A selective ER-phagy exerts neuroprotective effects via modulation of α-synuclein clearance in parkinsonian models.

The endoplasmic reticulum (ER) is selectively degraded by ER-phagy to maintain cell homeostasis. α-synuclein accumulates in the ER, causing ER stress that contributes to neurodegeneration in Parkinson's disease (PD), but the role of ER-phagy in α-synuclein modulation is largely unknown. Here, we investigated the mechanisms by which ER-phagy selectively recognizes α-synuclein for degradation in the ER. We found that ER-phagy played an important role in the degradation of α-synuclein and recovery of ER function through interaction with FAM134B, where calnexin is required for the selective FAM134B-mediated α-synuclein clearance via ER-phagy. Overexpression of α-synuclein in the ER of the substantia nigra (SN) resulted in marked loss of dopaminergic neurons and motor deficits, mimicking PD characteristics. However, enhancement of ER-phagy using FAM134B overexpression in the SN exerted neuroprotective effects on dopaminergic neurons and recovered motor performance. These data suggest that ER-phagy represents a specific ER clearance mechanism for the degradation of α-synuclein.

Energy Transfer Between i-Motif DNA Encapsulated Silver Nanoclusters and Fluorescein Amidite Efficiently Visualizes the Redox State of Live Cells.

The redox regulation, maintaining a balance between oxidation and reduction in living cells, is vital for cellular homeostasis, intricate signaling networks, and appropriate responses to physiological and environmental cues. Here, a novel redox sensor, based on DNA-encapsulated silver nanoclusters (DNA/AgNCs) and well-defined chemical fluorophores, effectively illustrating cellular redox states in live cells is introduced. Among various i-motif DNAs, the photophysical property of poly-cytosines (C20)-encapsulated AgNCs that sense reactive oxygen species (ROS) is adopted. However, the sensitivity of C20/AgNCs is insufficient for evaluating ROS levels in live cells. To overcome this drawback, the ROS sensing mechanism of C20/AgNCs through gel electrophoresis, mass spectrometry, and small-angle X-ray scattering is primarily defined. Then, by tethering fluorescein amidite (FAM) and Cyanine 5 (Cy5) dyes to each end of the C20/AgNCs sensor, an Energy Transfer (ET) between AgNCs and FAM is achieved, resulting in intensified green fluorescence upon ROS detection. Taken together, the FAM-C20/AgNCs-Cy5 redox sensor enables dynamic visualization of intracellular redox states, yielding insights into oxidative stress-related processes in live cells.

Mesenchymal Stem Cells Stabilize Axonal Transports for Autophagic Clearance of α-Synuclein in Parkinsonian Models.

Genome-wide association studies have identified two loci, SNCA and the microtubule (MT)-associated protein tau, as common risk factors for Parkinson's disease (PD). Specifically, α-synuclein directly destabilizes MT via tau phosphorylation and induces axonal transport deficits that are the primary events leading to an abnormal accumulation of α-synuclein that causes nigral dopaminergic cell loss. In this study, we demonstrated that mesenchymal stem cells (MSCs) could modulate cytoskeletal networks and trafficking to exert neuroprotective properties in wild-type or A53T α-synuclein overexpressing cells and mice. Moreover, we found that eukaryotic elongation factor 1A-2, a soluble factor derived from MSCs, stabilized MT assembly by decreasing calcium/calmodulin-dependent tau phosphorylation and induced autophagolysosome fusion, which was accompanied by an increase in the axonal motor proteins and increased neuronal survival. Our data suggest that MSCs have beneficial effects on axonal transports via MT stability by controlling α-synuclein-induced tau phosphorylation, indicating that MSCs may exert a protective role in the early stages of axonal transport defects in α-synucleinopathies. Stem Cells 2017;35:1934-1947.

Thiopurine Prodrugs Mediate Immunosuppressive Effects by Interfering with Rac1 Protein Function.

