Arsenic induces transgenerational behavior disorders in Caenorhabditis elegans and its underlying mechanisms.

The present study aimed to identify the effects of arsenic on behaviors in Caenorhabditis elegans (C. elegans) and the transgenerational effects. The synchronized C. elegans (P generation) were exposed to 0, 0.2, 1.0, and 5.0 mM NaAsO2 and the subsequent generations (F1 and F2) were maintained on fresh nematode growth medium (NGM). The behaviors and growth were recorded at 0, 12, 24, 36, 48, 60, and 72 h post synchronization. The results demonstrated that arsenic affected various indicators regarding the behavior (head thrash, body bend, movement speed, wavelength, amplitude and so on) and in general the effects started to accumulate from 24 h and lasted throughout the exposure. The behavior impairments were transgenerational with varying patterns, amongst the head thrash and body bend responded most sensitively though the responses gradually declined across generations. Arsenic exposure inhibited the growth (body length, body width, and body area) in P C. elegans from 24 h to 60 h, however there was no difference between treatments groups and the control at 72 h. Arsenic led to a dose-dependent degeneration of dopaminergic neurons in C. elegans, and inhibition of BAS-1 and CAT-2 expressions. The expressions of GCS-1, GSS-1, and SKN-1 were induced by arsenic exposure. Overall, chronic arsenic exposure impaired the behaviors and there were transgenerational effects. The head thrash and body bend responded most sensitively. Arsenic induced behavioral disorders might be attributed to degeneration of dopaminergic neurons which was associated with oxidative stress.

Paroxetine suppresses reactive microglia-mediated but not lipopolysaccharide-induced inflammatory responses in primary astrocytes.

BACKGROUND: Astrocytes are the most abundant glial cells in a brain that mediate inflammatory responses and provide trophic support for neurons. We have previously disclosed that paroxetine, a common selective serotonin reuptake inhibitor, ameliorates LPS-induced microglia activation. However, it remains elusive for the role of paroxetine in astrocytic responses. METHODS: Isolated primary astrocytes were pretreated with paroxetine and stimulated with different stimuli, lipopolysaccharide (LPS) or microglia conditioned medium pre-activated with LPS (M/Lps). Inflammatory and neurotrophic responses, underlying mechanisms and the impact on neuronal survival were assessed. RESULTS: Paroxetine had no impact on LPS-stimulated iNOS, TNF-α, and IL-1ß expression, but inhibited M/Lps-induced TNF-α and IL-1ß expression in primary astrocytes. Paroxetine suppressed M/Lps- but not LPS-induced activation of NF-κB and had no impact on the activation of MAPKs and STAT3. Incubation with the resulted astrocyte conditioned media caused no change in the viability of SH-SY5Y cells. BDNF and MANF mRNA expressions were upregulated by M/Lps and paroxetine, respectively. However, M/Lps- or LPS-induced extracellular releases of NO, TNF-α, and/or BDNF in astrocytes were in minor amount compared to those by microglia. CONCLUSIONS: Paroxetine ameliorates the reactive microglia-mediated inflammatory responses in astrocytes partially via inhibition of the NF-κB pathway but has no impact on LPS-stimulated astrocyte activation. While the effects of paroxetine on secondary astrocytic responses are not robust compared to its effect on the innate immune responses of microglia, the results together may implicate a therapeutic potential of paroxetine against neuroinflammation-associated neurological disorders such as Parkinson's disease.

SLC6A4 Repeat and Single-Nucleotide Polymorphisms Are Associated With Depression and Rest Tremor in Parkinson's Disease: An Exploratory Study.

Introduction: Level of serotonin is mainly regulated by the serotonin reuptake transporter encoded by SLC6A4. The promoter region of SLC6A4 bears a repeat polymorphism 5-HTTLPR and a single nucleotide polymorphism rs25531. We have previously studied the association between these two variants and sporadic PD. The objective of the current study was to determine whether the SLC6A4 polymorphisms were associated with key motor and non-motor symptoms of PD. Methods: A total of 370 PD patients of Han Chinese were included. Associations between the SLC6A4 polymorphisms and PD symptoms including depression, intellectual impairment, tremor and rigidity were analyzed. Results: 5-HTTLPR was associated with depression in PD patients and presence of the LL genotype was protective against the depression risk. The rs25531 was associated with rest tremor in PD and the A allele serves as a recessive risk allele. No associations were found in the two polymorphisms with respect to intellectual impairment and rigidity in the cohort. Conclusion: The current study reveals two PD symptoms associated with SLC6A4 polymorphisms, and provides new insight into how serotonergic system genetically participates in the symptomatic progression of PD. Further study is warranted in additional populations.

