Jin Young Shin

Increased arterial stiffness in healthy subjects with high-normal glucose levels and in subjects with pre-diabetes

BackgroundIncreased fasting plasma glucose (FPG), which includes impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes, is a risk factor for arterial stiffness. While IFG is widely accepted as a cardiovascular risk factor, recent studies have argued that subjects with high-normal glucose level were characterized by a high incidence of cardiovascular disease. The purpose of this study is to investigate the relationship between FPG and arterial stiffness in non-diabetic healthy subjects.MethodsWe recruited 697 subjects who visited the health promotion center of a university hospital from May 2007 to August 2008. Age, sex, body mass index (BMI), resting heart rate, smoking habits, alcohol intake, exercise, blood pressure, medical history, FPG, lipid profile, high sensitivity C-reactive protein (hs-CRP), and Brachial-ankle pulse wave velocity (ba-PWV) were measured. We performed correlation and multiple linear regression analyses to divide the research subjects into quartiles: Q1(n = 172), 65 mg/dL ≤FPG < 84 mg/dL; Q2(n = 188), 84 mg/dL ≤FPG < 91 mg/dl; Q3(n = 199), 91 mg/dL ≤FPG < 100 mg/dL; Q4(n = 138), 100 mg/dL ≤FPG < 126 mg/dL.ResultsFPG has an independent, positive association with ba-PWV in non-diabetic subjects after correcting for confounding variables, including age, sex, BMI, blood pressure, resting heart rate, hs-CRP, lipid profile, and behavioral habits. The mean ba-PWV of the high-normal glucose group (Q3, 1384 cm/s) was higher than that of the low-normal glucose group (1303 ± 196 cm/s vs.1328 ± 167 cm/s, P < 0.05). The mean ba-PWV value in the IFG group (1469 ± 220 cm/s) was higher than that in the normoglycemic group (P < 0.05, respectively).ConclusionsAn increase in FPG, even within the normal range, was associated with aggravated arterial stiffness. Further research is needed to determine the glycemic target value for the prevention of arterial stiffness in clinical and public health settings.

Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models

Current evidence suggests a central role for autophagy in Alzheimer disease (AD), and dysfunction in the autophagic system may lead to amyloid-β (Aβ) accumulation. Using in vitro and in vivo AD models, the present study investigated whether mesenchymal stem cells (MSCs) could enhance autophagy and thus exert a neuroprotective effect through modulation of Aβ clearance In Aβ-treated neuronal cells, MSCs increased cellular viability and enhanced LC3-II expression compared with cells treated with Aβ only. Immunofluorescence revealed that MSC coculture in Aβ-treated neuronal cells increased the number of LC3-II-positive autophagosomes that were colocalized with a lysosomal marker. Ultrastructural analysis revealed that most autophagic vacuoles (AVs) in Aβ-treated cells were not fused with lysosomes, whereas a large portion of autophagosomes were conjoined with lysosomes in MSCs cocultured with Aβ-treated neuronal cells. Furthermore, MSC coculture markedly increased Aβ immunoreactivity colocalized within lysosomes and decreased intracellular Aβ levels compared with Aβ-treated cells. In Aβ-treated animals, MSC administration significantly increased autophagosome induction, final maturation of late AVs, and fusion with lysosomes. Moreover, MSC administration significantly reduced the level of Aβ in the hippocampus, which was elevated in Aβ-treated mice, concomitant with increased survival of hippocampal neurons. Finally, MSC coculture upregulated BECN1/Beclin 1 expression in AD models. These results suggest that MSCs significantly enhance autolysosome formation and clearance of Aβ in AD models, which may lead to increased neuronal survival against Aβ toxicity. Modulation of the autophagy pathway to repair the damaged AD brain using MSCs would have a significant impact on future strategies for AD treatment.

Mesenchymal stem cells augment neurogenesis in the subventricular zone and enhance differentiation of neural precursor cells into dopaminergic neurons in the substantia nigra of a parkinsonian model.