6-Thiopurine (6-TP) prodrugs include 6-thioguanine and azathioprine. Both are widely used to treat autoimmune disorders and certain cancers. This study showed that a 6-thioguanosine triphosphate (6-TGTP), converted in T-cells from 6-TP, targets Rac1 to form a disulfide adduct between 6-TGTP and the redox-sensitive GXXXXGK(S/T)C motif of Rac1. This study also showed that, despite the conservation of the catalytic activity of RhoGAP (Rho-specific GAP) on the 6-TGTP-Rac1 adduct to produce the biologically inactive 6-thioguanosine diphosphate (6-TGDP)-Rac1 adduct, RhoGEF (Rho-specific GEF) cannot exchange the 6-TGDP adducted on Rac1 with free guanine nucleotide. The biologically inactive 6-TGDP-Rac1 adduct accumulates in cells because of the ongoing combined actions of RhoGEF and RhoGAP. Because other Rho GTPases, such as RhoA and Cdc42, also possess the GXXXXGK(S/T)C motif, the proposed mechanism for the inactivation of Rac1 also applies to RhoA and Cdc42. However, previous studies have shown that CD3/CD28-stimulated T-cells contain more activated Rac1 than other Rho GTPases such as RhoA and Cdc42. Accordingly, Rac1 is the main target of 6-TP in activated T-cells. This explains the T-cell-specific Rac1-targeting therapeutic action of 6-TP that suppresses the immune response. This proposed mechanism for the action of 6-TP on Rac1 performs a critical role in demonstrating the capability to design a Rac1-targeting chemotherapeutic agent(s) for autoimmune disorders. Nevertheless, the results also suggest that the targeting action of other Rho GTPases in other organ cells, such as RhoA in vascular cells, may be linked to cytotoxicities because RhoA plays a key role in vasculature functions.

Antioxidant and Hepatoprotective Effects of Procyanidins from Wild Grape (Vitis amurensis) Seeds in Ethanol-Induced Cells and Rats.

In the present study, we characterized the antioxidant and hepatoprotective mechanisms underlying of wild grape seed procyanidins (WGP) against oxidative stress damage in ethanol-treated HepG2 cell and Sprague-Dawley (SD)-rat models. In HepG2 cells, WGP not only diminished the ethanol (EtOH, 100 mM)-induced reactive oxygen species (ROS) formation and cytochrome P450 2E1 (CYP2E1) expression, but also renovated both the activity and expression of antioxidant enzymes including catalase, superoxide dismutase, and glutathione peroxidase. Additionally, to investigate the hepatoprotective effect of WGP, rats were orally administered 10 or 50 mg/kg WGP once daily for seven days prior to the single oral administration of EtOH (6 g/kg). The results show that WGP administration decreased the EtOH-induced augment of the levels of serum aspartate transaminase and alanine transaminase as well as serum alcohol and acetaldehyde. WGP treatment upregulated the activities and protein levels of hepatic alcohol dehydrogenase, aldehyde dehydrogenase, and antioxidant enzymes but downregulated the protein expression level of liver CYP2E1 in EtOH-treated rats. Moreover, the decreased phosphorylation levels of mitogen activated protein kinases (MAPKs) by ethanol were induced in both HepG2 cell and rat models. Overall, pretreatment of WGP displayed the protective activity against EtOH-mediated toxicity through the regulation of antioxidant enzymes and alcohol metabolism systems via MAPKs pathways.

Analysis of Insecticides in Dead Wild Birds in Korea from 2010 to 2013.

Wild birds are exposed to insecticides in a variety of ways, at different dose levels and via multiple routes, including ingestion of contaminated food items, and dermal, inhalation, preening, and embryonic exposure. Most poisoning by insecticides occurs as a result of misuse or accidental exposure, but intentional killing of unwanted animals also occurs. In this study, we investigated insecticides in the gastric contents of dead wild birds that were suspected to have died from insecticide poisoning based on necropsy. The wild birds were found dead in various regions and locations such as in mountains, and agricultural and urban areas. A total of 182 dead wild birds of 27 species were analyzed in this study, and insecticide residue levels were determined in 60.4% of the total samples analyzed. Monocrotophos and phosphamidon were the most common insecticides identified at rates of 50.0% and 30.7% of the insecticide-positive samples, respectively. Other insecticides identified in dead wild birds included organophosphorous, organochlorine and carbamate insecticides. However, there was limited evidence to conclusively establish the cause of death related to insecticides in this study. Nevertheless, considering the level of insecticide exposure, it is speculated that the exposure was mainly a result of accidental or intentional killing, and not from environmental residue.

Metabolic Syndrome in Korean Cancer Survivors and Family Members: A Study in a Health Promotion Center.

