Sex-dependent association of urate on the patterns of striatal dopamine depletion in Parkinson's disease.

BACKGROUND AND PURPOSE: The aim was to investigate the relationship between the serum urate (UA) levels and patterns of striatal dopamine depletion in patients with de novo Parkinson's disease (PD). METHODS: In all, 167 de novo PD patients who underwent 18 F-fluorinated N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane positron emission tomography scans were enrolled. After quantifying dopamine transporter (DAT) availability in each striatal subregion, sex-dependent patterns of striatal dopamine depletion were analysed by measuring (i) dopamine depletion in the other striatal subregions and posterior putamen (intersubregional ratio, ISR) and (ii) the interhemispheric asymmetry of dopamine depletion in the posterior putamen (asymmetric ratio, AR). RESULTS: The interaction analysis revealed a significant interaction effect of sex and serum UA levels on the ISR but not on the AR. The ISR was negatively correlated with the serum UA levels in all patients with PD (r = -0.156, P = 0.045), and this association was more prominent in male PD patients (r = -0.422, P < 0.001). However, no significant association between the AR and serum UA levels was found in any of the patients. In addition, serum UA levels were significantly associated with DAT availability in the posterior putamen on both the more affected side (r = 0.312, P = 0.005) and the less affected side (r = 0.312, P = 0.005) only in male PD patients. CONCLUSIONS: The present study demonstrated the potentially close sex-specific relationship between the serum UA levels and the anterior-posterior gradient of DAT patterns, suggesting a sex-specific protective effect of UA on nigrostriatal dopaminergic neurons in de novo PD.

Sex-specific association of urate and levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND AND PURPOSE: As a major antioxidant, uric acid (UA) is known to be associated with the clinical progression of Parkinson's disease (PD). This study investigated whether baseline UA levels are associated with the risk for levodopa-induced dyskinesia (LID) in PD in a sex-dependent manner. METHODS: In all, 152 patients with de novo PD (78 males and 74 females) who were followed up for >2 years were enrolled. The effect of baseline serum UA levels on LID-free survival was assessed by Cox regression, separately for sex, whilst being adjusted for potential confounding factors. The optimal UA level cut-off value to determine the high-risk group for LID was set using Contal and O'Quigley's method. RESULTS: Levodopa-induced dyskinesia developed in 23 (29.5%) male patients and 30 (40.5%) female patients. Cox regression showed a significant interaction between UA level and sex. Higher UA levels were associated with a higher risk for LID in male PD patients (hazard ratio 1.380; 95% confidence interval 1.038-1.835; P = 0.027), although this relationship was not observed in female PD patients. The optimal UA level cut-off for LID in male PD was 7.2 mg/dl, and the high UA group had a 5.7-fold higher risk of developing LID than the low UA group. CONCLUSIONS: Contrary to a presumptive beneficial role of UA, the present study demonstrated that higher UA levels are associated with increased risk of LID occurrence in male patients with PD, suggesting a sex-dependent role of UA in LID.

Evaluation of treatment pattern and symptom control in patients with gastroesophageal reflux disease: multihospital questionnaire survey on the current situation in Korea.

Proton pump inhibitors (PPIs) are the most effective treatment for gastroesophageal reflux disease (GERD); however, a considerable number of patients fail to respond to PPI therapy and complain of nocturnal heartburn and sleep disturbance. The aims of this study are to evaluate the treatment pattern of GERD-related medications and their efficacy in relieving nocturnal heartburn. A total of 334 patients with GERD receiving PPI therapy within 6 months were enrolled in a multihospital questionnaire survey from January, 2014 to March, 2015. GERD symptoms and patients' satisfaction were assessed by patient questionnaires, and treatment patterns of GERD-related medications were assessed by investigators. Among the 334 patients, 95.8% used PPI once daily and 58.6% used a half-dose of PPI. The PPI treatment pattern was changed in 26.6% of all patients, of those, 54% of the patients doubled the PPI dose, and 29.2% of the patients switched to another PPI. Approximately 60.3% of all patients were prescribed more than three GERD-related medications. The overall satisfaction rate was 61.8%, and 32.2% of patients experienced nocturnal heartburn and sleep disturbance. In the extended-release PPI group, there were fewer nocturnal symptoms compared with the conventional PPI group (10% vs. 33.7%, respectively, P = 0.027). The use of more than three medications was inversely associated with patients' satisfaction (OR = 0.355, 95% CI; 0.197-0.642, P = 0.001). Most patients were prescribed adjunctive medications other than PPIs; however, patients' satisfaction was inversely associated with multiple drugs. Patients' satisfaction was superior in extended-release PPIs than conventional PPIs for the relief of nocturnal heartburn in Korean patients.

