Role of striatal ΔFosB in l-Dopa-induced dyskinesias of parkinsonian nonhuman primates.

Long-term dopamine (DA) replacement therapy in Parkinson's disease (PD) leads to the development of abnormal involuntary movements known as l-Dopa-induced dyskinesia (LID). The transcription factor ΔFosB that is highly up-regulated in the striatum following chronic l-Dopa exposure may participate in the mechanisms of altered neuronal responses to DA generating LID. To identify intrinsic effects of elevated ΔFosB on l-Dopa responses, we induced transgenic ΔFosB overexpression in the striatum of parkinsonian nonhuman primates kept naïve of l-Dopa treatment. Elevated ΔFosB levels led to consistent appearance of LID since the initial acute l-Dopa tests. In line with this motor response, striatal projection neurons (SPNs) responded to DA with changes in firing frequency that reversed at the peak of the motor response, and these unstable SPN activity changes in response to DA are typically associated with the emergence of LID. Transgenic ΔFosB overexpression also induced up-regulation of other molecular markers of LID. These results support an autonomous role of striatal ΔFosB in the adaptive mechanisms altering motor responses to chronic DA replacement in PD.

Comparison of Effect of Two-Hour Exposure to Forest and Urban Environments on Cytokine, Anti-Oxidant, and Stress Levels in Young Adults.

The purpose of this study was to investigate the effect of two-hour exposure to a forest environment on cytokine, anti-oxidant and stress levels among university students and to compare the results to those measured in urban environments. Forty-one subjects were recruited. For our crossover design, subjects were divided into two groups based on similar demographic characteristics. Group A remained in the urban environment and was asked to perform regular breathing for 2 h. Blood samples were collected and the serum levels of cytokines including interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), and glutathione peroxidase (GPx) were examined. Subjects were moved to a small town in a rural area for an equal amount of time to exclude carryover effects, and then remained for another 2 h in a forest environment. The second set of blood samples was collected to assess the effect of exposure to the forest environment. Using the same method, Group B was first exposed to the forest environment, followed by exposure to the urban environment. Blood samples collected after the subjects were exposed to the forest environment showed significantly lower levels of IL-8 and TNF-α compared to those in samples collected after urban environment exposure (10.76 vs. 9.21, t = 4.559, p < 0.001, and 0.97 vs. 0.87, t = 4.130, p < 0.001). The GPx concentration increased significantly after exposure to the forest environment (LnGPx = 5.09 vs. LnGPx = 5.21, t = -2.039, p < 0.05).

Anti-inflammatory effects of essential oils extracted from Chamaecyparis obtusa on murine models of inflammation and RAW 264.7 cells.

Antimicrobial, antifungal and anti-inflammatory effects of essential oils extracted from Chamaecyparis obtusa (EOCO) have previously been reported. In the present study, the anti-inflammatory effects of EOCO were investigated in two murine models of inflammation: Carrageenan-induced paw edema and thioglycollate-induced peritonitis, and in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The expression levels of proinflammatory cytokines were analyzed by ELISA, the expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were determined by western blotting, and nitrite concentration was measured using Griess reagent. In mice with carrageenan-induced edema, paw thickness and the expression levels of interleukin (IL)­1ß and IL-6 in paw homogenates were significantly decreased in the EOCO (5 and 10 mg/kg) group, as compared with the control group. In mice with thioglycollate-induced peritonitis, treatment with EOCO (5 and 10 mg/kg) reduced the number of total cells and suppressed tumor necrosis factor­α (TNF­α), IL­1ß and IL­6 levels in peritoneal fluid. In addition, EOCO reduced nitric oxide, TNF­α and IL­6 production, and suppressed iNOS and COX­2 expression in LPS­stimulated RAW 264.7 cells. These results suggest that EOCO may exert anti­inflammatory effects in vivo and in vitro, and that these effects may be associated with the inhibition of inflammatory mediators. Therefore, EOCO may be considered an effective therapeutic agent for the treatment of inflammatory diseases.

Antinociceptive and anti-inflammatory effects of essential oil extracted from Chamaecyparis obtusa in mice.

Essential oil extracted from Chamaecyparis obtusa (EOCO) consists of several monoterpenes with anti-inflammatory effects. Monoterpenes are expected to have an analgesic effect through inhibition of pro-inflammatory mediators. The present study investigated the anti-nociceptive and anti-inflammatory effects of EOCO in animal models of pain. Intraperitoneal injection with EOCO (5 or 10mg/kg), aspirin (positive control, 300mg/kg), or DMSO (negative control) was performed 1h before the nociception tests: acetic acid-induced writhing response, formalin test, and hot plate test in mice, and acidic saline-induced allodynia in rats. The expression of pro-inflammatory cytokines and pro-inflammatory enzymes in formalin-injected paws was determined by ELISA and western blotting, respectively. Treatment with EOCO significantly reduced acetic acid-induced writhing and paw-licking time in late response of the formalin tests. The anti-nociceptive effect was comparable with aspirin. However, EOCO did not affect the reaction time of licking of the hind paws or jumping in hot plate test and the mechanical withdrawal thresholds in acidic saline-induced allodynia model. Formalin-injected paws of mice treated with EOCO revealed the down-regulated expression of tumor necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase, and cyclooxygenase-2, as compared with those of control mice. These data showed the anti-nociceptive and anti-inflammatory effects of EOCO. The pain-relieving effect might be attributed to inhibition of peripheral pain in association with inflammatory response. EOCO could be a useful therapeutic strategy to manage pain and inflammatory diseases.