This cross-sectional study evaluated the risk of metabolic syndrome (MetS) in cancer survivors and family members. Subjects were 48,934 adults (24,786 men, 24,148 women) aged ≥40yr who receive a routine health examination at 1 hospital from January 2010 to December 2012. There were 2468 cancer survivors, 18,211 with cancer patients in the family, and 28,255 noncancer subjects, who never experienced cancer and whose family members either. Associations between MetS and cancer experience were assessed using multiple logistic regression analysis. The odds ratio (OR) of MetS in female cancer survivors was significantly higher than noncancer subjects after adjusting for age, smoking, physical activity, and alcohol intake (OR = 1.22, 95% confidence intervals: 1.02-1.47]. However, the OR of MetS for male survivors did not differ from that of noncancer subjects. Gastric cancer survivors had a lower OR of MetS than noncancer subjects (0.37, 0.27-0.50). ORs of breast cancer (1.49, 1.00-2.23) and prostate cancer survivors (1.46, 1.07-1.99) were higher than the OR of MetS for noncancer subjects. There was no difference in the OR of MetS between the family members of cancer patients and non-cancer subjects. These findings suggest that the odds of MetS for cancer survivors may differ by cancer type and by sex.

Smokers With Adequate Vitamin C Intake Show a Preferable Pulmonary Function Test.

OBJECTIVE: Airflow obstruction often results from the chronic inflammation caused by cigarette smoke. It has been concluded that cigarette smoke-induced oxidative damage is prevented by ascorbic acid on a cellular level. The purpose of the current study was to explore the effect of vitamin C intake on pulmonary function in established smokers (100 or more cigarettes) and never-smokers in a Korean population. METHODS: The 2974 enrolled men and women over the age of 40 in the Korea National Health and Nutrition Examination Survey IV 2008 were divided into 4 groups based on smoking patterns (never-smoker vs established smoker) and vitamin C intake from dietary assessment (higher vs lower; median value: 77.18 mg/day). RESULTS: Univariate analysis showed associations between forced expiratory volume in 1 second (FEV1), FEV/forced vital capacity (FVC) and age, gender, body mass index (BMI), pack-years, vitamin C intake, and additional micronutrient intake. On multiple logistic regression analysis, the odds ratios (95% confidence interval) for FEV1 < 80% predicted were 1.000 (never-smokers, higher vitamin C intake), 1.067 (0.823, 1.383; never-smokers, lower vitamin C intake), 1.224 (0.871, 1.721; established smokers, higher vitamin C intake), and 1.479 (1.057, 2.072; established smokers, lower vitamin C intake). The odds ratios for FEV1/FVC < 0.70 were 1.177 (0.821, 1.687; never-smokers, lower vitamin C intake), 1.637 (1.094, 2.445; established smokers, higher vitamin C intake), and 2.093 (1.403, 3.122; established smokers, lower vitamin C intake) after adjusting for confounding factors (p < 0.001). CONCLUSIONS: Korean smokers with adequate vitamin C intake showed a preferable pulmonary function test.

Factors That Predict Persistent Smoking of Cancer Survivors.

We conducted this cross-sectional study to elucidate factors that predict persistent smoking of the Korean cancer survivors. The subjects were 130 adult (≥19 yr old) cancer survivors who were smokers at the diagnosis of cancer and have participated in the Korean National Health and Nutrition Examination Surveys conducted from 2007 to 2011. We categorized them into the persistent smokers and the quitters, according to change in smoking status between the time of cancer diagnosis and the time of the survey. Factors associated with persistent smoking were evaluated using the multiple logistic regression analysis. During 7.52 yr (standard deviation = 0.34) after the cancer diagnosis, 59.6% of the 130 cancer survivors have continued to smoke. After adjusting for covariates, following factors were independently associated with the risk of persistent smoking: female, low income, high-risk alcohol use, high body mass index (≥ 25 kg/m(2)), presence of household members who smoke, and longer duration of smoking. Alcohol Use Disorders Identification Test showed a positive association with the risk of persistent smoking (P for trend = 0.012). In conclusion, more efforts for smoking cessation should be in place for the cancer survivors with those risk factors associated with the persistent smoking.

Effect of fruits and vegetables on metabolic syndrome: a systematic review and meta-analysis of randomized controlled trials.

