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Chun-Chang Ho,1 Giha Kim,1 Chin Hee Mun,2 Ju-Won Kim,3 Jieun Han,3 Ji Yoon Park,1 Yong-Beom Park,2– 4 Sang-Kyou Lee1,5 1Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea; 2Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Department of Medical Science, Brain Korea 21 PLUS Project, Yonsei University, Seoul, Republic of Korea; 4Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea; 5Good T Cells, Inc., Seoul, Republic of KoreaCorrespondence: Sang-Kyou LeeDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of KoreaTel +82 2 2123 2889Email sjrlee@yonsei.ac.krPurpose: Th17 cells and their cytokines are implicated in the pathogenesis of various autoimmune diseases. Retinoic acid-related orphan receptor alpha (RORα) is a transcription factor for the differentiation and the inflammatory functions of Th17 cells. In this study, we generated the nucleus-transducible form of transcription modulation domain of RORα (nt-RORα-TMD) to investigate the functional roles of RORα in vitro and in vivo under normal physiological condition without genetic alteration.Methods: The functions of nt-RORα-TMD were analyzed in vitro through flow cytometry, luciferase assay, ELISA, and transcriptome sequencing. Finally, the in vivo therapeutic effects of nt-RORα-TMD were verified in dextran sulfate sodium (DSS)-induced colitis mice.Results: nt-RORα-TMD was effectively delivered into the cell nucleus in a dose- and time-dependent manner without any cellular toxicity. nt-RORα-TMD competitively inhibited the RORα-mediated transcription but not RORγt-mediated transcription. Secretion of IL-17A from the splenocytes was suppressed by nt-RORα-TMD without affecting the secretion of Th1- or Th2-type cytokine and T cell activation events such as induction of CD69 and CD25. The differentiation potential of naïve T cells into Th17 cells, not into Th1, Th2, or Treg cells, was significantly blocked by nt-RORα-TMD. Consistently, mRNA sequencing analysis showed that nt-RORα-TMD treatment down-regulated the expression of the genes related to the differentiation and functions of Th17 cells. Treatment of DSS-induced colitis mice with nt-RORα-TMD improved the overall symptoms of colitis, such as body weight change, colon length, infiltration of inflammatory cells, and the level of inflammatory cytokines in the serum. In the mesenteric lymph node (MLN) of the nt-RORα-TMD-treated mice, the population of CD4+IL-17A+ Th17 cells was reduced, and the population of CD4+Foxp3+ Treg cells increased.Conclusion: nt-RORα-TMD has a potential to be developed as a novel therapeutic reagent for treating various inflammatory diseases in which Th17 cells are the leading pathological player.Keywords: retinoic acid-related orphan receptor, T helper 17, transcriptional modulation, DSS-induced colitis, inflammatory disease

Chun-Sheng Hsu,1– 4 Shin-Tsu Chang,1,5,6 Oswald Ndi Nfor,2 Kuan-Jung Lee,2 Chien-Chang Ho,7,8 Chuan-Ching Liu,1 Shiuan-Shinn Lee,2 Yung-Po Liaw2,9 1Department of Physical Medicine and Rehabilitation, Taichung Veterans General Hospital, Taichung City, 40201, Taiwan; 2Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, 40201, Taiwan; 3School of Medicine, National Defense Medical Center, Taipei City, 11490, Taiwan; 4College of Medicine, National Chung Hsing University, Taichung City, 402, Taiwan; 5Department of Physical Medicine and Rehabilitation, Tri-Service General Hospital, School of Medicine, National Defense Medical Centre, Taipei City, 11490, Taiwan; 6Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Kaohsiung City, 813414, Taiwan; 7Department of Physical Education, Fu Jen Catholic University, New Taipei, 24205, Taiwan; 8Research and Development Center for Physical Education, Health, and Information Technology, Fu Jen Catholic University, New Taipei, 24205, Taiwan; 9Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, 40201, TaiwanCorrespondence: Yung-Po Liaw; Shiuan-Shinn LeeDepartment of Public Health and Institute of Public Health, Chung Shan Medical University, No. 110 Sec. 1 Jianguo N. Road, Taichung City, 40201, TaiwanTel +886 424730022 ext. 11838; +886 424730022 ext.12185Fax +886 423248179Email Liawyp@csmu.edu.tw; shinn@csmu.edu.twPurpose: The Lipoprotein lipase (LPL) gene is a