Coronary artery lesion risk and mediating mechanism in children with complete and incomplete Kawasaki disease.

To compare the risk of coronary artery lesions (CAL) in children with complete and incomplete Kawasaki disease (KD) before and after immunoglobulin therapy and explore the mediation mechanisms underlying this association. All patients with KD admitted to the Wenzhou Medical University affiliated Yuying Children's Hospital were divided into complete and incomplete KD groups. The independent effect of KD type on the risk of CAL and the intermediate effect of admission time on the association between KD type and CAL were assessed. The incidence of CAL in children with incomplete KD was higher than that in children with complete KD (33.9% vs 23.0%, p<0.001), and was also higher before therapy (27.5% vs 14.8%). Among children without CAL before therapy, there was no statistical difference in the incidence of CAL after treatment between the two groups. Mediation analysis found that the mediating effect of admission time was 1.07 (95% C: 1.01 to 1.13), and the direct effect of KD type on CAL was 1.59 (95% CI 1.17 to 2.16); proportion mediated was 15.71%. In conclusion, the risk of CAL among patients with incomplete KD was higher than that for complete KD, especially before therapy. In patients without CAL before treatment, the risk of CAL after treatment was equivalent for the two groups. Delayed admission may be one of the important mediating mechanisms for the higher risk of CAL in incomplete KD children.

Association analyses of variants of SIPA1L2, MIR4697, GCH1, VPS13C, and DDRGK1 with Parkinson's disease in East Asians.

A recent large-scale European-originated genome-wide association data meta-analysis followed by a replication study identified 6 new risk loci for Parkinson's disease (PD), which include rs10797576/SIPA1L2, rs117896735/INPP5F, rs329648/MIR4697, rs11158026/GCH1, rs2414739/VPS13C, and rs8118008/DDRGK1. However, whether these new loci are associated with PD in Asian populations remain elusive. The INPP5F is nonpolymorphic in Asians. The present study aimed to understand the effects of the other 5 new loci in a Han Chinese population comprising 579 sporadic PD patients and 642 controls. Significant associations with PD were observed in the variants of SIPA1L2 (p = 0.001) and VPS13C (p = 0.007), where the T (odd ratio [OR] = 1.484, 95% confidence interval [CI] 1.186-1.858) and A (OR = 1.362, 95% CI 1.087-1.707) alleles serve as the risk alleles, respectively. The genotype distributions in the SIPA1L2 and VPS13C variants were also different between the patients and controls (p = 0.002 and p = 0.023, respectively). In contrast, no significant association with PD was found in the variants of MIR4697, GCH1, and DDRGK1 either in allele or genotype frequencies. Noteworthy, a followed meta-analysis of East Asian studies suggested an association of the GCH1 variant with PD (p = 0.04, OR 1.08, 95% CI 1.00-1.16), while the other results are in line with those of our cohort. In conclusion, our study together with meta-analyses demonstrates that the variants of SIPA1L2 and VPS13C, potentially GCH1, but not of MIR4697 and DDRGK1, are associated with PD susceptibility in East Asians.

Hyperoside inhibits lipopolysaccharide-induced inflammatory responses in microglial cells via p38 and NFκB pathways.

Hyperoside (quercetin-3-O-ß-d-galactoside) is an active compound isolated from herbs. Neuroinflammation is a key mechanism involved in neurodegenerative disorders including Parkinson's disease. In this study, we aimed to investigate the potentiality of hyperoside in inhibiting microglia-mediated neuroinflammation. BV2 microglial cells were pretreated with hyperoside and stimulated with lipopolysaccharide (LPS). The results showed that hyperoside significantly inhibited LPS-induced production of nitric oxide and pro-inflammatory cytokines including IL-1ß and TNF-α, as well as the expression of inducible nitric oxide synthase. Similar results were observed in primary microglial cells isolated from neonatal mice. Analyses in MAPK and NFκB signaling combined with specific inhibitors suggested that hyperoside attenuated the LPS-induced inflammatory responses via p38 and NFκB pathways. Furthermore, hyperoside suppressed reactive microglia-mediated neurotoxicity as evidenced by conditioned media culture, but had no direct impact on MPP+-induced toxicity in SH-SY5Y neuroblastoma cells. Collectively, our data suggest that hyperoside may serve as a protective agent by alleviating microglia activation in disorders such as Parkinson's disease.