Evidence regarding the effect of fruit and vegetable consumption on metabolic syndrome remains inconclusive. Using MEDLINE, EMBASE, and Cochrane, we searched for relevant studies published before 10 December 2013. Of the 383 articles identified, eight randomized controlled trials with 396 participants (205 in intervention groups and 191 in control groups) were included in the final analyses. Fruit and vegetable intake was associated with a reduction in diastolic blood pressure (standardized mean difference: -0.29; 95% confidence interval: -0.57 to -0.02; p = 0.04); however, such intake did not affect waist circumference, systolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, and triglyceride levels in metabolic syndrome patients. In a subgroup analysis, there were no statistically significant differences found according to the intervention period and provision type. Our results suggest an inverse association between fruit and vegetable consumption and diastolic blood pressure in metabolic syndrome patients.

Characterization of concentration, particle size distribution, and contributing factors to ambient hexavalent chromium in an area with multiple emission sources.

Airborne hexavalent chromium (Cr(VI)) is a known pulmonary carcinogen and can be emitted from both natural and anthropogenic sources, including diesel emissions. However, there is limited knowledge about ambient Cr(VI) concentration levels and its particle size distribution. This pilot study characterized ambient Cr(VI) concentrations in the New Jersey Meadowlands (NJ ML) district, which is close to the heavily trafficked New Jersey Turnpike (NJTPK) as well as Chromium Ore Processing Residue (COPR) waste sites. Monitoring was simultaneously conducted at two sites, William site (~50 m from NJTPK) and MERI site (~700 m from NJTPK). The distance between the two sites is approximately 6.2 km. Ambient Cr(VI) concentrations and PM2.5 mass concentrations were concurrently measured at both sites during summer and winter. The summer concentrations (mean ± S.D. [median]), 0.13 ± 0.06 [0.12] ng/m3 at the MERI site and 0.08 ± 0.05 [0.07] ng/m3 at the William site, were all significantly higher than the winter concentrations, 0.02 ± 0.01 [0.02] ng/m3 and 0.03 ± 0.01 [0.03] ng/m3 at the MERI and William sites, respectively. The site difference (i.e., MERI > William) was observed for summer Cr(VI) concentrations; however, no differences for winter and pooled datasets. These results suggest higher Cr(VI) concentrations may be attributed from stronger atmospheric reactions such as photo-oxidation of Cr(III) to Cr(VI) in the summer. The Cr(VI) distribution as a function of particle size, ranging from 0.18 to 18 µm, was determined at the William site. It was found that Cr(VI) was enriched in the particles less than 2.5 µm in diameter (PM2.5). This finding suggested potential health concerns, because PM2.5 are easily inhaled and deposited in the alveoli. A multiple linear regression analysis confirmed ambient Cr(VI) concentrations were significantly affected by meteorological factors (i.e., temperature and humidity) and reactive gases/particles (i.e., O3, Fe and Mn).

Trivalent chromium solubility and its influence on quantification of hexavalent chromium in ambient particulate matter using EPA method 6800.

Measurement of carcinogenic Cr(VI) in ambient PM is challenging due to potential errors associated with conversion between Cr (VI) (a carcinogen) and Cr(III) (an essential nutrient). Cr(III) conversion is a particular concern due to its > 80% atomic abundance in total Cr. US. Environmental Protection Agency (EPA) method 6800 that uses water-soluble isotope spikes can be used to correct the interconversion. However, whether the enriched Cr(III) isotope spikes can adequately mimic the Cr(III) species originally in ambient PM is unknown. This study examined the water solubility of Cr(III) in ambient PM and discussed its influence on Cr(VI) measurement. Ambient PM10 samples were collected on Teflon filters at four sites in New Jersey that may have different Cr emission sources. The samples were ultrasonically extracted with 5 mL DI-H2O (pH 5.7) at room temperature for 40 min, and then analyzed by ion chromatography-inductively coupled plasma mass spectrometry (IC-ICPMS). Cr(III) was below detection limit (0.06 ng/m3) for all samples, suggesting water-soluble Cr(III) species, such as CrCl3, Cr(NO3)3, and amorphous Cr(OH)3, in the ambient PM were negligible. Therefore, the enriched 50Cr(III) isotope spike (in the form of Cr(NO3)3) could not mimic the original ambient Cr(III). Only the conversion of 53Cr(VI) (in the form of K2CrO4) was taken into account when correcting the interconversion. We then used NaHCO3-pretreated MCE filters (prespiked with enriched isotope species) to measure Cr(VI) in the ambient PM10. The samples were ultrasonically extracted at 60 C pH 9 solutions for 40 min followed by IC-ICPMS analysis. Due to the correction of Cr(VI) reduction, the Cr(VI) concentrations determined by EPA method 6800, 0.26 ± 0.16 (summer) and 0.16 ± 0.11(winter) ng/m3 (n = 64), were significantly greater than those by the external standard curve, 0.21 ± 0.17 (summer) and 0.10 ± 0.07 (winter) ng/m3 (n = 56) (p < 0.01, Student's t-test). Our study revealed that appropriate application of EPA method 6800 is important because it only applies to soluble fraction of Cr species in ambient PM. Implications: Accurate measurement of carcinogenic Cr(VI) in ambient PM is challenging due to conversion between Cr(VI) (a human carcinogen) and Cr(III) (a human essential nutrient). The conversion of CR(III) is of particular concern due to its dominant presence in total Cr (>80%). This study examined the water solubility of Cr(III) in ambient PM that was collected at four locations in New Jersey. Then we discussed the influence of Cr(III) solubility on the application of EPA method 6800, which utilizes enriched isotope spikes to correct the interconversion. Our results suggested that appropriate application of EPA method 6800 is important because it only applies to soluble fraction of Cr species.

