Loss and Recovery of Glutaredoxin 5 Is Inducible by Diet in a Murine Model of Diabesity and Mediated by Free Fatty Acids In Vitro.

Free fatty acids (FFA), hyperglycemia, and inflammatory cytokines are major mediators of ß-cell toxicity in type 2 diabetes mellitus, impairing mitochondrial metabolism. Glutaredoxin 5 (Glrx5) is a mitochondrial protein involved in the assembly of iron-sulfur clusters required for complexes of the respiratory chain. We have provided evidence that islet cells are deprived of Glrx5, correlating with impaired insulin secretion during diabetes in genetically obese mice. In this study, we induced diabesity in C57BL/6J mice in vivo by feeding the mice a high-fat diet (HFD) and modelled the diabetic metabolism in MIN6 cells through exposure to FFA, glucose, or inflammatory cytokines in vitro. qRT-PCR, ELISA, immunohisto-/cytochemistry, bioluminescence, and respirometry were employed to study Glrx5, insulin secretion, and mitochondrial biomarkers. The HFD induced a depletion of islet Glrx5 concomitant with an obese phenotype, elevated FFA in serum and reactive oxygen species in islets, and impaired glucose tolerance. Exposure of MIN6 cells to FFA led to a loss of Glrx5 in vitro. The FFA-induced depletion of Glrx5 coincided with significantly altered mitochondrial biomarkers. In summary, we provide evidence that Glrx5 is regulated by FFA in type 2 diabetes mellitus and is linked to mitochondrial dysfunction and blunted insulin secretion.

Correlation of Early Nutritional Supply and Development of Bronchopulmonary Dysplasia in Preterm Infants <1,000 g.

Background: Bronchopulmonary dysplasia (BPD) has multifactorial origins and is characterized by distorted physiological lung development. The impact of nutrition on the incidence of BPD is less studied so far. Methods: A retrospective single center analysis was performed on n = 207 preterm infants <1,000 g and <32 weeks of gestation without severe gastrointestinal complications to assess the impact of variations in nutritional supply during the first 2 weeks of life on the pulmonary outcome. Infants were grouped into no/mild and moderate/severe BPD to separate minor and major limitations in lung function. Results: After risk adjustment for gestational age, birth weight, sex, multiples, and antenatal steroids, a reduced total caloric intake and carbohydrate supply as the dominant energy source during the first 2 weeks of life prevailed statistically significant in infants developing moderate/severe BPD (p < 0.05). Enteral nutritional supply was increased at a slower rate with prolonged need for parenteral nutrition in the moderate/severe BPD group while breast milk provision and objective criteria of feeding intolerance were equally distributed in both groups. Conclusion: Early high caloric intake is correlated with a better pulmonary outcome in preterm infants <1,000 g. Our results are in line with the known strong impact of nutrient supply on somatic growth and psychomotor development. Our data encourage paying special attention to further decipher the ideal nutritional requirements for unrestricted lung development and promoting progressive enteral nutrition in the absence of objective criteria of feeding intolerance.

Fucose as a Cleavage Product of 2'Fucosyllactose Does Not Cross the Blood-Brain Barrier in Mice.

SCOPE: To further examine the role of the human milk oligosaccharide 2'fucosyllactose (2´FL) and fucose (Fuc) in cognition. Using 13 C-labeled 2'FL,thestudy previously showed in mice that 13 C-enrichment of the brain is not caused by 13 C1 -2´FL itself, but rather by microbial metabolites. Here, the study applies 13 C1 -Fuc in the same mouse model to investigate its uptake into the brain. METHODS AND RESULTS: Mice received 13 C1 -Fuc via oral gavage (2 mmol 13 C1 -Fuc/kg-1 body weight) or intravenously (0.4 mmol/kg-1 body weight). 13 C-enrichment is measured in organs, including various brain regions, biological fluids and excrements. By EA-IRMS, the study observes an early rise of 13 C-enrichment in plasma, 30 min after oral dosing. However, 13 C-enrichment in the brain does not occur until 3-5 h post-dosing, when the 13 C-Fuc bolus has already reached the lower gut. Therefore, the researcher assume that 13 C-Fuc is absorbed in the upper small intestine but cannot cross the blood-brain barrier which is also observed after intravenous application of 13 C1 -Fuc. CONCLUSIONS: Late 13 C-enrichment in the rodent brain may be derived from 13 C1 -Fuc metabolites derived from bacterial fermentation. The precise role that Fuc or 2´FL metabolites might play in gut-brain communication needs to be investigated in further studies.

Metabolic Fate and Distribution of 2´-Fucosyllactose: Direct Influence on Gut Microbial Activity but not on Brain.

