A cell-biased effect of estrogen in prion infection.

Prion disorders are associated with the accumulation of a misfolded form (PrP(Sc)) of the normal prion protein, PrP(C). Here, we show that estrogen acts as a regulator of the processes of both prion infection and prion maintenance. Estrogen was found to be cell biased in its effect; it protected cells against prion infection in a prevention mode and enabled prion maintenance in a treatment mode. These processes were regulated by the estrogen receptor subtypes Erα and Erß. By using specific receptor agonists, Erα was found to be the main receptor active in slowing prion infection, whereas in chronically infected cells, although Erα allowed partial maintenance of PrP(Sc) levels, Erß was the main receptor involved in maintaining PrP(Sc) in a treatment paradigm. A cell-biased effect of estrogen has been reported for other neurodegenerative disorders, including Alzheimer's disease. Estrogen's effect is dependent on the cell's health status, which impacts the use of estrogen. This work also identified that by targeting the estrogen receptors with the selective estrogen receptor modulators tamoxifen (Tam) and 4-hydroxy-tamoxifen (OHT), PrP(Sc) could be cleared from prion-infected cell culture. Tam and OHT had half-maximal inhibitory concentrations for clearance of PrP(Sc) of 0.47 µM and 0.14 nM, respectively. This work identifies further factors involved in the prion disease process, and through antagonism of the estrogen system, we demonstrate that the estrogen system is a target for controlling PrP(Sc) levels.

Human milk and infant formulae: Peptide differences and the opportunity to address the functional gap.

Bovine-derived formula milk (FM) is a common substitute to human milk (HM), but lacks key functional benefits associated with HM. Accordingly, there have been significant efforts to humanise FM. Recent research has demonstrated that HM-derived peptides convey an array of beneficial bioactivities. Given that peptides serve as important signalling molecules offering high specificity and potency, they represent a prime opportunity to humanise FM. To further understand how HM-derived peptides contribute to infant health, we used peptidomics and bioinformatics to compare the peptide profile of HM to commercially available FM. We found clear and substantial differences between HM and FM in terms of peptide physicochemical properties, protein coverage and abundance. We additionally identified 618 peptides specific to HM that represent an important untapped source to be explored for novel bioactivities. While further study is required, our findings highlight the potential of a peptide-based approach to address the functional gap in FM.

Preclinical Evaluation of a Food-Derived Functional Ingredient to Address Skeletal Muscle Atrophy.

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 Artificial Intelligence Characterised Functional Ingredient, Derived from Rice, Inhibits TNF-α and Significantly Improves Physical Strength in an Inflammaging Population.

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.

Cyclodextrins inhibit replication of scrapie prion protein in cell culture.

Prion diseases are fatal neurodegenerative disorders that are caused by the conversion of a normal host-encoded protein, PrP(C), to an abnormal, disease-causing form, PrP(Sc). This paper reports that cyclodextrins have the ability to reduce the pathogenic isoform of the prion protein PrP(Sc) to undetectable levels in scrapie-infected neuroblastoma cells. Beta-cyclodextrin removed PrP(Sc) from the cells at a concentration of 500 microM following 2 weeks of treatment. Structure activity studies revealed that antiprion activity was dependent on the size of the cyclodextrin. The half-maximal inhibitory concentration (IC(50)) for beta-cyclodextrin was 75 microM, whereas alpha-cyclodextrin, which possessed less antiprion activity, had an IC(50) of 750 microM. This report presents cyclodextrins as a new class of antiprion compound. For decades, the pharmaceutical industry has successfully used cyclodextrins for their complex-forming ability; this ability is due to the structural orientation of the glucopyranose units, which generate a hydrophobic cavity that can facilitate the encapsulation of hydrophobic moieties. Consequently, cyclodextrins could be ideal candidates for the treatment of prion diseases.