Maternal childhood trauma, caregiving behavior, and child cognitive development in the context of drug addiction.

Exposure to childhood trauma confers intergenerational risk on child development. However, the mechanism linking a mother's childhood trauma with her child's cognitive development remains poorly understood. This study recruited 71 mother-child dyads affected by substance use disorder from local, community-based, outpatient substance use treatment programs. Maternal exposure to childhood trauma, caregiving behavior, and child cognitive development were assessed in each mother-child dyad. These were measured through a comprehensive biopsychosocial interview, an observed dyadic interaction coded using the Coding Interactive Behavior system, and the Bayley Scales of Infant and Toddler Development, Screening Test, respectively. We hypothesized that compromised caregiving behavior would mediate a negative relationship between maternal childhood trauma and child cognitive development. Analyses did not support this hypothesis. Specifically, maternal childhood trauma was not significantly associated with child cognitive development nor the four dimensions of maternal caregiving behavior. However, caregiving behavior (specifically maternal sensitivity and limit setting) was associated with child cognitive development, when controlling for maternal childhood trauma and child age. The lack of associations observed suggests that protective factors may buffer the intergenerational impact of childhood trauma. Furthermore, the relationship between quality of caregiving and child cognitive development highlights the importance of interventions which foster sensitive caregiving behaviors that may bolster child cognitive development in the context of maternal substance use disorder and maternal childhood trauma. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Uric acid regulates α-synuclein transmission in Parkinsonian models.

Ample evidence demonstrates that α-synuclein (α-syn) has a critical role in the pathogenesis of Parkinson's disease (PD) with evidence indicating that its propagation from one area of the brain to others may be the primary mechanism for disease progression. Uric acid (UA), a natural antioxidant, has been proposed as a potential disease modifying candidate in PD. In the present study, we investigated whether UA treatment modulates cell-to-cell transmission of extracellular α-syn and protects dopaminergic neurons in the α-syn-enriched model. In a cellular model, UA treatment decreased internalized cytosolic α-syn levels and neuron-to-neuron transmission of α-syn in donor-acceptor cell models by modulating dynamin-mediated and clathrin-mediated endocytosis. Moreover, UA elevation in α-syn-inoculated mice inhibited propagation of extracellular α-syn which decreased expression of phosphorylated α-syn in the dopaminergic neurons of the substantia nigra leading to their increased survival. UA treatment did not lead to change in markers related with autophagolysosomal and microglial activity under the same experimental conditions. These findings suggest UA may control the pathological conditions of PD via additive mechanisms which modulate the propagation of α-syn.

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 (R (2) = 0.39, adjusted R (2) = 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.

Priming mesenchymal stem cells with α-synuclein enhances neuroprotective properties through induction of autophagy in Parkinsonian models.