Meta-analysis of brain iron levels of Parkinson's disease patients determined by postmortem and MRI measurements.

Brain iron levels in patients of Parkinson's disease (PD) are usually measured in postmortem samples or by MRI imaging including R2* and SWI. In this study we performed a meta-analysis to understand PD-associated iron changes in various brain regions, and to evaluate the accuracy of MRI detections comparing with postmortem results. Databases including Medline, Web of Science, CENTRAL and Embase were searched up to 19th November 2015. Ten brain regions were identified for analysis based on data extracted from thirty-three-articles. An increase in iron levels in substantia nigra of PD patients by postmortem, R2* or SWI measurements was observed. The postmortem and SWI measurements also suggested significant iron accumulation in putamen. Increased iron deposition was found in red nucleus as determined by both R2* and SWI, whereas no data were available in postmortem samples. Based on SWI, iron levels were increased significantly in the nucleus caudatus and globus pallidus. Of note, the analysis might be biased towards advanced disease and that the precise stage at which regions become involved could not be ascertained. Our analysis provides an overview of iron deposition in multiple brain regions of PD patients, and a comparison of outcomes from different methods detecting levels of iron.

Benzo-α-pyrene induced oxidative stress in Caenorhabditis elegans and the potential involvements of microRNA.

In the present study oxidative stress induced by Benzo-α-pyrene (BaP) exposure and the potential involvements of microRNA were investigated. The Caenorhabditis elegans (C. elegans) was applied as model organism. The C. elegans at L1-stage were randomly divided into 4 groups and exposed to 0, 0.2, 2.0, and 20µM BaP for 30h. Expressions of SKiNhead-1 (SKN-1), gamma-glutamine cysteine synthase heavy chain (GCS-1), and their potential regulatory factors in insulin/IGF-1/FOXO signaling pathway and the p38 MAPK pathway were analyzed. The expressions of potentially involved microRNAs were investigated as well. Results demonstrated that expressions of SKN-1 and GCS-1 were altered significantly following BaP exposure (P<0.05). Meanwhile, expressions of multiple related factors were changed after BaP treatments. The altered factors include AKT-1, DAF-16, glutathione synthetase (GSS-1), glutathione S-transferase-24 (GST-24), mitogen-activated protein kinase kinase-4 (MKK-4), multidrug resistance-associated protein-1 (MRP-1), and pyruvate dehydrogenase kinase-2 (PDHK-2) (P<0.05). In addition, results showed that exposure to BaP led to altered expressions of microRNA. Out of the 28 tested microRNAs, expressions of miR-1, miR-355, miR-50, miR-51, miR-58, miR-796, miR-797, and miR-84 were modified. Findings of the present study include that BaP exposure caused oxidative stress in C. elegans. The expressional response of GCS-1 to BaP exposure might be independent of the regulation of SKN-1 in C. elegans. The microRNAs might be involved in the regulations of SKN-1 and GCS-1 expression following BaP exposure in C. elegans.

Arsenic responsive microRNAs in vivo and their potential involvement in arsenic-induced oxidative stress.

Arsenic exposure is postulated to modify microRNA (miRNA) expression, leading to changes of gene expression and toxicities, but studies relating the responses of miRNAs to arsenic exposure are lacking, especially with respect to in vivo studies. We utilized high-throughput sequencing technology and generated miRNA expression profiles of liver tissues from Sprague Dawley (SD) rats exposed to various concentrations of sodium arsenite (0, 0.1, 1, 10 and 100mg/L) for 60days. Unsupervised hierarchical clustering analysis of the miRNA expression profiles clustered the SD rats into different groups based on the arsenic exposure status, indicating a highly significant association between arsenic exposure and cluster membership (p-value of 0.0012). Multiple miRNA expressions were altered by arsenic in an exposure concentration-dependent manner. Among the identified arsenic-responsive miRNAs, several are predicted to target Nfe2l2-regulated antioxidant genes, including glutamate-cysteine ligase (GCL) catalytic subunit (GCLC) and modifier subunit (GCLM) which are involved in glutathione (GSH) synthesis. Exposure to low concentrations of arsenic increased mRNA expression for Gclc and Gclm, while high concentrations significantly reduced their expression, which were correlated to changes in hepatic GCL activity and GSH level. Moreover, our data suggested that other mechanisms, e.g., miRNAs, rather than Nfe2l2-signaling pathway, could be involved in the regulation of mRNA expression of Gclc and Gclm post-arsenic exposure in vivo. Together, our findings show that arsenic exposure disrupts the genome-wide expression of miRNAs in vivo, which could lead to the biological consequence, such as an altered balance of antioxidant defense and oxidative stress.

