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Objectives: This study aimed to evaluate the glymphatic system function in patients with obstructive sleep apnea (OSA) compared to healthy controls using diffusion tensor imaging (DTI) with the perivascular space (DTI-ALPS) method. Our hypothesis is that patients with OSA may have glymphatic system dysfunction, which is correlated with OSA severity., Methods: We enrolled 24 patients with OSA and 24 healthy controls. All participants underwent DTI magnetic resonance imaging (MRI) using the same 3T MRI scanner, and we calculated the DTI-ALPS index from the DTI. We evaluated the differences in the DTI-ALPS index between patients with OSA and healthy controls. In addition, we conducted a correlation analysis between the DTI-ALPS index and clinical characteristics., Results: The DTI-ALPS index was significantly different between the groups. The DTI-ALPS in patients with OSA was significantly lower than in healthy controls (1.30450 vs. 1.61600, p = 0.0006). Furthermore, the DTI-ALPS index was significantly negatively correlated with the apnea-hypopnea index in sleep stage N (r = -0.427, p = 0.042) and oxygen desaturation index during sleep N (r = -0.497, p = 0.036)., Conclusion: We successfully demonstrated glymphatic system dysfunction in patients with OSA. In addition, glymphatic system dysfunction is well correlated with OSA severity, especially during sleep stage N. Thus, these findings can explain the effects of OSA on increased risk of developing dementia and highlight the importance of OSA treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: This study aimed to investigate the alterations in thalamic nuclei volumes and the intrinsic thalamic structural network in patients with de novo Parkinson's disease (PD) based on their predominant symptoms., Methods: We enrolled 65 patients with de novo PD (44 patients with tremor-dominant [TD] subtype and 21 patients with postural instability and gait disturbance [PIGD] subtype) and 20 healthy controls. All subjects underwent three-dimensional T1-weighted magnetic resonance imaging. The thalamic nuclei were segmented using the FreeSurfer program., Results: We obtained volumetric differences in the thalamic nuclei of each subtype of PD in comparison of healthy control. Volumes of the right and left suprageniculate nuclei were significantly increased, whereas that of the left parafascicular nucleus was decreased in patients with the TD subtype. Volumes of the right and left suprageniculate nuclei and right ventromedial nucleus were significantly increased, whereas those of the right and left parafascicular nuclei volumes were decreased in patients with the PIGD subtype. The measures of the intrinsic thalamic global network were not different between patients with TD PD and healthy controls. However, in patients with the PIGD subtype, the global and local efficiencies were significantly increased compared to healthy controls. Moreover, although there were no differences in thalamic volume and intrinsic thalamic global network between patients with the TD and PIGD variants, we identified significant differences in the intrinsic thalamic local network between the two groups., Conclusions: Alterations in thalamic nuclei volumes and the intrinsic thalamic network in patients with PD differed based on their predominant symptoms. These findings might be related to the underlying pathogenesis and suggest that PD is a heterogeneous syndrome., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Ferulic acid is a compound with potent anti-oxidant and anti-inflammatory activities. We previously reported the protective effects of ferulic acid administration against two animal models of Alzheimer's disease (AD): intracerebroventricular (i.c.v.) injection of Aß1-42 in mice and APP/PS1 mutant transgenic mice. In this study using the same AD animal models, we examined the effect of KMS4001, one of dimeric derivatives of ferulic acid. Intragastric pretreatment of mice with KMS4001 (30mg/kg/day) for 5 days significantly attenuated the Aß1-42 (i.c.v.)-induced memory impairment both in passive avoidance test and in Y-maze test. APP/PS1 mutant transgenic mice at KMS4001 doses of 3 and 30mg/kg/day via drinking water showed the significantly enhanced novel-object recognition memory at both 1.5 and 3 months after the start of KMS4001 treatment. Treatment of APP/PS1 mutant transgenic mice with KMS4001 for 3 months at the doses of 3 and 30mg/kg/day markedly decreased Aβ1-40 and Aβ1-42 levels in the frontal cortex. The KMS4001 dose-response relationships for Aβ decrease and for improvement in novel-object recognition test corresponded to each other. Taken together, these results suggest that KMS4001 could be an effective drug candidate against AD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Collaborative regulation of liver X receptor (LXR) and sterol regulatory element binding protein (SREBP)-1 are main determinants in hepatic steatosis, as shown in both animal models and human patients. Recent studies indicate that selective intervention of overly functional LXRα in the liver shows promise in treatment of fatty liver disease. In the present study, we evaluated the effects of meso-dihydroguaiaretic acid (MDGA) on LXRα activation and its ability to attenuate fatty liver in mice. MDGA inhibited activation of the LXRα ligand-binding domain by competitively binding to the pocket for agonist T0901317 and decreased the luciferase activity in LXRE-tk-Luc-transfected cells. MDGA significantly attenuated hepatic neutral lipid accumulation in T0901317- and high fat diet (HFD)-induced fatty liver. The effect of MDGA was so potent that treatment with 1mg/kg for 2 weeks completely reversed the lipid accumulation induced by HFD feeding. MDGA reduced the expression of LXRα co-activator protein RIP140 and LXRα target gene products associated with lipogenesis in HFD-fed mice. These results demonstrate that MDGA has the potential to attenuate nonalcoholic steatosis mediated by selective inhibition of LXRα in the liver in mice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: For the geriatric population, upper reference limits (URLs) for alanine aminotransferase (ALT) levels have not been established. The aim of the study was to determine the URLs for ALT and to describe the factors associated with elevated ALT level in an elderly population., Design and Methods: We set the URLs for ALT for participants aged 65 years and over (n=3646) based on the 2007-2009 Korea National Health and Nutrition Examination Survey at the 97.5th percentile of that population who were determined to be at low risk for liver disease (n=896; low risk was defined as testing negative for the HBs antigen, low alcohol intake, and the absence of metabolic syndrome, medical comorbidity, or medication use)., Results: The URLs for ALT were 39 IU/L for men and 30 IU/L for women. The weighted prevalence for the elevated ALT level was 8.0% (95% confidence interval [CI], 7.1% to 8.9%) in the sample, 5.8% (95% CI, 4.7% to 7.1%) in men and 9.5% (95% CI, 8.3% to 10.8%) in women., Conclusions: The URLs for ALT are established for the first time in the elderly, and our results may be useful for monitoring trends in the burden of liver disease, in addition to guiding the evaluation of ALT abnormalities in clinical practice., (Copyright © 2012. Published by Elsevier Inc.)