Growing evidence has demonstrated that neurogenesis in the subventricular zone (SVZ) is significantly decreased in Parkinsons disease (PD). Modulation of endogenous neurogenesis would have a significant impact on future therapeutic strategies for neurodegenerative diseases. In the present study, we investigated the augmentative effects of human mesenchymal stem cells (hMSCs) on neurogenesis in a PD model. Neurogenesis was assessed in vitro with 1-methyl-4-phenylpyridinium (MPP+) treatment using neural precursor cells (NPCs) isolated from the SVZ and in vivo with a BrdU-injected animal model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunochemical analyses were used to measure neurogenic activity. The number of BrdU-ir cells in the SVZ and the substantia nigra (SN) was significantly increased in the hMSC-treated PD group compared with the MPTP-only-treated group. Double-stained cells for BrdU and tyrosine hydroxylase were notably observed in the SN of hMSC-treated PD animals, and they did not colocalize with the nuclear matrix; however, double-stained cells were not detected in the SN of the MPTP-induced PD animal model. Furthermore, hMSC administration increased the expression of the epidermal growth factor receptor (EGFR) in the SVZ of PD animals, and the coculture of hMSCs significantly increased the release of EGF in the medium of MPP+-treated NPCs. The present study demonstrated that hMSC administration significantly augmented neurogenesis in both the SVZ and SN of PD animal models, which led to increased differentiation of NPCs into dopaminergic neurons in the SN. Additionally, hMSC-induced modulation of EGF seems to be an underlying contributor to the enhancement of neurogenesis by hMSCs. The modulation of endogenous adult neurogenesis to repair the damaged PD brain using hMSCs would have a significant impact on future strategies for PD treatment.

Neuroprotective effects of mesenchymal stem cells through autophagy modulation in a parkinsonian model

Autophagy is a major degradation pathway for abnormal aggregated proteins and organelles that cause various neurodegenerative diseases. Current evidence suggests a central role for autophagy in pathogenesis of Parkinsons disease, and that dysfunction in the autophagic system may lead to α-synuclein accumulation. In the present study, we investigated whether mesenchymal stem cells (MSCs) would enhance autophagy and thus exert a neuroprotective effect through the modulation of α-synuclein in parkinsonian models. In MPP(+)-treated neuronal cells, coculture with MSCs increased cellular viability, attenuated expression of α-synuclein, and enhanced the number of LC3-II-positive autophagosomes compared with cells treated with MPP(+) only. In an MPTP-treated animal model of Parkinsons disease, MSC administration significantly increased final maturation of late autophagic vacuoles, fusion with lysosomes. Moreover, MSC administration significantly reduced the level of α-synuclein in dopaminergic neurons, which was elevated in MPTP-treated mice. These results suggest that MSC treatment significantly enhances autophagolysosome formation and may modulate α-synuclein expression in parkinsonian models, which may lead to increased neuronal survival in the presence of neurotoxins.

Low vitamin D levels increase anemia risk in Korean women

BACKGROUNDnWe assessed the impact of vitamin D on hemoglobin levels in Korean adults, considering gender and menopausal status.nnnMETHODSnWe analyzed 2528 men and 3258 women divided into quartiles of vitamin D from the Fifth Korean National Health and Nutrition Examination Survey 2010. Anemia was defined as a hemoglobin level of <13 g/dl in men and <12 g/dl in women.nnnRESULTSnPre- and post-menopausal women in the lowest 25-hydroxyvitamin D group were at an increased risk of anemia, after adjusting for confounding factors (OR (95% CI); Premenopausal: Q1 (≥18.45 ng/ml), 1; Q2 (14.69-18.44 ng/ml), 1.120 (0.745, 1.683); Q3 (11.93-14.68 ng/ml), 1.427 (0.963, 2.116); and Q4 (≤11.92 ng/ml), 1.821 (1.240, 2.673); P=0.009; and Post: Q1 (≥22.04 ng/ml), 1; Q2 (16.92-22.03 ng/ml), 1.106 (0.697, 1.756); Q3 (13.37-16.91 ng/ml), 1.167 (0.740, 1.839); and Q4 (≤13.36 ng/ml), 1.583 (1.026, 2.447); P=0.038). In addition, pre- and post-menopausal women in the lower 25-hydroxyvitamin D group were at a higher risk of iron deficient anemia and anemia of inflammation. However, post-menopausal women did not show a higher risk of anemia with CKD (P=0.470). Men with the lowest 25-hydroxyvitamin D levels did not show a higher risk of anemia (P=0.528).nnnCONCLUSIONSnVitamin D-deficient Korean women had a higher risk of anemia.

