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In this study, we investigated the effect of Biochanin A (BioA), an O‐methylated isoflavone on the brown‐fat phenotype formation and on the associated thermogenic program including mitochondrial biogenesis and lipolysis in C3H10T1/2 MSCs. Our data demonstrates that Treatment with BioA in an adipogenic differentiation cocktail induced formation of brown‐fat–like adipocytes from C3H10T1/2 MSCs without treatment with a known browning inducer (rosiglitazone or T3) at an early stage of differentiation. The formation of brown‐fat–like adipocytes by BioA treatment was evidenced by upregulation of key thermogenic markers: Ucp1, Pgc1α, Prdm16, and Pparγ. BioA also increased the expression of beige (Cd137 and Fgf21) and brown (Elovl3 and Zic1)‐specific markers. Additionally, BioA treatment promoted mitochondrial biogenesis, judging by the upregulation of genes; Cox8b, Cidea, Dio2, Sirt1, Opa1, and Fis1. BioA treatment increased the amount of mitochondrial DNA and its encoded proteins: oxidative phosphorylation complexes (I–V); this change was associated with high oxygen consumption by C3H10T1/2 MSCs. A small‐interfering‐RNA–induced gene knockdown and experiments with dorsomorphin‐driven competitive inhibition revealed that BioA exerts the thermogenic action via activation of AMPK signaling. Our study shows the mechanism of BioA‐induced promotion of a brown‐fat phenotype. Nonetheless, clinical research is necessary to validate BioA as a brown‐fat‐like signature inducer. [ABSTRACT FROM AUTHOR]

Abstract: Obesity poses a substantial threat of a worldwide epidemic and requires better understanding of adipose‐tissue biology as well as necessitates research into the etiology and therapeutic interventions. In this study, Medicarpin (Med), a natural pterocarpan, was selected (by screening) as a small‐molecule inducer of adipocyte differentiation among 854 candidates by using C3H10T1/2 mesenchymal stem cell; a cellular model of adipogenesis. Med induced the expression of brown‐adipocyte commitment marker Bmp7 as well as the early regulators of brown fat fate Pparγ, Prdm16, and Pgc‐1α during differentiation of C3H10T1/2 mesenchymal stem cells. Med also induced the expression of a key thermogenic marker—uncoupling protein 1 (UCP1)—along with expression of other brown‐fat–specific markers and beige‐fat–specific markers. Of note, Med significantly reduced the expression of white fat markers too. Furthermore, Med treatment promoted formation of multilocular lipid droplets (LDs), expression of mitochondrial‐biogenesis–related genes, and increased oxygen consumption. Gene silencing study revealed that Med promotes the development of brown‐ and beige‐adipocyte characteristics in C3H10T1/2 mesenchymal stem cells through activation of the AMPK pathway, and our data allow us to propose Med as a candidate for therapeutics against obesity or related metabolic disorders. © 2017 BioFactors, 44(2):168–179, 2018 [ABSTRACT FROM AUTHOR]

Methyl gallate (MG) is a derivative of gallic acid and a potent antioxidant. In this study, we confirmed that MG treatment effectively inhibits lipid accumulation, which occurred mostly in the early stages of adipogenesis. We also showed that shortly after adipogenic induction, MG facilitated a G0/G1 cell cycle arrest. Mechanistic studies revealed that MG treatment inhibited ERK1/2 phosphorylation, which is a key regulator of the G1- to S-phase transition. Furthermore, MG treatment prevented the adipogenic hormonal stimuli-induced inhibition of the cyclin-dependent kinase inhibitor p27Kip1. This led to inhibition of the transcription factor E2F1 by preventing the phosphorylation of, and thereby activation of its destruction partner RB. MG treatment also downregulated factors that are upstream of RB-E2F1 signaling such as Cdk2, Cyclin E, Cdk4, and Cyclin D1 where Cyclin D3 level was unaffected. We also found that MG treatment markedly decreased the expression and phosphorylation of C/EBPβ, by phosphorylating, and therefore inactivating, GSK3β, which is a prerequisite for its DNA binding capacity, and thereby mitotic clonal expansion (MCE). Ultimately, MG treatment downregulates key terminal adipogenic transcription factors including C/EBPα, PPARγ, aP2 ( Fabp4), and adiponectin. Moreover, MG also protects adipocytes from oxidative stress by alleviating intracellular reactive oxygen species and activating Nrf2, HO-1, and PRDX3. Thus, this study provides a mechanistic insight into the anti-adipogenic actions of MG. © 2016 BioFactors, 42(6):716-726, 2016 [ABSTRACT FROM AUTHOR]