SCOPE: 2´-Fucosyllactose (2´FL) is an abundant oligosaccharide in human milk. It is hypothesized that its brain enrichment is associated with improved learning. Accumulation of 2´FL in organs, biological fluids, and feces is assessed in wild-type and germ-free mice. METHODS AND RESULTS: 13 C-labelled 2´FL is applied to NMRI wild-type mice intravenously (0.2 g kg-1 ) or orally (1 g kg-1 ), while controls receive saline. Biological samples are collected (0.5-15 h) and 13 C-enrichment is measured by elemental analysis isotope ratio mass spectrometry (EA-IRMS). After oral application, 2´FL is primarily eliminated in the feces. 13 C-enrichment in organs including the brain follows the same pattern as in plasma with a maximum peak after 5 h. However, 13 C-enrichment is only detected when the 13 C-2´FL bolus reaches the colon. In contrast, in germ-free mice, the 13 C-bolus remains in the intestinal content and is expelled via the feces. Furthermore, intravenously applied 13 C-2´FL is eliminated via urine; no 13 C-enrichment of organs is observed, suggesting that intact 2´FL is not retained. CONCLUSIONS: 13 C-enrichment in brain and other organs after oral application of 13 C-2´FL in wild-type mice indicates cleaved fucose or other gut microbial 2´FL metabolites may be incorporated, as opposed to intact 2´FL.

A diet rich in omega-3 fatty acids enhances expression of soluble epoxide hydrolase in murine brain.

Several studies suggest that intake of omega-3 polyunsaturated fatty acids (n3-PUFA) beneficially influences cognitive function. However, effects on the adult brain are not clear. Little is known about the impact of dietary intervention on the fatty acid profile in adult brain, the modulation in the expression of enzymes involved in fatty acid biosynthesis and metabolism as well as changes in resulting oxylipins. These questions were addressed in the present study in two independent n3-PUFA feeding experiments in mice. Supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA, 1% each in the diet) for 30days to adult NMRI and C57BL/6 mice led to a distinct shift in the brain PUFA pattern. While n3-PUFAs EPA, n3 docosapentaenoic acid and DHA were elevated, many n6-PUFAs were significantly decreased (except, e.g. C20:3 n6 which was increased). This shift in PUFAs was accompanied by immense differences in concentrations of oxidative metabolites derived from enzymatic conversion of PUFAs, esp. arachidonic acid whose products were uniformly decreased, and a modulation in the activity and expression pattern of delta-5 and delta-6 desaturases. In both mouse strains a remarkable increase in the soluble epoxide hydrolase (sEH) activity (decreased epoxy-FA concentrations and epoxy-FA to dihydroxy-FA-ratios) as well as sEH expression was observed. Taking the high biological activity of epoxy-FA, e.g. on blood flow and nociceptive signaling into account, this finding might be of relevance for the effects of n3-PUFAs in neurodegenerative diseases. On any account, our study suggests a new distinct regulation of brain PUFA and oxylipin pattern by supplementation of n3-PUFAs to adult rodents.

Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer's disease--therapeutic aspects.

As a fully differentiated organ, our brain is very sensitive to cumulative oxidative damage of proteins, lipids, and DNA occurring during normal aging because of its high energy metabolism and the relative low activity of antioxidative defense mechanisms. As a major consequence, perturbations of energy metabolism including mitochondrial dysfunction, alterations of signaling mechanisms and of gene expression culminate in functional deficits. With the increasing average life span of humans, age-related cognitive disorders such as Alzheimer's disease (AD) are a major health concern in our society. Age-related mitochondrial dysfunction underlies most neurodegenerative diseases, where it is potentiated by disease-specific factors. AD is characterized by two major histopathological hallmarks, initially intracellular and with the progression of the disease extracellular accumulation of oligomeric and fibrillar beta-amyloid peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. In this review, we focus on findings in AD animal and cell models indicating that these histopathological alterations induce functional deficits of the respiratory chain complexes and therefore consecutively result in mitochondrial dysfunction and oxidative stress. These parameters lead synergistically with the alterations of the brain aging process to typical signs of neurodegeneration in the later state of the disease, including synaptic dysfunction, loss of synapses and neurites, and finally neuronal loss. We suggest that mitochondrial protection and subsequent reduction of oxidative stress are important targets for prevention and long-term treatment of early stages of AD.

Traditional used Plants against Cognitive Decline and Alzheimer Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive memory deficits, impaired cognitive function, and altered and inappropriate behavior. Aging represents the most important risk factor for AD and the global trend in the phenomenon of population aging has dramatic consequences for public health, healthcare financing, and delivery systems in the word and, especially in developing countries. Mounting evidence obtained in in vitro and in vivo studies, suggests that various traditionally used plants in Asia, India, and Europe significantly affect key metabolic alterations culminating in AD-typical neurodegeneration. The present article aims to bring the reader up-to-date on the most recent studies and advances describing the direct and indirect activities of traditional used plants and its constituents possibly relieving features of AD. A variety of traditional used plants and its extracts exerted activities on AD related drug targets including AChE activity, antioxidative activity, modulation of Aß-producing secretase activities, Aß-degradation, heavy metal chelating, induction of neurotrophic factors, and cell death mechanisms. Although pre-clinical investigations identified promising drug candidates for AD, clinical evidences are still pending.