Significance of high-normal serum uric acid level as a risk factor for arterial stiffness in healthy Korean men

A high serum uric acid (SUA) level is a known risk factor for cardiovascular disease. However, little is known about the relationship between arterial stiffness and uric acid in healthy subjects with a normal SUA level. We assessed whether a high-normal uric acid level increased arterial stiffness by measuring brachial–ankle pulse wave velocity (ba-PWV) in healthy subjects. Among 779 subjects who visited the health promotion center, 393 men and 234 women with normal SUA levels (male: 3.5–8.0 mg/dl, female: 2.5–5.4 mg/dl) were divided into quartiles: in men, Q1 (n = 90, 3.5–4.3 mg/dl), Q2 (n = 94, 4.4–5.1 mg/dl), Q3 (n = 106, 5.2–5.9 mg/dl) and Q4 (n = 103, 6.0–8.0 mg/dl); in women, Q1 (n = 57, 2.5–3.6 mg/dl), Q2 (n = 49, 3.7–4.1 mg/dl), Q3 (n = 61, 4.2–4.6 mg/dl) and Q4 (n = 67, 4.7–5.4 mg/dl). The mean values of ba-PWV increased gradually by SUA quartile. The men’s SUA had an independent, positive association with ba-PWV after correcting for age, glucose, body mass index, blood pressure, resting heart rate, high-sensitivity C-reactive protein (hs-CRP), high-density lipoprotein (HDL)-cholesterol and triglyceride (R2 = 0.39, adjusted R2 = 0.37, p < 0.001). The odds ratios (95% CI) for high ba-PWVs (> 75th percentile, 1473 cm/s) in men were 1.89 (0.69–5.20, Q2), 2.36 (1.10–5.08, Q3), and 2.91 (1.39–6.11, Q4), after adjusting for confounding factors (p < 0.001). In women, SUA showed no independent association with ba-PWV (p = 0.186). After adjusting for confounding factors, the mean ba-PWV values of Q3 (1418 cm/s) and Q4 (1421 cm/s) in men were higher than those of Q1 (1355 cm/s) (p < 0.05). Above the SUA level of 5.2 mg/dl, arterial stiffness was increased in healthy Korean men.

Mesenchymal Stem Cells Inhibit Transmission of α-Synuclein by Modulating Clathrin-Mediated Endocytosis in a Parkinsonian Model

Ample evidence suggests that α-synuclein is released from cells and propagated from one area of the brain to others via cell-to-cell transmission. In terms of their prion-like behavior, α-synuclein propagation plays key roles in the pathogenesis and progression of α-synucleinopathies. Using α-synuclein-enriched models, we show that mesenchymal stem cells (MSCs) inhibited α-synuclein transmission by blocking the clathrin-mediated endocytosis of extracellular α-synuclein via modulation of the interaction with N-methyl-D-aspartate receptors, which led to a prosurvival effect on cortical and dopaminergic neurons with functional improvement of motor deficits in α-synuclein-enriched models. Furthermore, we identify that galectin-1, a soluble factor derived from MSCs, played an important role in the transmission control of aggregated α-synuclein in these models. The present data indicated that MSCs exert neuroprotective properties through inhibition of extracellular α-synuclein transmission, suggesting that the property of MSCs may act as a disease-modifying therapy in subjects with α-synucleinopathies.

Mesenchymal stem cells stabilize the blood–brain barrier through regulation of astrocytes

IntroductionThe blood–brain barrier (BBB) protects the brain against potentially neurotoxic molecules in the circulation, and loss of its integrity may contribute to disease progression in neurodegenerative conditions. Recently, the active role of reactive astrocytes in BBB disruption has become evident in the inflamed brain. In the present study, we investigated whether mesenchymal stem cell (MSC) treatment might modulate reactive astrocytes and thus stabilize BBB integrity through vascular endothelial growth factor A (VEGF-A) signaling in inflammatory conditions.MethodsFor the inflamed brain, we injected LPS using a stereotaxic apparatus and MSCs were injected into the tail vein. At 6xa0hours and 7xa0days after LPS injection, we analyzed modulatory effects of MSCs on the change of BBB permeability through VEGF-A signaling using immunochemistry and western blot. To determine the effects of MSCs on VEGF-A-related signaling in cellular system, we had used endothelial cells treated with VEGF-A and co-cultured astrocyte and BV 2 cells treated with lipopolysaccharide (LPS) and then these cells were co-cultured with MSCs.ResultsIn LPS-treated rats, MSCs restored Evans blue infiltration and the number of endothelial-barrier antigen (EBA) and P-glycoprotein (p-gp)-expressing cells, which were significantly altered in LPS-treated animals. Additionally, MSC administration following LPS treatment markedly increased the density of astrocytic filaments around vessels and reversed LPS-induced elevations in VEGF-A levels as well as endothelial nitric oxide synthase (eNOS)-dependent downregulation of tight junction proteins in the endothelium. Consequently, MSC treatment reduced neutrophil infiltration and enhanced survival of midbrain dopaminergic neurons in LPS-treated animals. In cellular system, MSC treatment led to a significant reversion of VEGF-A-induced eNOS and tight junction protein expression in endothelial cells, which led to increased EBA expressing cells. Additionally, MSC treatment significantly attenuated LPS-induced increased expressions of IL-1β in microglia and VEGF-A in astrocytes with an increase in IL-10 levels.ConclusionThe present study indicated that MSCs may stabilize BBB permeability by modulating astrocytic endfeet and VEGF-A signaling, which may be relevant to the treatment of Parkinsonian diseases as a candidate for disease modifying therapeutics.