Delphinidin (Del) is a major anthocyanin that is widely found in pigmented fruits and vegetables. Herein, we investigated the antiadipogenic effect and the molecular mechanism by which Del affects 3T3-L1 preadipocyte differentiation. We found that Del effectively reduced intracellular lipid accumulation and promoted lipolysis while regulating the expression of adipogenic transcription factors and their target genes. This lipid lowering effect of Del was largely limited to the early phase of adipogenesis, which is governed by the delayed cell cycle progression due to G1 cell cycle arrest. Subsequently, Del suppressed the expression of early adipogenic transcription factors, such as C/EBPβ and C/EBPδ, as well as that of intermediate markers, C/EBPα, PPARγ, and the PPARγ-target adipocyte markers adiponectin and aP2 (FABP4). Furthermore, Del treatment activated Wnt1, Wnt10b, the Wnt receptor Fzd2, and the coreceptors Lrp5/6, while it inactivated Gsk3β, a member of the β-catenin destruction complex. Moreover, Del treatment stabilized cytoplasmic β-catenin levels and promoted its nuclear translocation, with subsequent activation of the expression of its downstream target genes, c-Myc and cyclin D1. Our findings therefore suggest that Del can effectively inhibit adipogenesis followed by the stabilization of β-catenin during early 3T3-L1 differentiation via inhibition of its destructive complexes and activation of Wnt signaling, and may thus be a promising candidate for the prevention of metabolic diseases, including obesity. © 2016 BioFactors, 42(1):49-59, 2016 [ABSTRACT FROM AUTHOR]

Trimethyltin (TMT) is known as a potent neurotoxicant that causes neuronal cell death and neuroinflammation, particularly in the hippocampus. Microglial activation is one of the prominent pathological features of TMT neurotoxicity. Nevertheless, it remains unclear how microglial activation occurs in TMT intoxication. In this study, we aimed to investigate the signaling pathways in TMT-induced microglial activation using BV-2 murine microglial cells. Our results revealed that TMT generates reactive oxygen species (ROS) and increases the expression of CD11b and nuclear factor-κB- (NF-κB-) mediated nitric oxide (NO) and tumor necrosis factor- (TNF-) α in BV-2 cells. We also observed that NF-κB activation was controlled by p38 and JNK phosphorylation. Moreover, TMT-induced ROS generation occurred via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in BV-2 cells. Interestingly, treatment with the NADPH oxidase inhibitor apocynin significantly suppressed p38 and JNK phosphorylation and NF-κB activation and ultimately the production of proinflammatory mediators upon TMT exposure. These findings indicate that NADPH oxidase-dependent ROS generation activated p38 and JNK mitogen-activated protein kinases (MAPKs), which then stimulated NF-κB to release proinflammatory mediators in the TMT-treated BV-2 cells. [ABSTRACT FROM AUTHOR]