Investigation of a method for real time quantification of gas bubbles in pipelines.

The need to measure the dynamic void fraction (the proportion of flowing bubbly liquid that is gas) is common across many power, processing and manufacturing industries. Many such pipelines and liquids are optically opaque, and work on margins that require a low cost solution that is not commensurate with the size of the challenge. Such a solution will therefore be a compromise, and in this paper costs are reduced by using a narrowband acoustic solution that cannot, on its own, contain enough information to characterize the void fraction in real time unambiguously. The ambiguity is reduced using likely estimates of the general shape of the bubble size distribution so that, with a single source-receiver pair attached to the outside of the pipe, the absolute gas content can be estimated. While the data that are required a priori (the general shape of the bubble size distribution) are not identical to the output of the inversion (the absolute void fraction of gas entrained as bubbles in the flow), the requirement for such a priori information could limit the usefulness of the technique in industry.

SRF is a nuclear repressor of Smad3-mediated TGF-beta signaling.

Serum response factor (SRF) is a widely expressed transcription factor involved in immediate-early and tissue-specific gene expression, cell proliferation and differentiation. We defined a new role of SRF as a nuclear repressor of the tumor growth factor beta1 (TGF-beta1) growth-inhibitory signal during cell proliferation. We show that SRF significantly inhibits the TGF-beta1/Smad-dependent transcription by associating with Smad3. SRF causes resistance to the TGF-beta1 cytostatic response by directly repressing the Smad transcriptional activity and Smad binding to DNA. Furthermore, we demonstrated that overexpression of SRF markedly decreases the level of Smad3 complex binding to the promoters of Smad3 target genes, p15(INK4b) and p21(Cip1). This leads to the inhibition of expression of TGF-beta1-responsive genes. SRF therefore acts as a nuclear repressor of Smad3-mediated TGF-beta1 signaling.

Biophoton emission of MDCK cell with hydrogen peroxide and 60 Hz AC magnetic field.

We studied biophoton characteristics of Madin-Darby canine kidney (MDCK) cells under the influence of H2O2 by employing a photomultiplier tube (PMT) and a fluorescence microscope. H2O2 was used for producing reactive oxygen species (ROS) in the measurement. Images from a fluorescence microscope show an increase of photon intensity emitted from the sample due to H2O2. By using a PMT we measured quantitative change in biophoton emission with application of H2O2 to the MDCK cell culture, found that the increase of the biophoton is dependent upon the amount of H2O2. The agreement between the results of the PMT and the fluorescence microscope suggests the possibility of quantitative measurement of the influence of ROS on living tissue or cell. In addition we applied a 60 HzAC magnetic field on the cells to investigate the change in reaction between MDCK cell and ROS. It showed that a decay of chemiluminescence intensity has taken a different path following exposure to the magnetic field. As a result, the PMT measurement might be considered as a useful tool for studying biochemical characteristics in relation to ROS.

Centromere-linkage analysis and consolidation of the zebrafish genetic map.

The ease of isolating mutations in zebrafish will contribute to an understanding of a variety of processes common to all vertebrates. To facilitate genetic analysis of such mutations, we have identified DNA polymorphisms closely linked to each of the 25 centromeres of zebrafish, placed centromeres on the linkage map, increased the number of mapped PCR-based markers to 652, and consolidated the number of linkage groups to the number of chromosomes. This work makes possible centromere-linkage analysis, a novel, rapid method to assign mutations to a specific linkage group using half-tetrads.

Acylshikonin analogues: synthesis and inhibition of DNA topoisomerase-I.

