Circulating FABP4 (Fatty Acid-Binding Protein 4) Is a Novel Prognostic Biomarker in Patients With Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: FABP4 (fatty acid-binding protein 4) is an intracellular lipid chaperone involved in coordination of lipid transportation and atherogenesis. This study aimed at observing the effect of FABP4 on the 3-month outcomes in Chinese patients with acute ischemic stroke. METHODS: In a prospective multicenter observational study, serum concentrations of FABP4 were on admission measured in plasma of 737 consecutive patients with acute ischemic stroke. Serum concentrations of FABP4, National Institutes of Health Stroke Scale score, and conventional risk factors were evaluated to determine their value to predict functional outcome and mortality within 3 months. RESULTS: During follow-up, an unfavorable functional outcome was found in 260 patients (35.3%), and 94 patients (12.8%) died. In multivariate models comparing the third and fourth quartiles to the first quartile of FABP4, the concentrations of FABP4 were associated with poor functional outcome and mortality. Compared with the reference category (Q1-Q3), the concentrations of FABP4 in Q4 had a relative risk of 4.77 (95% confidence interval [CI], 2.02-8.15; P<0.001) for poor functional outcome and mortality (odds ratio, 6.15; 95% CI, 3.43-12.68) after adjusting for other significant outcome predictors in univariate logistic regression analysis. Receiver-operating characteristic curves to predict poor functional outcome and mortality demonstrated areas under the curve of FABP4 of 0.78 (95% CI, 0.75-0.82) and 0.83 (95% CI, 0.79-0.88), which improved the prognostic accuracy of National Institutes of Health Stroke Scale score with combined areas under the curve of 0.83 (95% CI, 0.76-0.89; P<0.01) and 0.86 (95% CI, 0.81-0.92), respectively. CONCLUSIONS: Data show that FABP4 is a novel independent prognostic marker improving the currently used risk stratification of stroke patients.

AGEs induce cell death via oxidative and endoplasmic reticulum stresses in both human SH-SY5Y neuroblastoma cells and rat cortical neurons.

Advanced glycation endproducts (AGEs) are elevated in aging and neurodegenerative diseases such as Alzheimer's disease (AD), and they can stimulate the generation of reactive oxygen species (ROSs) via NADPH oxidase, induce oxidative stress that lead to cell death. In the current study, we investigated the molecular events underlying the process that AGEs induce cell death in SH-SY5Y cells and rat cortical neurons. We found: (1) AGEs increase intracellular ROSs; (2) AGEs cause cell death after ROSs increase; (3) oxidative stress-induced cell death is inhibited via the blockage of AGEs receptor (RAGE), the down-regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and the increase of scavenging by anti-oxidant alpha-lipoic acid (ALA); (4) endoplasmic reticulum (ER) stress was triggered by AGE-induced oxidative stress, resulting in the activation of C/EBP homologous protein (CHOP) and caspase-12 that consequently initiates cell death, taurine-conjugated ursodeoxycholic acid (TUDCA) inhibited AGE-induced ER stress and cell death. Blocking RAGE-NADPH oxidase, and RAGE-NADPH oxidase-ROSs and ER stress scavenging pathways could efficiently prevent the oxidative and ER stresses, and consequently inhibited cell death. Our results suggest a new prevention and or therapeutic approach in AGE-induced cell death.

Dopaminergic neuronal conversion from adult rat skeletal muscle-derived stem cells in vitro.

Muscle-derived stem cells reside in the skeletal muscle tissues and are known for their multipotency to differentiate toward the mesodermal lineage. Recent studies have demonstrated their capacity of neuroectodermal differentiation, including neurons and astrocytes. In this study, we investigated the possibility of dopaminergic neuronal conversion from adult rat skeletal muscle-derived stem cells. Using a neurosphere protocol, muscle-derived stem cells form neurosphere-like cell clusters after cultivation as a suspension, displaying an obvious expression of nestin and a remarkable down-regulation of myogenic associated factors desmin, MyoD, Myf5 and myogenin. Subsequently, these neurosphere-like cell clusters were further directed to dopaminergic differentiation through two major induction steps, patterning to midbrain progenitors with sonic hedgehog and fibroblast growth factor 8, followed by the differentiation to dopaminergic neurons with neurotrophic factors (glial cell line-derived neurotrophic factor) and chemicals (ascorbic acid, forskolin). After the differentiation, these cells expressed tyrosine hydroxylase, dopamine transporter, dopamine D1 receptor and synapse-associated protein synapsin I. Several genes, Nurr1, Lmx1b, and En1, which are critically related with the development of dopaminergic neurons, were also significantly up-regulated. The present results indicate that adult skeletal muscle-derived stem cells could provide a promising cell source for autologous transplantation for neurodegenerative diseases in the future, especially the Parkinson's disease.

Inhibitory effect of fucoidan on nitric oxide production in lipopolysaccharide-activated primary microglia.