Type A personality, hostility, time urgency and unintentional injuries among Chinese undergraduates: a matched case-control study.

BACKGROUND: Associations between type A behaviour pattern (TABP) and injuries are inconsistent. These inconsistencies may be due to different effects of various components of TABP, namely time urgency/impatience, hostility and competitive drive. It is important to examine the relationship between the global TABP, its two components, and unintentional injuries, among undergraduates in China. METHODS: On the basis of a previous cross-sectional study, we conducted a matched case-control study. 253 cases and an equal number of age-, gender-, and major-matched controls were included. The questionnaire solicited socio-demographic information, the experience of injuries, the scale of TABP, and other potential confounding factors. Besides the correlation between the global TABP and injuries, the influences of the two components of TABP on injuries were also evaluated. Conditional logistic regression was used to determine the crude odds ratios (ORs) and adjusted ORs of injury events. RESULTS: A dose-response relationship was apparent among students who rated themselves higher on the TABP scale (P-value for trend, 0.002), with a crude OR of 2.93 (95% CI: 0.93-9.19) for injuries comparing those with TABP to those with type B behaviour pattern (TBBP). After adjustment for potential confounding factors, TABP remained statistically significant, and the adjusted OR was 5.52 (95% CI: 1.43-21.27); from a comparison of students with TABP to those with TBBP. A dose-response relationship was also apparent between the hostility component and nonfatal injuries, both in crude analysis and after adjusting for other confounders. The relationship between time-hurry and injuries was not statistically significant, based on univariate and multivariate analyses. CONCLUSIONS: Both the global TABP and the hostility component were associated with a dose response increase in the risk of non-fatal unintentional injuries among Chinese undergraduates. Further studies need to be conducted to confirm or reject this correlation.

[Effect of lead exposure on gene expression of Fgf3 in zebrafish embryonic development].

OBJECTIVE: To investigate the effect of lead exposure on the gene expression of fibroblast growth factor 3 (Fgf3) in zebrafish embryonic development and the mechanism of lead-induced embryonic developmental toxicity. METHODS: The embryos of zebrafish (wild types A and B) were exposed to lead acetate (PbAc) at the doses of 0, 0.1, 0.5, 2.5, and 12.5 µmol/L separately. Total RNA was extracted from each treatment group of zebrafish embryos at 8, 12, 16, 24, 36, 48, and 72 hours post fertilization (hpf). The total mRNA expression of Fgf3 was measured by real-time quantitative PCR. The spatial expression of Fgf3 in zebrafish embryos was determined by whole-mount in situ hybridization using synthesized Fgf3 RNA probe. RESULTS: The mRNA expression of Fgf3 in each group peaked at 12 hpf (P < 0.01). With the increase in PbAc concentration, the mRNA expression of Fgf3 rose. Compared with the mRNA expression level of Fgf3 in the control group, the relative mRNA expression levels of Fgf3 in the 0.1, 0.5, 2.5, and 12.5 µmol/L PbAc exposure groups were 1.02 ± 0.24, 1.05 ± 0.26, 1.22 ± 0.46, and 1.25 ± 0.38, respectively, and the 2.5 and 12.5 µmol/L PbAc exposure groups showed significantly higher Fgf3 expression than the control group (P < 0.05). The whole-mount in situ hybridization results showed that Fgf3 expression occurred mainly in the head and tail in the early stage of embryonic development and in the midbrain, fin bud, and pharyngeal arch in the middle/late stage of embryonic development; there were the most significant regions and intensities of positive hybridization signals at 12 hpf; but no significant differences were found between the control group and exposure groups in the location and intensity of Fgf3 expression CONCLUSION: Lead exposure can result in the upregulation of Fgf3 expression in zebrafish embryonic development, which might contribute to lead-induced embryonic developmental toxicity.

Polybrominated diphenyl ethers (PBDEs) in human serum from Southeast China.

