hypoxia when induced by the HFS. Anti-TNF, 3,6 dithiothalidomide (a TNF-α synthesis inhibitor) and SB203580 (a p38 MAPK inhibitor) significantly reduced this effect. These results indicate an important modulatory role for elevated TNF-α levels on LTP in the hippocampus after an acute hypoxic event.

Food-derived bioactive peptides offer great potential for the treatment and maintenance of various health conditions, including chronic inflammation. Using in vitro testing in human macrophages, a rice derived functional ingredient natural peptide network (NPN) significantly reduced Tumour Necrosis Factor (TNF)-α secretion in response to lipopolysaccharides (LPS). Using artificial intelligence (AI) to characterize rice NPNs lead to the identification of seven potentially active peptides, the presence of which was confirmed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Characterization of this network revealed the constituent peptides displayed anti-inflammatory properties as predicted in vitro. The rice NPN was then tested in an elderly “inflammaging” population with a view to subjectively assess symptoms of digestive discomfort through a questionnaire. While the primary subjective endpoint was not achieved, analysis of objectively measured physiological and physical secondary readouts showed clear significant benefits on the ability to carry out physical challenges such as a chair stand test that correlated with a decrease in blood circulating TNF-α. Importantly, the changes observed were without additional exercise or specific dietary alterations. Further health benefits were reported such as significant improvement in glucose control, a decrease in serum LDL concentration, and an increase in HDL concentration; however, this was compliance dependent. Here we provide in vitro and human efficacy data for a safe immunomodulatory functional ingredient characterized by AI.

les explants de peau humaine. Enfin, dans notre etude clinique de preuve de concept, l'application de pep_RTE626 sur 28 jours a d emontr e un potentiel stimulant anti-rides et collag ene. CONCLUSION: pep_RTE62G repr esente un peptide naturel, non modifi e avec des propri et es anti-âge pr edites par l'IA et valid ees exp erimentalement. Nos r esultats confirment l'utilit e de l'IA dans la d ecouverte de nouveaux ingr edients topiques fonctionnels.