Aims: Antipsychotic-induced autonomic dysregulation may lead to a wide range of subjective sideeffects in schizophrenia patients. Using heart rate variability (HRV) measures, we prospectively examined the relationship between subjective side-effects and cardiac autonomic regulation in unmedicated schizophrenia patients. Methods: Forty-five unmedicated schizophrenia patients were assessed for antipsychotic-associated side-effects and HRV parameters at baseline and after 6 weeks of treatment. Psychiatric symptoms and subjective side-effects were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Liverpool University Neuroleptic Side-effect Rating Scale (LUNSERS). Results: Correlations between subjective adverse effects and HRV measures at baseline and at week 6 varied. Nonetheless, the changes in the psychic sideeffects domain were significantly correlated with the changes in time-domain HRV measures and sample entropy (SampEn). In addition, the change in SampEn was significantly associated with that in the scores of extrapyramidal, anticholinergic, miscellaneous, and red herring domains as well as the mean total LUNSERS score. Conclusion: Baseline HRV measures may predict clinical response and adverse events associated with treatment adherence. Also, subjective side-effects may correspond well with the changes in neurocardiac dynamics, and the changes in SampEn may effectively reflect subjective discomfort in patients receiving antipsychotic treatment. [ABSTRACT FROM AUTHOR]

ABSTRACT Oxidative injury can occur in the lung through the generation of reactive oxygen species (ROS) via redox cycling owing to intentional or accidental ingestion of paraquat (PQ), a common herbicide. A wide array of phytochemicals has been shown to reduce cellular oxidative damage by modulating cytoprotective genes. Quercetin, a well-known flavonoid, has been reported to display cytoprotective effects by up-regulating certain cytoprotective genes. In this context, we investigated the effect of quercetin on PQ-induced cytotoxicity in alveolar A549 cells, modulation of antioxidant genes, activation of transcription factor-Nrf2 and its target HO-1 expression. Quercetin reduced PQ-induced cytotoxicity in A549 cells that was evaluated by both 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Modulation of antioxidant genes was compared when cells were treated with PQ, quercetin and both using qRT-PCR. Activation of transcription factor-Nrf2 and induction of its target gene, HO-1 was demonstrated by western blot analysis. A remarkable reduction in the ROS level as well as an increase in the total cellular glutathione (GSH) level occurred when PQ-exposed cells were treated with quercetin. Our findings suggest that quercetin may be used to mitigate or minimize oxidative stress via reducing the generation of ROS. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective This study assessed whether the subjective experience of patients with schizophrenia improved after switching from an oral antipsychotic to flexibly-dosed paliperidone extended-release. Methods We conducted a 24-week, multicenter, non-comparative, open-label trial. A total of 387 patients with schizophrenia participated the study. The primary study outcome was the change in subjective symptoms measured by the Symptom Checklist-90-Revised version (SCL-90-R) from baseline. Visual analogue scales were used for sleep and daytime somnolence as secondary subjective assessments. The clinical global impression-schizophrenia-severity scale was used to assess overall symptom severity. Social functioning was evaluated by the personal and social performance scale. Adverse events were also evaluated. Results All subjective symptoms measured by the SCL-90-R improved significantly. The early responders, who achieved >20% reduction in the SCL-90-R within 1 week, maintained significantly lower severity through the 24 weeks. The clinical global impression-schizophrenia-severity scale and personal and social performance scores also improved significantly. The visual analogue scales revealed that daytime somnolence improved significantly, whereas nocturnal sleep quality was unaltered. Conclusion Our results suggest that switching to paliperidone extended-release was associated with improvements in various subjective symptoms, decreased overall symptom severity, and increased social functioning. The results also suggest that early detection and reduction of subjective symptoms are important for treatment outcome. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background and Aim: We investigated long-term outcomes and prognostic factors in patients with hepatitis B virus (HBV)-related liver cirrhosis in the era of oral nucleos(t)ide analog antiviral agents. Methods: Between January 1999 and February 2009, a total of 240 consecutive patients who had HBV-related cirrhosis without malignancy were treated with lamivudine and second line nucleos(t)ide analogs. The group of historical controls consisted of 481 consecutive patients with HBV-related cirrhosis who were managed without any antiviral treatment prior to 1999. Results: In 78% of the patients who received antiviral treatment, sustained viral suppression (serum HBV DNA < 105 copies/mL) was achieved during a mean follow-up period of 46 months. The occurrences of death, hepatic decompensation, and hepatocellular carcinoma (HCC) were less frequent in the treated cohort than in untreated historical controls, with the 5-year cumulative incidences being 19.4% versus 43.9% (log-rank P < 0.001), 15.4% versus 45.4% ( P = 0.001), and 13.8% versus 23.4% ( P = 0.074), respectively. For patients who received antiviral treatment, suboptimal viral suppression (HBV DNA > 105 copies/mL at last follow-up) was an important independent risk factor of death ( P < 0.001) and hepatic decompensation ( P = 0.019), and was linked to an increased risk of HCC ( P = 0.042). Although the Child-Pugh grade remained a useful prognostic factor, no significant differences were found between patients with Child-Pugh grade B and C cirrhosis at the beginning of antiviral treatment ( P = 0.656). Conclusions: Oral antiviral agents have improved the prognosis of patients with HBV-related cirrhosis and affected the prognostic values of factors constituting the Child-Pugh system, necessitating a more efficient prognostic system. [ABSTRACT FROM AUTHOR]