BACKGROUND: Mesenchymal stem cells (MSCs) may be one of candidates for disease-modifying therapy in Parkinsonian diseases. As knowledge regarding the therapeutic properties of MSCs accumulates, some obstacles still remain to be overcome, especially, successful clinical translation requires the development of culture systems that mimic the natural MSC niche, while allowing clinical-scale cell expansion without compromising quality and function of the cells. In recent years, priming approaches using bioactive peptide or complement components have been investigated to enhance the therapeutic potential of MSCs. METHODS: We investigated an innovative priming strategy by conditioning the MSCs with α-synuclein (α-syn). To induce priming, MSCs were treated with different concentrations of α-syn and various time course. We evaluated whether α-syn enhances stemness properties of MSCs and priming MSCs with α-syn would modulate autophagy-related gene expression profiles. RESULTS: Treatment of naïve MSCs with α-syn upregulated transcriptional factors responsible for regulation of stemness, which was associated with the elevated expression of genes involved in glycolysis and cell re-programming. Primed MSCs with α-syn enhanced the expression of autophagy-regulating miRNA, and exosomes derived from primed MSCs were packed with autophagy-associated miRNA. In α-syn-overexpressing neuronal cells, primed MSCs with α-syn enhanced neuronal viability relative to naïve MSCs, through the induction of autophagy and lysosome activity. Animal study using an α-syn-overexpressing mice showed that the pro-survival effect of MSCs on dopaminergic neurons was more prominent in primed MSC-treated mice compared with that in naïve MSC-treated mice. CONCLUSIONS: The present data suggest that MSC priming with α-syn exerts neuroprotective effects through augmented stemness and possibly the enhancement of autophagy-mediated α-syn modulation in Parkinsonian models.

Uric Acid Enhances Neurogenesis in a Parkinsonian Model by Remodeling Mitochondria.

Background: Adult neurogenesis is the process of generating new neurons to enter neural circuits and differentiate into functional neurons. However, it is significantly reduced in Parkinson's disease (PD). Uric acid (UA), a natural antioxidant, has neuroprotective properties in patients with PD. This study aimed to investigate whether UA would enhance neurogenesis in PD. Methods: We evaluated whether elevating serum UA levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mouse model would restore neurogenesis in the subventricular zone (SVZ). For a cellular model, we primary cultured neural precursor cells (NPCs) from post-natal day 1 rat and evaluated whether UA treatment promoted cell proliferation against 1-methyl-4-phenylpyridinium (MPP+). Results: Uric acid enhanced neurogenesis in both in vivo and in vitro parkinsonian model. UA-elevating therapy significantly increased the number of bromodeoxyuridine (BrdU)-positive cells in the SVZ of PD animals as compared to PD mice with normal UA levels. In a cellular model, UA treatment increased the expression of Ki-67. In the process of modulating neurogenesis, UA elevation up-regulated the expression of mitochondrial fusion markers. Conclusion: In MPTP-induced parkinsonian model, UA probably enhanced neurogenesis via regulating mitochondrial dynamics, promoting fusion machinery, and inhibiting fission process.

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

BACKGROUND: Increased 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. METHODS: We 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. RESULTS: FPG 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). CONCLUSIONS: An 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.

Decreased interleukin-18 response in asthmatic children with severe Mycoplasma pneumoniae pneumonia.

PURPOSE: Mycoplasma pneumoniae (M. pneumoniae) is a common causative agent of pneumonia in children. The aim of this study is to determine whether there is any difference in selected cytokine or chemokines response in asthmatic children compared to non-asthmatic children during acute M. pneumoniae pneumonia. METHODS: Seventy-five children, 6-12 years of age, admitted with M. pneumoniae pneumonia were enrolled. Two patient groups were defined: the children with known asthma (N=40) and non-asthmatic children (N=35). Interleukin (IL)-18 and selected chemokines, IL-8, CXCL9, CXCL10, and regulation upon activation normal T-cell expressed and secreted (RANTES) were measured by means of ELISA in the plasma samples of the patients collected on admission. We investigated the values of these mediators in relation to the asthma status and symptom severity of the patients. Twenty age-matched, non-infected controls were also studied. RESULTS: Plasma levels of IL-18 and the chemokines increased significantly in the patients with M. pneumoniae pneumonia compared to non-infected, age-matched controls (P<0.01). However, the asthmatic patients showed significantly reduced IL-18 and CXCL10 responses (P<0.01, <0.05, respectively) and had more severe pneumonia symptoms (P<0.01) compared to non-asthmatic patients. IL-18 was significantly lower in severe pneumonia group than in non-severe group (P<0.05). CONCLUSIONS: Our study suggests that IL-18 and the chemokines are importantly involved in the pathogenesis of M. pneumoniae pneumonia. It also indicates that some asthmatic children have deficient IL-18 response when affected by M. pneumoniae pneumonia, which might be associated with more severe pneumonia observed in this group of patients.