1. Microglial activation plays an important role in the pathogenesis of neurodegenerative diseases by producing various pro-inflammatory cytokines. Microglia-derived nitric oxide (NO) is critical for the lipopolysaccharide (LPS)-induced selective loss of dopaminergic neurons. 2. Fucoidan is a sulphated polysaccharide extracted from brown seaweeds. It has a variety of biological actions, including anticoagulant, antiviral and anti-inflammatory effects. The aim of the present study was to investigate the effects of fucoidan on LPS-induced cellular activation in microglia and to evaluate the inhibitory mechanisms involved. 3. To investigate the effects of fucoidan on LPS-induced cellular activation in microglia, primary microglial cells were preincubated with fucoidan (31.25, 62.5 and 125 microg/mL) for 10 min, followed by stimulation with LPS (0.01 microg/mL). Then, cell shape and NO production were determined 24 h after LPS stimulation, whereas inducible nitric oxide synthase (iNOS) mRNA and protein expression were determined at 6 and 18 h after LPS stimulation, respectively. To evaluate the inhibitory mechanisms involved, mitogen-activated protein kinase (MAPK) activation was also evaluated. 4. Lipopolysaccharide transformed cells into an amoeboid shape, whereas 62.5 microg/mL fucoidan inhibited this activation. Moreover, 125 microg/mL fucoidan significantly inhibited microglial NO production to 75% of that in LPS-treated group and also significantly diminished the expression of iNOS mRNA and protein by nearly 50%. Fucoidan (125 microg/mL) also suppressed phosphorylation of p38 and extracellular signal-regulated kinase (ERK) by approximately 50%, but not that of c-Jun N-terminal kinase. 5. The results provide the first evidence that fucoidan has a potent inhibitory effect against LPS-induced NO production by microglia. The results also suggest that this inhibitory action of fucoidan involves suppression of p38 and ERK phosphorylation.

[Fucoidan: advances in the study of its anti-inflammatory and anti-oxidative effects].

Fucoidan is a natural polysaccharide extracted from brown seaweeds, with a wide variety of biological features, especially the anti-inflammatory and anti-oxidative effects. Studies indicated that the anti-inflammatory effect of fucoidan related to its capacity to interact with the selectin or scavenger receptor on the cell membrane. Fucoidan can also inhibit the synthesis and release of reactive oxygen species (ROS), as well as promote its clearance, showing the anti-oxidative activity.

Copeptin and NT-proBNP for prediction of all-cause and cardiovascular death in ischemic stroke.

OBJECTIVE: To evaluate long-term mortality in patients with acute ischemic stroke (AIS) by exploring the correlation between death and plasma concentrations of copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a cohort study. METHODS: In a prospective, multicenter observational study of 4,215 patients with AIS, copeptin and NT-proBNP levels were measured with a standardized method when patients were admitted to hospital. The primary endpoint was all-cause mortality or cardiovascular disease (CVD) mortality within 1 year. RESULTS: During a follow-up period, 906 patients (20.1%, 95% confidence interval [CI] 18.9-21.2) died, including 589 cases of CVD mortality (13.1%, 95% CI 12.1-14.0). With the use of a multivariate analysis, both markers were found to have prognostic value in the same model (CVD mortality: odds ratio [OR] for fourth quartile of copeptin and NT-proBNP 1.68 and 2.58, 95% CI 1.22-2.49 and 1.76-4.05, respectively; all-cause mortality: OR for fourth quartile of copeptin and NT-proBNP 1.48 and 2.47, 95% CI 1.22-2.03 and 1.68-3.95, respectively). In a receiver operating characteristics analysis of CVD mortality, the area under the curve varied from 0.80 to 0.83 (95% CI 0.79-0.87) when the index of NT-proBNP was added and increased to 0.86 (95% CI 0.83-0.90) when both markers were added. CONCLUSIONS: Copeptin and NT-proBNP may be useful independent prognostic markers of all-cause or CVD mortality in Chinese patients with AIS.

Pioglitazone improves cognitive function via increasing insulin sensitivity and strengthening antioxidant defense system in fructose-drinking insulin resistance rats.

Insulin resistance (IR) links Alzheimer's disease (AD) with oxidative damage, cholinergic deficit, and cognitive impairment. Peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone previously used to treat type 2 diabetes mellitus (T2DM) has also been demonstrated to be effective in anti-inflammatory reaction and anti-oxidative stress in the animal models of AD and other neuroinflammatory diseases. Here, we investigated the effect of pioglitazone on learning and memory impairment and the molecular events that may cause it in fructose-drinking insulin resistance rats. We found that long-term fructose-drinking causes insulin resistance, oxidative stress, down-regulated activity of cholinergic system, and cognitive deficit, which could be ameliorated by pioglitazone administration. The results from the present study provide experimental evidence for using pioglitazone in the treatment of brain damage caused by insulin resistance.