Gender plays significant role in short-term heart rate variability.

This study examined the role of gender on short-term heart rate variability (HRV) and the correlation between subjective ratings of stress and HRV in healthy adults. Standardized short-term HRV measurement and self-administered stress response inventory (SRI) were obtained in 441 healthy women and 1440 healthy men. Hierarchical multiple regressions suggested that there was no gender by stress interaction in explaining HRV. However, there were significant gender differences in the associations between stress and HRV (the standard deviation of the NN interval (SDNN), high frequency (HF), low frequency (LF)/HF (F(1, 1878) = 7.706, p < .01; F(1, 1878) = 29.132, p < .01; F(1, 1878) = 49.685, p < .01). In men, only HF (r = -.56, p = .031) showed such an association; whereas in women, the SRI total scores were negatively correlated with SDNN (r = -.103, p = .032), total power (TP) (r = -.104, p = .030), and HF (r = -.129, p = .007), and positively correlated with LF/HF (r = .111, p = .020) when adjusted for age, alcohol drinking, smoking, and caffeine intake. There are gender differences in the association between psychological stress response and HRV. Gender also showed a significant impact on short-term HRV measurement. Given that both clinicians and researchers are increasingly relying on HRV assessment, our work suggest that gender based norms are very important.

Apoptosis signal-regulating kinase 1 modulates the phenotype of α-synuclein transgenic mice.

α-Synuclein is a key pathogenic protein in α-synucleinopathies including Parkinson's disease, and its overexpression and aggregation in model systems are associated with a neuroinflammatory response and increased oxidative stress. Apoptosis signal-regulating kinase 1 (ASK1) is activated upon stress signaling events such as oxidative stress and is a central player linking oxidative stress with neuroinflammation. Here, we demonstrate that overexpression of human α-synuclein activates ASK1 in both PC12 cells and in the brains of α-synuclein transgenic mice. Deleting ASK1 in mice mitigates the neuronal damage and neuroinflammation induced by α-synuclein and improves performance of the animals on the rotarod. ASK1 deletion does not impact the aggregation profile or phosphorylation state of α-synuclein in the mouse brain. These results collectively implicate ASK1 in the cascade of events triggered by α-synuclein overexpression, likely because of the inflammatory response and oxidative stress that lead to ASK1 activation. These conclusions raise the possibility that potent antioxidants and anti-inflammatory agents may ameliorate the phenotype of α-synucleinopathies.

Twelve-month prevalence and predictors of self-reported suicidal ideation and suicide attempt among Korean adolescents in a web-based nationwide survey.

OBJECTIVE: The suicide rate in South Korea was the highest among the Organisation for Economic Co-operation and Development (OECD) countries in 2011. Although the suicide rate in adolescents is lower than that of adults and is reported to be decreasing in young males in some countries, it has consistently increased in recent years in South Korea. We aimed to determine the prevalence, pattern, and predictors of suicidal ideation and attempt in the past 12 months. METHODS: A total sample of 72,623 adolescents aged 12-18 years who responded to a web-based anonymous self-reported survey between September and October 2010 was used for the analysis. RESULTS: The suicidal ideation and suicide attempt rates were 19.1% and 4.9%, respectively. Being female, having a poor perceived socioeconomic status and a poor perceived academic performance, subjective feelings of depression, cigarette smoking, alcohol use, perceived general medical health, and experiences of any involvement with sexual intercourse were the contributing factors that predicted elevated risks for suicidal ideation and suicide attempt. In contrast to previous reports in other countries, the suicide attempt rate in Korean female adolescents peaked at age 13 years, and there were no differences in suicidal ideation in females by age. There were no differences in both suicidal ideation and attempt rates in males by age. CONCLUSION: A multidisciplinary approach that takes into consideration the characteristics of Korean adolescents with suicidal ideation or suicide attempt is warranted for developing prevention and treatment programs.

Effects of essential oil from Chamaecyparis obtusa on cytokine genes in the hippocampus of maternal separation rats.

We investigated the effects of an essential oil from Chamaecyparis obtusa (EOCO) on early life stress, using maternal separation (MS) rats and a microarray method to analyze the changes in gene expressions caused by EOCO in the hippocampus of MS rats. Rats in the MS groups were separated from their respective mothers from postnatal day (pnd) 14 to 28. Rats in the EOCO-treated groups were exposed to EOCO for 1 or 2 h by inhalation from pnd 21 to 28. The EOCO-treated MS rats showed decreased anxiety-related behaviors compared with the untreated MS rats in the elevated plus-maze (EPM) test. In the microarray analysis, we found that EOCO downregulated the expressions of cytokine genes such as Ccl2, Il6, Cxcl10, Ccl19, and Il1rl in the hippocampus of MS rats, and also confirmed that using reverse transcriptase - PCR. In particular, the expressions of Ccl2 and Il6 were predominantly decreased by EOCO in the hippocampus of MS rats. Interestingly, protein expression was also reduced by EOCO in MS rats. These results indicate that EOCO decreases MS-induced anxiety-related behaviors, and modulates cytokines, particularly Ccl2 and Il6, in the hippocampus of MS rats.

DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway.

DJ-1, which is linked to recessively inherited Parkinson's disease when mutated, is a multi-functional protein with anti-oxidant and transcription regulatory activities. However, the mechanism(s) through which DJ-1 and the genes it regulates provide neuroprotection is not fully understood. Here, we show that wild-type DJ-1 induces the expression of thioredoxin 1 (Trx1), a protein disulfide oxidoreductase, whereas pathogenic mutant isoforms L166P and M26I cannot. Conversely, DJ-1 knockdown in SH-SY5Y cells and DJ-1 knockout in mice result in significant decrease in Trx1 protein and mRNA expression levels. The importance of Trx1 in the cytoprotective function of DJ-1 is confirmed using a pharmacological inhibitor of Trx reductase, 1-chloro-2,4-dinitrobenzene, and Trx1 siRNA. Both approaches result in partial loss of DJ-1-mediated protection. Additionally, knockdown of Trx1 significantly abrogates DJ-1-dependent, hydrogen peroxide-induced activation of the pro-survival factor AKT. Promoter analysis of the human Trx1 gene identified an antioxidant response element (ARE) that is required for DJ-1-dependent induction of Trx1 expression. The transcription factor Nuclear factor erythroid-2 related factor 2 (Nrf2), which is a critical inducer of ARE-mediated expression, is regulated by DJ-1. Overexpression of DJ-1 results in increased Nrf2 protein levels, promotes its translocation into the nucleus and enhances its recruitment onto the ARE site in the Trx1 promoter. Further, Nrf2 knockdown abolishes DJ-1-mediated Trx1 induction and cytoprotection against hydrogen peroxide, indicating the critical role of Nrf2 in carrying out the protective functions of DJ-1 against oxidative stress. These findings provide a new mechanism to support the antioxidant function of DJ-1 by increasing Trx1 expression via Nrf2-mediated transcriptional induction.

Determinants for heart rate variability in a normal Korean population.

This study examined the normal ranges and the determinants for various parameters of the short-term heart rate variability (HRV) measurements in a large Korean sample of healthy people. HRV measurements were obtained in 2,748 healthy men and 735 healthy women 18-65 yr of age. The mean total power (TP), low frequency (LF), high frequency (HF), and LF/HF ratio were 1,358.9 ± 1,840.8 ms(2), 417.3 ± 807.6 ms(2), 254.1 ± 414.1 ms(2), and 2.4 ± 20.9 ms(2) in the frequency-domain spectral analysis. The mean standard deviation of the normal-to-normal (NN) interval (SDNN) and the square root of the mean squared differences of successive NN intervals (RMSSD) were 39.6 ± 22.1 ms and 29.7 ± 18.1 ms in the time-domain analysis. The female subjects had significantly higher SDNN, RMSSD, and HF values than the male subjects. After controlling for age, there was no statistically significant difference in the SDNN. Quantile regression analysis showed that age and mean heart rate had a significant impact on short-term HRV measurement. Given that both clinicians and researchers are increasingly relying on short-term HRV assessment in measuring stress, our work suggests that age and gender should be considered as independent determinants for HRV.

[Correlates of self-rated fatigue in Korean employees].

OBJECTIVE: To elucidate the correlates of self-rated fatigue in Korean employees. METHODS: The data for 10,176 (men, 7984; women, 2192; mean age, 34.2; SD: 8.8) employees recruited from a nation-wide sample were examined. A structured questionnaire was used to measure the participants' fatigue, sociodemographics (sex, age, education, and marital status), job-related characteristics (work duration, grade at work, work hours, shiftwork, employment type, and magnitude of workplace), and health-related habits (smoking, drinking, coffee intake, and exercise). Two types of measurement for fatigue were used to evaluate the magnitude of fatigue: self-rated question and a standardized measurement tool (Multidimensional Fatigue Scale: MFS). RESULTS: According to the self-rated fatigue, 32% of employees reported that they felt fatigue for the past two weeks, and 9.6% of males and 8.7% of females had experienced excessive fatigue (6 months or more). Hierarchical multiple regression analysis showed that fatigue measured by MFS was more common in women, younger, college or more graduated, single, and employees who do not regularly exercise. Fatigue was also associated with long work hours, and the size of the workplace (< 1000 employees). CONCLUSIONS: These results suggest that fatigue has been considered as a common complaint, and that it is affected by job-related factors like work hours and the workplace size as well as sociodemographics or health-related behaviors. Further research is needed to clarify the effects of fatigue on adverse health,outcomes, work performance, work disability, sick absence and medical utilization, and to examine the relationship of job characteristics (e.g.: work demand, decision latitude) to fatigue.