Dipeptide Mimetic of the BDNF GSB-106 with Antidepressant-Like Activity Stimulates Synaptogenesis

Dipeptide mimetic of the brain-derived neurotrophic factor bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (working name GSB-106), which reproduces the homodimeric structure of BDNF and the beta-turn of its fourth loop, activates TrkB, AKT, and ERK, exhibits neuroprotective and antidepressant activity, and is able to stimulate neurogenesis in the hippocamp of stressed mice. Using Western blot hybridization and synaptophysin (synaptogenesis marker), we showed the ability of chronically administered GSB-106 to stimulate synaptogenesis, increasing the synaptic density in the hippocamp by 50%. Under the same conditions, GSB-106 exhibited antidepressant activity (decreased (by 18%) immobility of animals in Porsolt test), which may be associated with the stimulation of neurogenesis and synaptogenesis in the hippocamp.     

Derivation of scenario-specific water quality guidelines for acid mine drainage in South Africa,using a risk-based approach

Acid mine drainage (AMD) continues to threaten water quality in many mining regions globally. Data paucity renders it challenging to inform appropriate water quality management strategies for a succinct scientific understanding of the effects of AMD on freshwater ecosystems. The current study investigated the effects of AMD collected from a defunct coalmine in Mpumalanga, South Africa, on freshwater ecosystems using a risk-based approach on five indigenous species, Adenophlebia auriculata, Burnupia stenochorias, Caridina nilotica, Pseudokirchneriella subcapitata and Oreochromis mossambicus in 2016. Species responded differently to AMD after 96 hours and 240 hours of exposure in static experimental test designs. Burnupia stenochorias was more sensitive to AMD after 96 and 240 hours of exposure, whereas O. mossambicus was tolerant during short-term exposure, but became more sensitive after 240 hours of exposure than the other species tested. The availability of metals in AMD was directly associated with dilution rate. Scenario-specific water quality guidelines for AMD have been derived as 0.122% for short-term and 0.014% for long-term exposure. These may form important indicative dilutions for other AMDs that do not match the scenarios of this study. The toxicity of AMD to a wide range of aquatic species, including field validations, requires further investigation.     

Differential cadmium and zinc distribution in relation to their physiological impact in the leaves of the accumulating Zygophyllum fabago L.

Cadmium and zinc share many similar physiochemical properties, but their compartmentation, complexation and impact on other mineral element distribution in plant tissues may drastically differ. In this study, we address the impact of 10 μm Cd or 50 μm Zn treatments on ion distribution in leaves of a metallicolous population of the non‐hyperaccumulating species Zygophyllum fabago at tissue and cell level, and the consequences on the plant response through a combined physiological, proteomic and metabolite approach. Micro‐proton‐induced X‐ray emission and laser ablation inductively coupled mass spectrometry analyses indicated hot spots of Cd concentrations in the vicinity of vascular bundles in response to Cd treatment, essentially bound to S‐containing compounds as revealed by extended X‐ray absorption fine structure and non‐protein thiol compounds analyses. A preferential accumulation of Zn occurred in vascular bundle and spongy mesophyll in response to Zn treatment, and was mainly bound to O/N‐ligands. Leaf proteomics and physiological status evidenced a protection of photosynthetically active tissues and the maintenance of cell turgor through specific distribution and complexation of toxic ions, reallocation of some essential elements, synthesis of proteins involved in photosynthetic apparatus or C‐metabolism, and metabolite synthesis with some specificities regarding the considered heavy metal treatment.     

Design and synthesis of dipeptide mimetics of the brain-derived neurotrophic factor

Low-molecular-weight mimetics of loops 1 and 4 of the brain-derived neurotrophic factor (BDNF) have been designed and synthesized. The compounds represent monomeric and dimeric amides of N-acyldipeptides. Their dipeptide fragments coincide in sequence with the central regions of beta-turns of the corresponding neurotrophin loops, and acyl groups are the bioesosteres of preceding amino acid residues. Hexa- or heptamethylenediamines were used as spacers to link the C-terminal regions of dipeptides in dimeric mimetics of BDNF. These compounds were synthesized by classical methods of peptide synthesis in solution and received the laboratory codes GSB-104 (HO-Suc-Ser-Lys-NH₂), GSB-106 {[HO-Suc-Ser-Lys-NH-(CH₂)₃?]₂}, GSB-207 (HO-Suc-Met-Ser-NH₂), and GSB-214 ([HO-Suc-Met-Ser-NH-(CH₂)_7/2-]₂). It was shown using immortalized hippocampal cells of the HT22 line under conditions of oxidative stress that the dimeric mimetics of both loops at concentrations of 10^?5?10^?8 M possess a neuroprotective activity. The monomeric loop 1 mimetic GSB-207 in the same concentration range is inactive, and the monomeric loop 4 mimetic GSB-104 at a concentration of 10^?7 impairs the survival of neurons. The finding that only dimeric mimetics possess the neuroprotective activity is consistent with the data indicating that BDNF is active in the homodimeric form. As opposed to the dimeric loop 1 mimetic GSB-214, the dimeric loop 4 mimetic GSB-106 exhibits the antidepressant activity typical for BDNF in the Porsolt test on rats at doses of 0.1 and 1 mg/kg injected intraperitoneally. This suggests that the antidepressant activity of BDNF is related to its 4th loop. We believe that the compounds obtained will be useful in studies of the mechanism of action of BDNF and may form the basis for the design of a novel group of drugs with antidepressant and neuroprotective activities.     

NADH diaphorase polymorphism in goat erythrocytes

This paper describes for the first time polymorphism of the erythrocyte diaphorase in goats. Three diaphorase 1 phenotypes were observed in the red cells of goats. Breeding data indicated that polymorphism was controlled by two autosomal codominant alleles, DiaF and DiaS, the frequencies of which were determined in 14 different Spanish breeds of goat.     

Activation of phospholipase hydrolysis in the process of oxidative cell damage]

Effect of tert-butyl hydroperoxide toxic action on phospholipase A2 activity and the changes in phospholipid composition from mastocytoma P815 cells were investigated. Oxidative damage of tumor cell membranes was accompanied by the release of arachidonic acid from membrane phospholipids and the accumulation of lysophosphatidylcholine, the product of phospholipase A2 reaction and a potent detergent. Tert-butyl hydroperoxide also increased relative contents of sphingomyelin, phosphatidylserine and phosphatidic acid in tumor cell membranes. It is possible that phospholipase A2 activation and the changes of phospholipid molecular species contents may cause the damage of cell membrane stability.     

Detection of large deletions of mitochondrial DNA in tissues of mice exposed to X-rays

Large mtDNA deletions in mouse brain and spleen cells, induced by X-radiation at doses of 2 and 5 Gy were studied within four weeks after the exposure of animals to X-rays. Variations in the content of extra-cellular deleted mtDNA were examined in the blood plasma of mice irradiated with 5 Gy in the same postir-radiation times. Ionizing radiation was shown to effectively induce large mtDNA deletions at the doses chosen. The level of deletion mtDNA was dependent on dose and postirradiation time.