significant contributor to dyslipidemia. It has shown associations with several conditions including atherosclerosis, obesity, and metabolic syndrome (MetS). We assessed the interactive association between MetS and rs3779788 of the LPL gene based on aerobic exercise.Materials and Methods: Data were available for 7532 Taiwan Biobank (TWB) participants recruited between 2008 and 2016. We used multiple logistic regression to determine the odds ratios (OR) for MetS and their 95% confident intervals (C.I.). Potential variables included LPL rs3779788, aerobic exercise, sex, age, education, marital status, body mass index (BMI), smoking, alcohol consumption, midnight snacking, vegetarian diet, coffee, dietary fat, and tea drinking.Results: Aerobic exercise was protective against MetS (OR, 0.858; 95% C.I., 0.743– 0.991). Compared to CC/CT genotype, the OR for developing MetS was 0.875, (95% C.I., 0.571– 1.341) in TT individuals. The test for interaction was significant for the rs3779788 variant and aerobic exercise (p = 0.0484). In our group analyses, the OR for MetS was 0.841 (95% C.I., 0.727– 0.974) in CC/CT and 4.076 (95% C.I., 1.158– 14.346) in TT individuals who did aerobic exercise compared to those who did not.Conclusion: Our study indicated that aerobic exercise improved metabolic syndrome in Taiwanese adults with rs3779788 CC/CT genotype relative to those with TT genotype.Keywords: polymorphisms, variant, physical activity, metabolic disorders

Jui-Wen Peng,1 Oswald Ndi Nfor,2 Chien-Chang Ho,3,4 Shu-Yi Hsu,2 Chia-Chi Lung,2 Disline Manli Tantoh,2,5 Ming-Chih Chou,1 Yung-Po Liaw2,5 1Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan; 2Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, 40201, Taiwan; 3Department of Physical Education, Fu-Jen Catholic University, New Taipei City, 24205, Taiwan; 4Research and Development Center for Physical Education, Health, and Information Technology, Fu Jen Catholic University, New Taipei, 24205, Taiwan; 5Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, 40201, TaiwanCorrespondence: Yung-Po LiawDepartment of Public Health and Institute of Public Health, Chung Shan Medical University, No. 110, Sec. 1 Jianguo N. Road, Taichung, 40201, TaiwanTel +886424730022 ext. 11838Fax +886423248179Email Liawyp@csmu.edu.twMing-Chih ChouInstitute of Medicine, Chung Shan Medical University, No. 110, Sec. 1 Jianguo N. Road, Taichung, 40201, TaiwanTel +886424730022 ext. 11191Fax +886423248130Email juhan0223@yahoo.com.twPurpose: Ischemic stroke accounts for approximately 85% of all strokes. Risk factors include atrial fibrillation, metabolic disorders, and genetic and lifestyle factors. There is limited evidence to support the association between atrial fibrillation and the risk of ischemic stroke based on genetic variants. We assessed the relationship between ischemic stroke and atrial fibrillation among participants in Taiwan Biobank (TWB) based on the rs2860905 variant of the cytochrome P450 Family 2 Subfamily C Member 9 (CYP2C9) gene.Materials and Methods: Using logistic regression analysis, we estimated the odds ratios (OR) and 95% confidence intervals (CI) for ischemic stroke among 17,726 biobank adults recruited from 2008 through 2015.Results: Of the eligible participants (n = 17,726), 906 were identified with ischemic stroke. Atrial fibrillation was positively associated with ischemic stroke (OR=3.70; 95% CI, 2.21– 6.20), whereas the rs2860905 variant was not. The OR for ischemic stroke among those with GA/AA genotype was 1.00 (95% CI, 0.82– 1.22) compared to those with the GG genotype. Based on the genotype-stratified analysis, the OR for ischemic stroke was 4.68 (95% CI, 2.70– 8.09) among individuals with GG genotype who had atrial fibrillation compared to those who did not.Conclusion: These results demonstrate that the GG genotype of the CYP2C9 rs2860905 variant appears to enhance the risk of ischemic stroke among adults in Taiwan. It could be essential to factor this genotype-specific contributor to ischemic stroke into clinical and experimental investigations of the disease in Taiwan.Keywords: genetic variation, risk prediction, stroke