Compounds bearing an acyl group of a various size at 1'-OH of shikonin were synthesized as acyl analogues of shikonin, which was isolated from the root of Lithospermum erythrorhizon, and evaluated for inhibitory effect on topoisomerase-I activity. A selective acylation at 1'-OH of shikonin in the presence of dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine gave rise to a good yield of corresponding acylshikonin derivatives. In general, analogues with an acyl group of shorter chain lengths (C2-C6) exerted a stronger inhibitory action than those with longer chain lengths (C7-C20). While the halogen substitution at C-2 of the acetyl moiety failed to increase the inhibitory potency, the placement of double bonds in the acyl group (C5-C7) augmented the potency remarkably. Of the 32 derivatives evaluated, 15 compounds exhibited a higher inhibitory effect than shikonin. Noteworthy, the inhibitory potency of acetylshikonin, propanoylshikonin, and 4-pentenoylshikonin was approximately 4-fold greater than that of camptothecin. All these data suggest that the size of acyl moiety is important for the enhancement of potency, and the presence of olefinic double bonds is also beneficial.

In vitro anti-inflammatory effects of cynaropicrin, a sesquiterpene lactone, from Saussurea lappa.

We investigated in vitro anti-inflammatory effects of cynaropicrin, a sesquiterpene lactone from Saussurea lappa, on tumor necrosis factor (TNF)-alpha and nitric oxide (NO) release, and lymphocyte proliferation. Cynaropicrin strongly inhibited TNF-alpha release from lipopolysaccharide-stimulated murine macrophage, RAW264.7 cells, and differentiated human macrophage, U937 cells, proved to produce notable amount of TNF-alpha. It also potently attenuated the accumulation of NO released from lipopolysaccharide- and interferon-gamma-stimulated RAW264.7 cells in a dose-dependent manner. In addition, the immunosuppressive effects of the compound on lymphocyte proliferation in response to mitogenic stimuli were examined. Cynaropicrin also dose-dependently suppressed the proliferation of lymphocytes from splenocytes and interleukin-2-sensitive cytotoxic T lymphocyte, CTLL-2 cells, stimulated by lipopolysaccharide, concanavalin A, phytohemagglutinin and interleukin-2. However, treatment with sulphydryl compound, L-cysteine, abrogated all these inhibitory effects. These results suggest that cynaropicrin may participate in the inflammatory response by inhibiting the production of inflammatory mediators and the proliferation of lymphocytes and its inhibitory effect is mediated through conjugation with sulphydryl groups of target protein(s).

Immunomodulatory effect of arctigenin, a lignan compound, on tumour necrosis factor-alpha and nitric oxide production, and lymphocyte proliferation.

We have investigated the immunomodulatory effects of arctigenin, a dibenzyl butyrolactone lignan compound, on tumour necrosis factor (TNF)-alpha and nitric oxide (NO) production, and lymphocyte proliferation. Arctigenin inhibited strongly TNF-alpha production by lipopolysaccharide-stimulated murine macrophage RAW264.7 and differentiated human macrophage U937 with IC50 values of 5.0 and 3.9 microM, respectively, without displaying cytotoxicity. The TNF-alpha inhibitory effect of arctigenin in lipopolysaccharide-triggered RAW264.7 cells was increased by co-treatment with several known TNF-alpha inhibitors. It also potently attenuated T and B cell proliferation stimulated by concanavalin A and lipopolysaccharide in a dose-dependent manner with IC50 values of 2.9 and 14.6 microM, respectively. In contrast, the compound showed a different pattern in lipopolysaccharide- and interferon (IFN)-gamma-induced NO production from RAW264.7 cells. Arctigenin inhibited NO release by IFN-gamma signal, whereas it significantly enhanced lipopolysaccharide-triggered NO production in RAW264.7 cells. The results suggested that arctigenin may regulate immune responses in activated macrophages and lymphocytes including TNF-alpha and NO production and lymphocyte proliferation.

In-vitro and in-vivo immunomodulatory effects of syringin.

Syringin was found to possess immunomodulatory activity by which it inhibited the in-vitro immunohaemolysis of antibody-coated sheep erythrocytes by guinea-pig serum through suppression of C3-convertase of the classical complement. In this study, we examined its in-vitro and in-vivo activity on tumour necrosis factor (TNF)-alpha and nitric oxide (NO) production, CD4+ T cell and CD8+ cytotoxic T cell (CTLL-2) proliferation, and croton oil-, arachidonic acid- and fluorescein-isothiocynate (FITC)-induced mouse ear oedema model. Syringin significantly inhibited both TNF-alpha production from lipopolysaccharide (LPS)-stimulated RAW264.7 cells and CD8+ T cell (CTLL-2) proliferation in a dose-dependent manner, whereas neither NO production nor CD4+ T cell proliferation were blocked even by high concentrations of syringin. In the invivo experiments, syringin also significantly suppressed FITC-induced ear oedema in mice but not the ear oedema induced by croton or arachidonic acid. These results suggest that syringin may be implicated as an immunomodulator having an anti-allergic effect rather than an anti-inflammatory effect. The anti-allergic effect of syringin seems to be due, in part, to inhibition of TNF-alpha production and cytotoxic T cell proliferation.