Aggregated β-amyloid (Aβ) plays crucial roles in Alzheimer's disease (AD) pathogenesis, therefore blockade of Aβ aggregation is considered as a potential therapeutic target. We designed and synthesized small molecules to reduce Aβ-induced cytotoxicity by inhibiting Aβ aggregation. The small molecules were screened via ThT, MTT, and cell-based cytotoxicity assay (Aβ burden assay). Selected compounds 1c, 1d, 1e, and 1f were then investigated by evaluating their effects on cognitive impairment of acute AD mice model. Learning and memory dysfunction by injection of Aβ(1-42) was recovered by administration of these molecules. Especially, 1d showed the best recovery activity in Y-maze task, object recognition task, and passive avoidance task with dose dependent manner. These results suggest that 1d has high potential as a therapeutic agent for AD., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

IkappaB kinase (IKK) is critical in proinflammatory cytokine-induced IkappaBalpha phosphorylation and subsequent activation of the nuclear transcription factor NF-kappaB complex. The activated NF-kappaB plays a major role in the pathogenesis of a number of human disorders, such as rheumatic and chronic inflammatory diseases. The inhibition of NF-kappaB activation by small molecule inhibitors that targets IKKbeta may provide a pharmacological basis for interfering with these acute processes. To date, only three inhibitors have passed preclinical trials; on the other hand, identifying novel IKKbeta inhibitors could evolve as potential candidates to meet the clinical requirements in the future. In the present work, we have employed a virtual screening (VS) method to identify novel compounds. The VS scheme is comprised of pharmacophore filtering and, subsequently, receptor based screening. The VS scheme was applied to the databases of 1.04 million compounds to identify three novel compounds that can inhibit the IKKbeta at a micro molar range. Moreover, these compounds can be raised into a potential anti-inflammatory drug candidate after optimizing and passing several phases of clinical trials.