Objective To compare the effectiveness of amisulpride in acute (up to 8 weeks) and maintenance (week 8 to 12 months) phases of a 12-month course of treatment in a heterogeneous group of patients with schizophrenia. Methods We conducted a 12-month, open-label clinical trial with flexible doses of amisulpride among 129 Korean patients with schizophrenia. The Positive and Negative Symptom Scale (PANSS) and several other scales measuring efficacy and tolerability were analyzed during the acute and maintenance phases. Results The completion rates were 78.3% by week 8 and 55.8% by month 12. Total PANSS scores and scores on the negative-symptom and general-symptom subscales improved significantly during both acute and maintenance periods, but scores on the positive-symptom subscale improved only during the acute phase. Improvement during both treatment phases was significant in all other scales except for the Drug Attitude Inventory. The negative-symptom and mixed-symptom groups showed significant improvement in the PANSS negative subscale, the Clinical Global Impression scale, and the Global Assessment of Functioning during the maintenance period. Hyperprolactinemia and related events were commonly reported. Conclusions This study demonstrated the significant effectiveness and a good safety profile of amisulpride for treating acute and 12-month phases of schizophrenia under natural conditions. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article deals with a study which prepared polymeric calcium phosphate cements (PCPC) derived from biodegradable poly-y-glutamic acid (y-PGA) in an effort to improve the mechanical strength of calcium phosphate cement (CPC). A comparison was made between the characteristics of the PCPCs and those of cement incorporated with citric acid. It was noted that the PCPCs derived from c-PGA has a higher mechanical strength than that of the cements incorporated with citric acid.

The biocompatibility of CoCr alloy was significantly improved by forming a rough TiO2 layer on its surface. The TiO2 layer was formed by coating the CoCr alloy with titanium (Ti) through electron beam deposition followed by microarc oxidation (MAO). When Ti was coated on the surface, the biocompatibility of the CoCr alloy was enhanced and it was further improved by the MAO treatment. There were close relationships between the phase, morphology, and thickness of the TiO2 layer and the applied voltage. The biocompatibility of the specimens coated with Ti and subjected to MAO treatment was evaluated by in vitro alkaline phosphatase activity tests. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009 [ABSTRACT FROM AUTHOR]

Objectives: Although a broad range of circadian rhythm variations have been reported, analyses of chronotypes in bipolar I disorder (BDI) and schizophrenia are rare. The present study aimed to investigate specific chronotype patterns in BDI and schizophrenia compared with healthy subjects. Methods: All patients were clinically stable and recruited from the outpatient clinics of Seoul National University Hospital. They were diagnosed according to DSM-IV criteria. ‘Morningness/eveningness’, a chronotype correlated with circadian phase, was evaluated using the Composite Scale of Morningness (CSM) among 92 patients with BDI, 113 patients with schizophrenia (SZ), and 95 control individuals. Results: The CSM scores were significantly correlated with age in the control group, but a significant correlation with age was not observed in the schizophrenia or BDI groups. After controlling for age, there were significant differences between the BDI and control groups. The SZ patients did not differ from the BDI or control groups. Conclusions: In this Korean sample, patients with BDI showed a significantly greater preference for ‘eveningness’ (including delayed sleep timing) than control individuals. The influences of pharmacotherapy or clinical status on CSM scores need to be clarified. [ABSTRACT FROM AUTHOR]