Inhibitor of tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW264.7 cells from Amorpha fruticosa.

Certain flavonoids were reported to show an immunoregulatory activity against lymphocyte proliferation and cytokine production. In the course of a search for tumor necrosis factor (TNF)-alpha inhibitory compounds from natural plants, we also isolated a prenylfavanone type of flavonoid, amoradicin, from the extract of Amorpha fruticosa by activity-guided fractionation. This compound significantly inhibited TNF-alpha production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells with an IC(50) value of 28.5 microM. The activity was comparable or higher than those of standard flavonoid compounds, genistein and silybin with IC(50) of 24.9 and 140.3 microM, respectively.

Eudesmin inhibits tumor necrosis factor-alpha production and T cell proliferation.

Possible antiinflammatory effects of eudesmin were examined by assessing the effects on tumor necrosis factor (TNF)-alpha production and lymphocyte proliferation as well as cytotoxicity against murine and human macrophages. The compound significantly inhibited TNF-alpha production by lipopolysaccharide (LPS)-stimulated murine macrophage RAW264.7 without displaying cytotoxicity suggesting that eudesmin may inhibit TNF-alpha production without any interference of normal cell function. It also significantly attenuated T cell proliferation stimulated by concanavalin A (Con A) in a dose-dependent manner.

Effects of restricted feeding, low-energy diet, and implantation of trenbolone acetate plus estradiol on growth, carcass traits, and circulating concentrations of insulin-like growth factor (IGF)-I and IGF-binding protein-3 in finishing barrows.

Effects of restricted feeding (80% ad libitum), feeding a low-energy diet containing 84% DE (2.95 Mcal/kg) of the control diet, and implantation of Revalor H (140 mg trenbolone acetate plus 14 mg estradiol-17beta) on growth, carcass traits, and serum concentrations of insulin-like growth factor (IGF)-I and IGFbinding protein-3 (IGFBP-3) were studied in crossbred finishing barrows beginning from 59 +/- 0.9 kg of body weight. Blood samples were taken every 3 wk and the animals were slaughtered at approximately 105 kg body weight. Restricted feeding caused a decrease (P < 0.01) in ADG; feeding the low-energy diet was effective in reducing backfat thickness but decreased gain:feed; the implantation caused a decrease in ADG, feed intake, and backfat thickness and increased gain:feed. Overall pork quality based on pH, drip loss, and the lightness in color of longissimus muscle was not affected by any of the treatments. Serum IGF-I concentration increased following the implantation but did not change (P > 0.05) due to other treatments. Immunoreactive IGFBP-3 concentration was not changed by any of the treatments. Overall ADG was positively correlated with early-stage (d 21) IGF-I and IGFBP-3 concentrations only in unimplanted barrows, whereas backfat thickness was negatively correlated with d-42 IGF-I concentration in all but unimplanted barrows with ad libitum intake. A strong positive correlation (P < 0.01) between IGF-I and IGFBP-3 concentrations was apparent with increasing age of the animals. Results suggest that growth rate and backfat thickness are decreased by a moderate restriction of feed or energy intake with no accompanying changes in circulating IGF-I and IGFBP-3 concentrations and that the beneficial effect of Revalor H implantation on feed efficiency may be mediated, in part, by IGF-I. Moreover, both IGF-I and IGFBP-3 concentrations may be useful as growth indices in pigs.

Noble 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-isoindolinone derivatives. part I: synthesis and SAR studies for the inhibition of TNF-alpha production.

This study describes the synthesis and in vitro evaluation of noble 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-isoindolinone derivatives for the inhibition of TNF-alpha production. Among these compounds, 2-[3-(cyclopentyloxy)-4-methoxyphenyll-3-methyl-1-isoindolinone (5) was the most potent in inhibitory activity of TNF-alpha production in LPS-stimulated RAW264.7 cells.

