Ursodeoxycholic acid, which in vivo is converted to its taurine conjugate tauroursodeoxycholic acid (TUDC), is a mainstay for the treatment of cholestatic liver disease. Earlier work showed that TUDC exerts its choleretic properties in the perfused rat liver in an a 5 b 1 integrin-mediated way. However, the molecular basis of TUDC-sensing in the liver is unknown. We herein show that TUDC (20 lmol/L) induces in perfused rat liver and human HepG2 cells the rapid appearance of the active conformation of the b 1 subunit of a 5 b 1 integrins, followed by an activating phosphorylation of extracellular signal-regulated kinases. TUDCinduced kinase activation was no longer observed after b 1 integrin knockdown in isolated rat hepatocytes or in the presence of an integrin-antagonistic hexapeptide in perfused rat liver. TUDC-induced b 1 integrin activation occurred predominantly inside the hepatocyte and required TUDC uptake by way of the Na 1 /taurocholate cotransporting peptide. Molecular dynamics simulations of a 3D model of a 5 b 1 integrin with TUDC bound revealed significant conformational changes within the head region that have been linked to integrin activation before. Conclusions: TUDC can directly activate intrahepatocytic b 1 integrins, which trigger signal transduction pathways toward choleresis.

Knowledge of physiological aging in healthy human brain is increasingly important for neuroscientific research and clinical diagnosis. To investigate neuronal decline in normal aging brain eighty-one healthy subjects aged between 20 to 70 years were studied with MRI and whole-brain 1H-MR spectroscopic imaging. Concentrations of brain metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), myo-inositol (mI), and glutamine+glutamate (Glx) in ratios to internal water, and the fractional volumes of brain tissue were estimated simultaneously in eight cerebral lobes and in cerebellum. Results demonstrated that an age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Both lobar NAA and the fractional volume of gray matter (FVGM) decreased with age in all cerebral lobes, indicating that the decreased NAA was predominantly associated with decreased gray matter volume and neuronal density or metabolic activity. In cerebral white matter Cho, tCr, and mI increased with age in association with increased fractional volume, showing altered cellular membrane turn-over, energy metabolism, and glial activity in human aging white matter. In cerebellum tCr increased while brain tissue volume decreased with age, showing difference to cerebral aging. The observed age-related metabolic and microstructural variations suggest that physiological neuronal decline in aging human brain is associated with a reduction of gray matter volume and neuronal density, in combination with cellular aging in white matter indicated by microstructural alterations and altered energy metabolism in the cerebellum.

Mesenchymal stem cells derived from bone marrow and adipose tissue are being considered for use in neural repair because they can differentiate after appropriate induction in culture into neurons and glia. The question we asked was if neurospheres could be harvested from adipose-derived stem cells and if they then could differentiate in culture to peripheral glial-like cells. Here, we demonstrate that adipose-derived mesenchymal stem cells can form nestin-positive non-adherent neurosphere cellular aggregates when cultured with basic fibroblast growth factor and epidermal growth factor. Dissociation of these neurospheres and removal of mitogens results in expression of the characteristic Schwann cell markers S100 and p75 nerve growth factor receptor and GFAP. The simultaneous expression of these glia markers are characteristic features of Schwann cells and olfactory ensheathing cells which have unique properties regarding remyelination and enhancement of axonal regeneration. When co-cultured with dorsal root ganglion neurons, the peripheral glial-like cells derived from adipose mesenchymal stem cells aligned with neuritis and stimulated neuritic outgrowth. These results indicate that neurospheres can be generated from adipose-derived mesenchymal stem cells, and upon mitogen withdrawal can differentiate into peripheral glial cells with neurotrophic effects.

Age-related accumulative metabolic changes in aging human brain correlated with reduced neuronal metabolic activity and density, reflected by decreased NAA, reduced mitochondrial activity by decreased ATP, and reduced membrane synthesis by decreased PME. These changes are associated with age-related decrease of neuronal volume. Global NAA and ATP might be used as surrogate biomarker for monitoring aging in human brain.

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Adaptive response of human brain to stress plays a key role in maintaining health. Knowledge about how stress affects neurometabolism may help to understand adaptive stress responses, and distinguish maladaptation in neuropsychiatric disorders. In this study, neurometabolic responses to fasting stress in healthy women were investigated. Fifteen healthy females were examined for mood and cognition and using whole-brain MR spectroscopic imaging before and immediately after a 72-h fasting. Results were compared to 15 age-matched healthy females who did not taken part in fasting (non-fasting). Maps of the distributions in the brain of N-acetylaspartate (NAA), total choline (tCho), total creatine (tCr), glutamine/glutamate (Glx), and myo-Inositol (mI) were derived. Metabolite concentrations of each brain lobe and cerebellum measured before fasting were compared to those of post-fasting and non-fasting by repeated-measures ANOVA. After fasting, mood scores significantly increased. Glx decreased in all nine brain regions, tCho in eight, NAA in four and tCr in one, with Glx having the greatest change and the frontal lobes being the most affected brain region. In conclusion, fasting directly influences neurometabolism, and the adaptive brain response to maintain energy homeostasis under food deprivation in healthy women is associated with metabolite-selective and region-dependent changes of metabolite contents.

Background About 50% of the patients 5-7 years after kidney transplantation show impairment of memory, attention and executive function. Tacrolimus frequently induces neurological complications in the first few weeks after transplantation. Furthermore, tacrolimus treatment is associated with impaired cognitive function in the long-term in patients after liver transplantation. We hypothesize that long-term tacrolimus therapy is associated with cognitive dysfunction and alterations of brain structure and metabolism in patients after kidney transplantation. Methods Twenty-one patients 10 years after kidney transplantation underwent cognitive testing, magnetic resonance imaging and whole brain 31-phosphor magnetic resonance spectroscopy for the assessment of brain function, structure and energy metabolism. Using a cross-sectional study design the results were compared to those of patients 1 (n = 11) and 5 years (n = 10) after kidney transplantation, and healthy controls (n = 17). To further analyze the share of transplantation, tacrolimus therapy and kidney dysfunction on the results patients after liver transplantation (n = 9) were selected as a patient control group.