Abstract: To gain insight into the mechanism by which Gli-similar 2 (Glis2) regulates transcription, we performed yeast-two hybrid cDNA library screening using Glis2 as bait. This screening identified β-catenin as a potential Glis2-interacting protein. Mammalian two-hybrid, co-immunoprecipitation, and GST-pulldown analyses supported the interaction between Glis2 and β-catenin. Pulldown analyses with several Glis2 deletion mutants indicated that the 1st zinc finger motif of Glis2 is critical for its interaction with β-catenin, while the armadillo repeats of β-catenin are important in its interaction with Glis2. Reporter analyses showed that Glis2 represses T-cell factor (TCF)-mediated transcriptional activation. In addition, Glis2 represses the expression of the TCF target gene cyclin D1. Our results indicate that Glis2 interacts with β-catenin and suggest that Glis2 functions as a negative modulator of β-catenin/TCF-mediated transcription. [Copyright &y& Elsevier]

Haloperidol, a dopamine D2 receptor blocker, is a classical neuroleptic drug that elicits extrapyramidal symptoms. Its metabolites include 3-(4-fluorobenzoyl) propionic acid (FBPA) and 4-(4-chlorophenyl)-4-piperidinol (CPHP). Until now, the biological significance of these metabolites has remained largely unknown. Here, we report that the administration of FBPA to mice effected a suppression of locomotor activity and induced catalepsy in a manner similar to that observed with haloperidol, whereas CPHP had no significant effects. Neither of these two metabolites, however, exhibited any ability to bind to the dopamine D2 receptor. FBPA blocked dopamine-induced extracellular signal-regulated kinase 1/2 phosphorylation, and it specifically affected mitogen-activated protein kinase kinase (MEK)1/2 activity in hippocampal HN33 cells. Moreover, FBPA was capable of direct interaction with MEK1/2, and inhibited its activity in vitro. We demonstrated the generation of haloperidol metabolites within haloperidol-treated cells by mass spectrometric analyses. Collectively, our results confirm the biological activity of FBPA, and provide initial clues as to the receptor-independent role of haloperidol. [ABSTRACT FROM AUTHOR]

We compared the severity of subjective and objective symptomatology of akathisia between the acute and chronic subtypes of neuroleptic‐induced akathisia. Sixty‐one schizophrenic subjects were evaluated. Multivariate analysis revealed that motor manifestations and distress of akathisia were less severe in chronic akathisia than in acute akathisia. The severity of subjective restlessness was not significantly different between the two groups. In conclusion, there were differences in the severity of symptoms and signs between the acute and chronic subtypes of akathisia, suggesting that the severity of the subjective and objective components of akathisia may be differentially affected by the duration of akathisia. © 2005 Movement Disorder Society [ABSTRACT FROM AUTHOR]

We investigated the effect of 10 μM clozapine on the activity of glycogen synthase kinase-3β (GSK-3β) and its upstream and downstream molecules in SH-SY5Y human neuroblastoma cells. Clozapine activates both Akt- and Dvl-mediated phosphorylation of GSK-3β through phosphorylation at Ser9, and increased total cellular and intranuclear levels of β-catenin. Pretreatment with the specific inhibitor of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, LY294002 (20 μM), prevented the phosphorylation of Akt but did not affect the phosphorylation of GSK-3β. These results suggest that clozapine regulates the phosphorylation of GSK-3β through Wnt signal pathways involving Dvl upstream but not through the PI3K-Akt pathway in SH-SY5Y cells. [Copyright &y& Elsevier]

