The slow-releasing and mitochondria-targeted hydrogen sulfide (H2s) delivery molecule ap39 induces brain tolerance to ischemia

This is the final version. Available on open access from MDPI via the DOI in this recordIschemic stroke is the third leading cause of death in the world, which accounts for almost 12% of the total deaths worldwide. Despite decades of research, the available and effective pharmacotherapy is limited. Some evidence underlines the beneficial properties of hydrogen sulfide (H2S) donors, such as NaSH, in an animal model of brain ischemia and in in vitro research; however, these data are ambiguous. This study was undertaken to verify the neuroprotective activity of AP39, a slow-releasing mitochondria-targeted H2S delivery molecule. We administered AP39 for 7 days prior to ischemia onset, and the potential to induce brain tolerance to ischemia was verified. To do this, we used the rat model of 90-min middle cerebral artery occlusion (MCAO) and used LC-MS/MS, RT-PCR, Luminex™ assays, Western blot and immunofluorescent double-staining to determine the absolute H2S levels, inflammatory markers, neurotrophic factor signaling pathways and apoptosis marker in the ipsilateral frontal cortex, hippocampus and in the dorsal striatum 24 h after ischemia onset. AP39 (50 nmol/kg) reduced the infarct volume, neurological deficit and reduced the microglia marker (Iba1) expression. AP39 also exerted prominent anti-inflammatory activity in reducing the release of Il-1β, Il-6 and TNFα in brain areas particularly affected by ischemia. Furthermore, AP39 enhanced the pro-survival pathways of neurotrophic factors BDNF-TrkB and NGF-TrkA and reduced the proapoptotic proNGF-p75NTR-sortilin pathway activity. These changes corresponded with reduced levels of cleaved caspase 3. Altogether, AP39 treatment induced adaptative changes within the brain and, by that, developed brain tolerance to ischemia.National Science Center, PolandMedical Research Council (MRC

Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis

Alcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol use with the goal to self-medicate and ameliorate the behavioral symptoms of a genetically induced innate depression. An induced over-expression of acid sphingomyelinase (ASM), as was observed in depressed patients, enhanced the consumption of alcohol in a mouse model of depression. ASM hyperactivity facilitates the establishment of the conditioned behavioral effects of alcohol, and thus drug memories. Opposite effects on drinking and alcohol reward learning were observed in animals with reduced ASM function. Importantly, free-choice alcohol drinking—but not forced alcohol exposure—reduces depression-like behavior selectively in depressed animals through the normalization of brain ASM activity. No such effects were observed in normal mice. ASM hyperactivity caused sphingolipid and subsequent monoamine transmitter hypo-activity in the brain. Free-choice alcohol drinking restores nucleus accumbens sphingolipid- and monoamine homeostasis selectively in depressed mice. A gene expression analysis suggested strong control of ASM on the expression of genes related to the regulation of pH, ion transmembrane transport, behavioral fear response, neuroprotection and neuropeptide signaling pathways. These findings suggest that the paradoxical antidepressant effects of alcohol in depressed organisms are mediated by ASM and its control of sphingolipid homeostasis. Both emerge as a new treatment target specifically for depression-induced alcoholism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-016-1658-6) contains supplementary material, which is available to authorized users

Wplyw metali ciezkich na rosliny rosnace na terenach poprzemyslowych - aspekt fizjologiczny

Badano akumulację metali ciężkich (Zn, Cd, Pb, Fe, Cu), aktywność peroksydazy guajakolowej (POD E.C. 1.11.1.7) oraz zawartość niebiałkowych grup -SH w liściach Betula pendula Ehrh, Salix cinerea L., Silene vulgaris Moench (Garcke), Tussilago farfara L., rosnących na terenach poprzemysłowych. Zaobserwowano następujący szereg zdolności kumulacji metali przez badane rośliny: Zn > Fe > Pb > Cd > Cu. Metale ciężkie (z wyjątkiem Zn) były bardziej biodostępne na hałdzie w Piekarach niż na terenie pogalmanowym „Warpie”. Wyższe aktywności peroksydazy w liściach badanych roślin, szczególnie u Tussilago farfara stwierdzono na terenie pogalmanowym. Najwyższą zawartość niebiałkowych grup -SH stwierdzono w liściach Salix cinerea pozyskanych na hałdzie w Piekarach.The heavy metal accumulation (Zn, Pb, Cd, Fe, Cu) and activity of peroxidase (POD) E.C. 1.11.1.7 and non - protein -SH group content were investigated in Betula pendula Ehrh, Salix cinerea L, Silene vulgaris Moench (Garcke), Tussilago farfara L., grown in the postindustrial areas (1-dump after non-ferrous metal ores in Piekary, 2-calamine site in Dąbrowa Górnicza). The higher heavy metal accumulation was determined in leaves of plants collected in Piekary (except Zn). The following order of heavy metals accumulation ability in plants: Zn > Fe > Pb > Cd > Cu was found. The metals (except Zn) were more bioavailable in Piekary than in the calamine site. Higher activities of peroxidase were determined in plants (especially in Tussilago farfara), collected in the calamine site. The highest content of non-protein -SH group was found in Salix cinerea leaves collected in Piekary dump

Organizacja pracy poczty. Przegląd Zagadnień Łączności, 1966, nr 2 (53)

Opracowania na podstawie artykułó