Inhibitory effect of lignans from the rhizomes of Coptis japonica var. dissecta on tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW264.7 cells.

The inhibitory effect of 10 lignan constituents isolated from the rhizomes of Coptis japonica var. dissecta on tumor necrosis factor (TNF)-alpha production in lipopolysaccharide (LPS)-stimulated macrophage cell line (RAW264.7 cells) has been studied. Among them, pinoresinol, woorenoside-V and lariciresinol glycoside showed significant inhibitory activities in the range from 37% to 55% at the concentration of 25 micrograms/ml. The results are first report that the lignans isolated from Coptis japonica inhibit TNF-alpha production, and suggest that the lignan components may partly participate in antiinflammatory and antiallergic effect of Coptis japonica through the inhibition of TNF-alpha production.

Isolation and identification of inhibitory compounds on TNF-alpha production from Magnolia fargesii.

Three TNF alpha-inhibitory lignans were isolated from the flower buds of Magnolia fargesii through bioassay-guided isolation. They were identified as eudesmin, magnolin and lirioresinol-B dimethylether on the basis of their spectroscopic data. All three lignans showed inhibitory effects on TNF-alpha production in LPS-stimulated murine macrophage cell line, RAW264.7 and eudesmin showed the strongest activity (IC50 = 51 microM).

Correlates of psychological distress in involuntary job loss.

This study estimated correlates of psychological distress with a heterogeneous sample of American subjects (N = 122; M age = 33.5 yr.) who were involuntarily displaced from work. Expectation of finding a new job is a significant source of psychological distress in job loss after taking into account length of unemployment and economic dependence. Psychological distress also showed significant negative association with self-esteem and significant positive relationship with job-seeking effort. Other important findings are discussed.

Preferential killing of human lung cancer cell lines with mitochondrial dysfunction by nonthermal dielectric barrier discharge plasma.

The distinctive cellular and mitochondrial dysfunctions of two human lung cancer cell lines (H460 and HCC1588) from two human lung normal cell lines (MRC5 and L132) have been studied by dielectric barrier discharge (DBD) plasma treatment. This cytotoxicity is exposure time-dependent, which is strongly mediated by the large amount of H2O2 and NOx in culture media generated by DBD nonthermal plasma. It is found that the cell number of lung cancer cells has been reduced more than that of the lung normal cells. The mitochondrial vulnerability to reactive species in H460 may induce distinctively selective responses. Differential mitochondrial membrane potential decrease, mitochondrial enzymatic dysfunction, and mitochondrial morphological alteration are exhibited in two cell lines. These results suggest the nonthermal plasma treatment as an efficacious modality in lung cancer therapy.

AMP-activated protein kinase-α1 as an activating kinase of TGF-ß-activated kinase 1 has a key role in inflammatory signals.

Although previous studies have proposed plausible mechanisms of the activation of transforming growth factor-ß-activated kinase 1 (TAK1) in inflammatory signals, including Toll-like receptors (TLRs), its activating kinase still remains to be unclear. In the present study, we have provided evidences that AMP-activated protein kinase (AMPK)-α1 has a pivotal role for activating TAK1, and thereby regulate NF-κB-dependent gene expressions in inflammatory signaling mediated by TLR4 and TNF-α stimulation. AMPK-α1 specifically interacts with TAK1 and reciprocally regulates their kinase activities. Upon the stimulation of lipopolysaccharide, AMPK-α1-knockdown (AMPK-α1(KD)) or TAK1-knockdown human monocytic THP-1 cells exhibit a dramatic reduction in the TAK1 or AMPK-α1 kinase activity, respectively, and subsequent suppressions of its downstream signaling cascades, which further leads to inhibitions of NF-κB and thereby productions of proinflammatory cytokines, such as TNF-α, IL-1ß, and IL-6. Importantly, the microarray analysis of AMPK-α1(KD) cells revealed a dramatic reduction in the NF-κB-dependent genes induced by TLR4 and TNF-α stimulation, and the observation was in significant correlation with the results of quantitative real-time PCR. Moreover, AMPK-α1(KD) cells are highly sensitive to the TNF-α-induced apoptosis, which is accompanied with dramatic reductions in the NF-κB-dependent and anti-apoptotic genes. As a result, our data demonstrate that AMPK-α1 as an activating kinase of TAK1 has a key role in mediating inflammatory signals triggered by TLR4 and TNF-α.