Background: Multiple colon polyps and early cancers are often detected at colonoscopy, but we could not collect all polypectomied specimens in one insertion of a colonoscope. Endoscopic mucosal resection (EMR) may often be very difficult for the collection of the size, type, form, or location of the polyps. Methods: We performed EMR to collect plural polypectomied specimens by a modified new technique using a clip connected with a string in 40 patients (25 male, 15 female) who visited Saiseikai Nakatsu Hospital and Mitsubishi Kobe Hospital for colonoscopic treatment. The method was as follows: (i) insert a colonoscope; (ii) check polyps by indigocarmine pigmentation and endoscopic ultrasonography (EUS); (iii) check the lift-up sign by submucosal injection of 2.5% hypersaline-epinephrine containing indigocarmine; (iv) make a clip connected with string (Tegusu-3 go) and insert the clip kit through the channel of the colonoscope; (v) clip the polyp; (vi) insert snare in the channel of an endoscope, passing the string through the center of the snare; (vii) snare the polyp with counter traction of string and cutting by bipolar electric power; (viii) check for bleeding. If there is bleeding from the polypectomied site, another clip is necessary; and (ix) collect polyp. If there are many polyps, flags connecting the string are required. Results and Conclusion: All polyps were treated and collected in all patients by one insertion of the colonoscope without complications. Our modified EMR method was useful in the collection of multiple polypectomied polyps. [ABSTRACT FROM AUTHOR]

Results of genome-wide association studies (GWASs) for bipolar disorder (BD) have indicated ANK3 as one of the most promising candidates for a susceptibility gene. In this study, we performed genetic association analysis of two single-nucleotide polymorphisms (SNPs) in ANK3 (rs1938526 and rs10994336), whose genome-wide significant associations were reported in a previous meta-analysis of GWASs, using genotyping data of Korean and Japanese case-control samples and a part of data from a GWAS in Han-Chinese from Taiwan. The total number of participants was 2,212 cases (352 from Korea, 860 from Japan, and 1,000 from Taiwan) and 2,244 controls (349 from Korea, 895 from Japan, and 1,000 from Taiwan). We could not detect any significant difference of allele frequency in individual analyses using each of the three populations. However, when we combined the three data sets and performed a meta-analysis, rs1938526 showed nominally significant association (P = 0.048, odds ratio = 1.09). The over-represented allele in BD was same as that reported in Caucasian GWASs. On the other hand, any significant association was not detected in rs10994336. This discrepancy between two SNPs may be explained by the different degree of linkage disequilibrium between Asian and Caucasian. These findings further supported the association between ANK3 and BD, and also suggested the genomic region around rs1938526 as a common risk locus across ethnicities., (Copyright © 2011 Wiley-Liss, Inc.)

Early growth response (EGR) genes play critical roles in signal transduction in the brain, which is involved in neuronal activation, brain development, and synaptic plasticity. EGR genes, including EGR2, EGR3, and EGR4, showed significant association with schizophrenia in Japanese schizophrenic pedigrees. In particular, EGR3, which resides at the chromosomal location 8p21.3, was suggested to be a potential susceptibility gene in schizophrenia based on a study of Japanese cases. However, this requires further replication with an independent sample set. We investigated the association of the EGR3 and EGR2 genes, which were suggested as potential susceptibility genes for schizophrenia supported by both genetic association and postmortem brain expression studies, with schizophrenia in Korean patients. Along with 350 healthy individuals, 244 schizophrenic patients were analyzed. Among the four examined single-nucleotide polymorphisms (SNPs) of EGR3 (rs1008949, rs7009708, rs35201266, and rs3750192), SNP rs35201266 in intron 1 of the EGR3 gene showed a significant association with schizophrenia (P = 0.0008, χ(2) = 11.156, OR = 1.493), which withstands multiple testing correction. In addition, the "T-G-C-G" haplotype of EGR3 was under-represented in the patients with schizophrenia (P = 0.0073, χ(2) = 7.188, OR = 0.697). However, an association between the SNPs of EGR2 (rs2295814 and rs2297488) and schizophrenia was not found. These findings are consistent with the previous genetic association of the EGR3 gene in Japanese cohorts, which is the first replication concerning the association of EGR3 with schizophrenia in an independent cohort. Taken together, EGR3 could be suggested as a compelling susceptibility gene in schizophrenia.