Polybrominated diphenyl ethers (PBDEs) have been used extensively in electrical and electronic products, but little is known about the exposure level in the electrical appliance factories workers and nearby local residents. In this study, we assessed body burdens of PBDEs in 194 Chinese injection workers from electrical appliance factories and also measured 205 blood samples from catering workers, leather factory workers, umbilical cord and infertile men for comparison. Twelve PBDE congeners in serum samples were measured by GC-MS. The highest concentration for total PBDEs was found in injection workers, which is positively correlated to employment duration. BDE-209 was the most dominant congener followed by BDE-47, 28 and 99. We also found the presence of all twelve PBDEs in cord blood, suggesting an evidence of fetal exposure. Concentration of BDE-47 was particularly higher in serum samples from infertile men in comparison with that of catering workers and leather factory workers.

Status and risk factors of unintentional injuries among Chinese undergraduates: a cross-sectional study.

BACKGROUND: Injuries affect all age groups but have a particular impact on young people. To evaluate the incidence of non-fatal, unintentional, injuries among undergraduates in Wenzhou, China, assess the burden caused by these injuries, and explore the associated risk factors for unintentional injuries among these undergraduates, we conducted a college-based cross-sectional study. METHODS: Participants were selected by a multi-stage random sampling method, and 2,287 students were asked whether they had had an injury in the last 12 months; the location, cause, and consequences of the event. The questionnaire included demographic and socioeconomic characteristics, lifestyle habits, and the scale of type A behaviour pattern (TABP). Multivariate logistic regression models were used; crude odds ratios (ORs), adjusted ORs and their 95% confidence intervals (CIs) were estimated, with students having no injuries as the reference group. RESULTS: The incidence of injuries among undergraduates in Wenzhou was 18.71 injuries per 100 person-years (95%CI: 17.12~20.31 injuries per 100 person-years). Falls were the leading cause of injury, followed by traffic injuries, and animal/insect bites. Male students were more likely to be injured than female students. Risk factors associated with unintentional injuries among undergraduates were: students majoring in non-medicine (adjusted OR: 1.53; 95% CI: 1.19-1.96); type A behaviour pattern (adjusted OR: 2.99; 95% CI: 1.45-6.14); liking sports (adjusted OR: 1.86; 95% CI: 1.41-2.45). CONCLUSIONS: Injuries have become a public health problem among undergraduates. Falls were the major cause of non-fatal injury. Therefore, individuals, families, schools and governments should promptly adopt preventive measures aimed at preventing and controlling morbidity due to non-fatal injury, especially among students identified to be at high-risk; such as male students with type A behaviour pattern who like sports.

Levels of arsenic in drinking-water and cutaneous lesions in Inner Mongolia.

The most common health effects from drinking-water containing dissolved arsenic are skin abnormalities and lesions that are typically diagnosed as keratosis and pigment disorder. It was previously reported that the prevalence of cutaneous lesions was about 44% in arsenic-affected villages. However, there has been little research on the relationship between levels of arsenic in drinking-water and cutaneous lesions in Inner Mongolia. One study examined the association between the prevalence of keratosis and levels of arsenic exposure and the relationship between pigment disorder and levels of arsenic exposure among villagers aged 18 years or older in the arsenic-affected village of Hetao Plain in Inner Mongolia, PR China. The study included 227 participants who were affected by cutaneous lesions and 221 participants who were not affected by cutaneous lesions diagnosed in 1996 and 1998. Well-water drunk by the participants was collected to analyze arsenic content. Adjusting for age, sex, and smoking, logistic regression was applied to calculate the risks that arsenic in drinking-water will lead to cutaneous lesions. The results from the logistic regression showed that, with the increase of arsenic concentration in water, the risk of pigment disorder also increased (odds ratio [OR]=5.25, 95% confidence interval [CI] 1.32-83.24 for 50-199 microg/L; OR=10.97, 95% CI 1.50-79.95 for 200-499 [microg/L; OR=10.00, 95% CI 1.39-71.77 for > or = 500 microg/L (p=0.000), but the association between risk of keratosis and levels of arsenic was not significant (p=0.346). The findings suggest that keratosis is an early feature of arsenic poisoning, and the development of pigment disorder depends on higher doses of arsenic intake rather than keratosis. Further studies are needed to confirm that cutaneous lesions and other adverse health effects occur at low levels of arsenic exposure.