We screened a library of 11,000 small molecular weight chemicals, looking for compounds that affect cell viability. We have identified 2-amino-N-quinoline-8-yl-benzenesulfonamide (QBS) as a potent cytotoxic compound that induces cell cycle arrest and apoptosis. Treatment of Jurkat T cells with QBS increased the levels of cyclin B1 as well as phosphorylated-cdc2, which was accompanied by reduced activity of cdc2 kinase, suggesting that QBS may induce cell cycle arrest at G2 phase. Structural analogues of QBS also exhibited similar effects on cell cycle progression and cell viability. Long-term treatment with QBS resulted in DNA fragmentation, cytochrome C release, and PARP cleavage, and an increase in the number of subdiploidy cells, indicative of cellular apoptosis. Moreover, QBS-induced apoptosis was blocked by z-VAD-fmk, a pan-caspase inhibitor. These results suggest that QBS is a novel and potent compound that induces G2 arrest and subsequent apoptosis, implicating it as a putative candidate for chemotherapy.

Light exposure can exacerbate the condition of a variety of human retinal diseases by increasing the rate of photoreceptor cell death. How light negatively affects photoreceptor cell survival is not yet fully understood. Previous studies involving light damage models have revealed two independent apoptotic pathways: low levels of light induce retinal degeneration in the arrestin -/- mouse via constitutive activation of the phototransduction cascade, whereas strong light exposure to the retina, such as in an albino eye, elicits photoreceptor cell death via activator protein (AP-1) induction. In order to better understand the initial gene expression changes underlying light damage, dark-reared arrestin -/- and albino BALB/c mice were exposed to constant white light (2000 lux), and their retinal morphology was assessed as a function of time. The expression profiles of retinal transcripts were then compared between dark-adapted and light-exposed arrestin -/-, pigmented wild-type and BALB/c mice at a time point when morphological changes were minimal. As expected, the dark-adapted samples showed little difference in expression pattern between the three genotypes. Among the genes differentially regulated by light in BALB/c, but not arrestin -/- retinas, were c-fos and other stress-induced early response genes. In both mouse models, a marked increase in expression of the bZIP family of transcription factors was observed. Our results show a select group of unique and overlapping sets of genes induced by light in the two mouse models. These expression changes may constitute the underlying initiating events leading to the two distinct mechanisms of light damage.

Flavonoids are natural polyphenolic compounds that have anti-inflammatory, cytoprotective and anticarcinogenic effects. In this study, we investigated the effects of several flavonoids on nuclear factor-kappa B (NF-kappa B) activation by using luciferase reporter gene assay. Among the flavonoids examined, luteolin showed the most potent inhibition on lipopolysaccharide (LPS)-stimulated NF-kappa B transcriptional activity in Rat-1 fibroblasts. Luteolin did not inhibit either I kappa B alpha degradation or NF-kappa B nuclear translocation, DNA binding or phosphorylation by LPS. However, luteolin prevented LPS-stimulated interaction between the p65 subunit of NF-kappa B and the transcriptional coactivator CBP. In addition, a specific PKA inhibitor that blocked the phosphorylation of CREB and c-Jun by luteolin partially reversed the inhibitory effect of luteolin on NF-kappa B.CBP complex formation and NF-kappa B transcriptional activity by LPS. These data imply that inhibition of NF-kappa B transcriptional activity by luteolin may occur through competition with transcription factors for coactivator that is available in limited amounts. Taken together, this study provides a molecular basis for the understanding of the anti-inflammatory effects of luteolin.

The neurotoxicity of dithiocarbamates has been previously reported, however, the detailed mechanism underlying the neurotoxicity is still not fully understood. Among the dithiocarbamates, we investigated thiram and ziram in a neuronal-like pheochromocytoma (PC12) cells. Thiram and ziram strongly induced cell death in both dose- and time-dependent manners with the LC(50) of 0.3 and 2 microM, respectively. The cell death showed typical apoptotic features, such as DNA fragmentation and an increase of subdiploidy nuclei. Interestingly, both thiram and ziram induced rapid and sustained increases of intracellular Ca(2+) in PC12 cells, which were almost completely blocked by flufenamic acid (FFA), an inhibitor of non-selective cation channel. BAPTA-AM, an intracellular Ca(2+) chelator, inhibited the thiram- and ziram-induced apoptotic cell death. These results suggest that thiram and ziram induce apoptotic neuronal cell death by Ca(2+) influx through non-selective cation channels. The present study may provide a clue for understanding the mechanism of neurotoxicity of thiram and ziram.