Potential applications of stress solutes from extremophiles in protein folding diseases and healthcare

Protein misfolding, aggregation and deposition in the brain, in the form of amyloid, are implicated in the etiology of several neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and prion diseases. Drugs available on the market reduce the symptoms, but they are not a cure. Therefore, it is urgent to identify promising targets and develop effective drugs. Preservation of protein native conformation and/or inhibition of protein aggregation seem pertinent targets for drug development. Several studies have shown that organic solutes, produced by extremophilic microorganisms in response to osmotic and/or heat stress, prevent denaturation and aggregation of model proteins. Among these stress solutes, mannosylglycerate, mannosylglyceramide, di-myo-inositol phosphate, diglycerol phosphate and ectoine are effective in preventing amyloid formation by Alzheimer’s Aβ peptide and/or α-synuclein in vitro. Moreover, mannosylglycerate is a potent inhibitor of Aβ and α-synuclein aggregation in living cells, and mannosylglyceramide and ectoine inhibit aggregation and reduce prion peptide-induced toxicity in human cells. This review focuses on the efficacy of stress solutes from hyper/thermophiles and ectoines to prevent amyloid formation in vitro and in vivo and their potential application in drug development against protein misfolding diseases. Current and envisaged applications of these extremolytes in neurodegenerative diseases and healthcare will also be addressed.     

Guanosine and GMP increase the number of granular cerebellar neurons in culture: dependence on adenosine A2A and ionotropic glutamate receptors

Purinergic Signalling - The guanine-based purines (GBPs) have essential extracellular functions such as modulation of glutamatergic transmission and trophic effects on neurons and astrocytes. We...     

Oral levodopa rescues retinal morphology and visual function in a murine model of human albinism

Albinism is a group of disorders characterized by pigment deficiency and abnormal retinal development. Despite being a common cause for visual impairment worldwide, there is a paucity of treatments and patients typically suffer lifelong visual disability. Residual plasticity of the developing retina in young children with albinism has been demonstrated, suggesting a post‐natal window for therapeutic rescue. L‐3, 4 dihydroxyphenylalanine (L‐DOPA), a key signalling molecule which is essential for normal retinal development, is known to be deficient in albinism. In this study, we demonstrate for the first time that post‐natal L‐DOPA supplementation can rescue retinal development, morphology and visual function in a murine model of human albinism, but only if administered from birth or 15 days post‐natal age.     

Taurine modulates hepatic oxidative status and gut inflammatory markers of European seabass (Dicentrarchus labrax) fed plant feedstuffs-based diets

Amino Acids - This study aimed to evaluate the effect of taurine (tau) supplementation to low fishmeal (FM) diets on growth performance, oxidative status, and immune response of European seabass...     

The dual functionality of antimicrobial peptides Os and Os‐C in human leukocytes

Antimicrobial peptides (AMPs), Os and Os‐C, have been identified as multifunctional peptides with antibacterial, antiendotoxin, and anti‐inflammatory properties. For further development of Os and Os‐C as therapeutic peptides, it is essential to evaluate these effects in human mononuclear (MN) and polymorphonuclear (PMN) leukocytes. The cytotoxicity and the effects of both peptides on MN and PMN morphology were determined with the Alamar‐Blue assay and scanning electron microscopy, respectively. The ability of Os and Os‐C to induce reactive oxygen species (ROS) and to protect against 2,2′‐azobis(2‐amidinopropane) dihydrochloride–induced oxidative damage in both cell populations was evaluated using 2′,7′‐dichlorofluorescin diacetate (DCFH‐DA). Using fluorescently labeled peptides, the ability of the peptides to cross the cell membranes of MN and PMN was also evaluated. At the minimum bactericidal concentrations of Os and Os‐C, neither peptide was cytotoxic. Os caused morphological features of toxicity at 100 μM, entered MN cells, and also protected these cells against oxidative damage. Os‐C caused MN and PMN leukocyte activation associated with ROS formation and was unable to penetrate cell membranes, indicating extracellular membrane interactions. This study confirms that both Os and Os‐C at less than 100 μM are not cytotoxic. The MN‐specific uptake of Os identifies it as a cell‐specific cargo‐carrier peptide, with additional anti‐inflammatory properties. In contrast, the ability of Os‐C to activate MN and PMN cells implies that this peptide should be further evaluated as an AMP, which, in addition to its ability to eradicate infection, can further enhance host immunity. These novel characteristics of Os and Os‐C indicate that these AMPs as peptides can be further developed for specific applications.     

Using behavioral observation for the longitudinal study of anger regulation in middle childhood

Assessing anger regulation via self-reports is fraught with problems, especially among children. Behavioral observation provides an ecologically valid alternative for measuring anger regulation. The present study uses data from two waves of a longitudinal study to present a behavioral observation approach for measuring anger regulation in middle childhood. At T1, 599 children from Germany (6–10 years old) were observed during an anger eliciting task, and the use of anger regulation strategies was coded. At T2, 3 years later, the observation was repeated with an age-appropriate version of the same task. Partial metric measurement invariance over time demonstrated the structural equivalence of the two versions. Maladaptive anger regulation between the two time points showed moderate stability. Validity was established by showing correlations with aggressive behavior, peer problems, and conduct problems (concurrent and predictive criterion validity). The study presents an ecologically valid and economic approach to assessing anger regulation strategies in situ.     

Unravelling the interactions of the environmental host Acanthamoeba castellanii with fungi through the recognition by mannose‐binding proteins

Free‐living amoebae (FLAs) are major reservoirs for a variety of bacteria, viruses, and fungi. The most studied mycophagic FLA, Acanthamoeba castellanii (Ac), is a potential environmental host for endemic fungal pathogens such as Cryptococcus spp., Histoplasma capsulatum, Blastomyces dermatitides, and Sporothrix schenckii. However, the mechanisms involved in this interaction are poorly understood. The aim of this work was to characterize the molecular instances that enable Ac to interact with and ingest fungal pathogens, a process that could lead to selection and maintenance of possible virulence factors. The interaction of Ac with a variety of fungal pathogens was analysed in a multifactorial evaluation that included the role of multiplicity of infection over time. Fungal binding to Ac surface by living image consisted of a quick process, and fungal initial extrusion (vomocytosis) was detected from 15 to 80 min depending on the organism. When these fungi were cocultured with the amoeba, only Candida albicans and Cryptococcus neoformans were able to grow, whereas Paracoccidioides brasiliensis and Sporothrix brasiliensis displayed unchanged viability. Yeasts of H. capsulatum and Saccharomyces cerevisiae were rapidly killed by Ac; however, some cells remained viable after 48 hr. To evaluate changes in fungal virulence upon cocultivation with Ac, recovered yeasts were used to infect Galleria mellonella, and in all instances, they killed the larvae faster than control yeasts. Surface biotinylated extracts of Ac exhibited intense fungal binding by FACS and fluorescence microscopy. Binding was also intense to mannose, and mass spectrometry identified Ac proteins with affinity to fungal surfaces including two putative transmembrane mannose‐binding proteins (MBP, L8WXW7 and MBP1, Q6J288). Consistent with interactions with such mannose‐binding proteins, Ac–fungi interactions were inhibited by mannose. These MBPs may be involved in fungal recognition by amoeba and promotes interactions that allow the emergence and maintenance of fungal virulence for animals.