Elevated homocysteine by levodopa is detrimental to neurogenesis in parkinsonian model.

Background Modulation of neurogenesis that acts as an endogenous repair mechanism would have a significant impact on future therapeutic strategies for Parkinson’s disease (PD). Several studies demonstrated dopaminergic modulation of neurogenesis in the subventricular zone (SVZ) of the adult brain. Levodopa, the gold standard therapy for PD, causes an increase in homocysteine levels that induces neuronal death via N-methyl-D-aspartate (NMDA) receptor. The present study investigated whether elevated homocysteine by levodopa treatment in a parkinsonian model would modulate neurogenesis via NMDA receptor signal cascade and compared the effect of levodopa and pramipexol (PPX) on neurogenic activity. Methodology/Principal Findings Neurogenesis was assessed in vitro using neural progenitor cells (NPCs) isolated from the SVZ and in vivo with the BrdU-injected animal model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Modulation of homocysteine levels was evaluated using co-cultures of NPCs and astrocytes and PD animals. Immunochemical and Western blot analyses were used to measure neurogenesis and determine the cell death signaling. Levodopa treatment increased release of homocysteine on astrocytes culture media as well as in plasma and brain of PD animals. Increased homocysteine by levodopa led to increased apoptosis of NPCs through the NMDA receptor-dependent the extracellular signal-regulated kinase (ERK) signaling pathways. The administration of a NMDA antagonist significantly attenuated apoptotic cell death in levodopa-treated NPCs and markedly increased the number of BrdU-positive cells in the SVZ of levodopa-treated PD animals. Comparative analysis revealed that PPX treatment significantly increased the number of NPCs and BrdU-positive cells in the SVZ of PD animals compared to levodopa treatment. Our present study demonstrated that increased homocysteine by levodopa has a detrimental effect on neurogenesis through NMDA receptor-mediated ERK signaling pathway. Conclusions/Significance Modulation of levodopa-induced elevated homocysteine by NMDA antagonist or dopamine agonist has a clinical relevance for PD treatment in terms of adult neurogenesis.

Serum carcinoembryonic antigen level is associated with arterial stiffness in healthy Korean adult

BACKGROUNDnCarcinoembryonic antigen (CEA), a widely used tumor marker, has been reported to be related with atherosclerosis and cardiovascular disease. However, little is known about the relationship between arterial stiffness and CEA level. We assessed whether serum CEA level is related with arterial stiffness by measuring brachial-ankle pulse wave velocity (ba-PWV) in healthy subjects.nnnMETHODSnSerum CEA level, ba-PWV and conventional risk factors were measured in 2909 subjects (1767 men and 1142 women) who underwent routine health checkup. We performed correlation, multiple linear regression and multiple logistic regression analyses to divide into quartiles according to CEA level.nnnRESULTSnThe mean values of ba-PWV increased gradually by CEA quartile. After correcting for significantly correlated variables, the ba-PWV was independently associated with CEA (P<0.001). The odds ratios (95% CI) for high ba-PWV (>75th percentile; men: 1518 cm/s, women: 1487 cm/s) according to CEA quartile were 1.00 (Q1), 1.044 (0.659-1.652; Q2), 1.075 (0.688-1.681; Q3), and 1.595 (1.009-2.520; Q4) after adjusting for age, blood pressure, BMI, fasting glucose, heart rate, log hs-CRP, LDL-cholesterol, WBC count, alcohol intake, smoking and exercise in men (P<0.001). The odds ratios (95% CIs) in women were 1.00 (Q1), 1.719 (0.971-3.032; Q2), 1.793 (1.019-3.156; Q3), and 2.330 (1.312-4.139; Q4) (P<0.001) after adjusting for age, blood pressure, BMI, fasting glucose, heart rate, log hs-CRP, lipid profile, uric acid, WBC count, alcohol intake, smoking and exercise.nnnCONCLUSIONSnThe CEA level is associated with arterial stiffness which measured by ba-PWV in healthy Korean men and women.