Huan-Cheng Chang,1,2 Oswald Ndi Nfor,3 Chien-Chang Ho,4,5 Pei-Hsin Chen,3 Ya-Yu Kung,6 Shu-Yi Hsu,3 Disline Manli Tantoh,3,7 Yi-Ching Liaw,8 Chuan-Fa Hsieh,9,10 Yung-Po Liaw3,7 1Division of Family Medicine, Department of Community Medicine, Landseed International Hospital, Taoyuan City 324, Taiwan; 2Department of Health Business Management Administration, Hungkuang University, Taichung City 43302, Taiwan; 3Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City 40201, Taiwan; 4Department of Physical Education, Fu Jen Catholic University, New Taipei 24205, Taiwan; 5Research and Development Center for Physical Education, Health, and Information Technology, Fu Jen Catholic University, New Taipei 24205, Taiwan; 6Division of Health Management, Landseed International Hospital, Taoyuan City 324, Taiwan; 7Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan; 8Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan; 9Department of Medical Education, Research & Quality Management, Landseed International Hospital, Taoyuan City 324, Taiwan; 10College of Health Sciences & Technology, National Central University, Taoyuan City 32001, TaiwanCorrespondence: Yung-Po LiawDepartment of Public Health and Institute of Public Health, Chung Shan Medical University, No. 110, Sec. 1 Jianguo N. Road, Taichung City 40201, TaiwanTel +886-4-24730022 ext.11838Fax +886-4-23248179Email Liawyp@csmu.edu.twChuan-Fa HsiehDepartment of Medical Education, Research & Quality Management, Landseed International Hospital, No. 77, Guangtai Road, Pingzhen City, Taoyuan, TaiwanTel +886-3-4941234 ext. 2172Fax +886-3-20641333-4246Email hsiehcf@landseed.com.twPurpose: High-density lipoprotein cholesterol (HDL-C) is essential for cardiometabolic health. Coffee consumption influences the body’s ability to regulate serum lipid profile. Although there is extensive information on coffee and cholesterol, not much is known whether changes in HDL-C concentrations are affected by coffee with or without flavoring substances.Materials and Methods: Using historical data collected from 1272 participants in Li-Shin (Landseed) International Hospital in Northern Taiwan, we examined the relationship between HDL-C and consumption of plain black coffee with and without additives. Data on coffee consumption between 2006 and 2019 were collected based on self-reported questionnaires while HDL-C measurements were obtained from the electronic medical records of the hospital. t-test, chi-square test and multivariate linear regression analysis were used for analysis.Results: In our primary analysis, we found that coffee consumption of ≥ 5 cups per week was positively associated with HDL-C (β = 1.9586, p=0.0442) compared with the lowest level (< 1 cup/week) of consumption. We found in a separate model that higher (≥ 5 cups/week) or lower (1– 4 cups/week) consumption of plain black coffee without additives was associated with higher HDL-C. The corresponding β values were 4.0674 (p = 0.0007) and 4.1253 (p = 0.0008), respectively. However, HDL-C levels were not affected by coffee with additives.Conclusion: We found that consumption of black coffee without additives was associated with higher concentrations of HDL-C among Taiwanese adults over the age of 30. However, HDL-C levels did not change significantly among individuals who consumed black coffee with additives.Keywords: coffee, cardiometabolic health, caffeine, lipid

Sirtuin 3 (SIRT3) is a protein deacetylase regulating beta cell function through inhibiting oxidative stress in obese and diabetic mice, but the detailed mechanism and potential effect of beta cell specific SIRT3 on metabolic homeostasis, and its potential effect on other metabolic organs are unknown. We found glucose tolerance and glucose stimulated insulin secretion (GSIS) were impaired in high fat diet (HFD)-fed beta cell selective Sirt3 knockout (Sirt3f/f;Cre/+) mice. In addition, Sirt3f/f;Cre/+ mice had more severe hepatic steatosis than Sirt3f/f mice upon HFD feeding. RNA sequencing (RNA-Seq) of islets suggested that Sirt3 deficiency over-activated 5-hydroxytryptamine (5-HT) synthesis as evidenced by up-regulation of tryptophan hydroxylase 1 (TPH1). 5-HT concentration was increased in both islets and serum of Sirt3f/f;Cre/+ mice. 5-HT also facilitated the effect of palmitate to increase lipid deposition. Treatment with TPH1 inhibitor ameliorated hepatic steatosis and reduced weight gain in HFD-fed Sirt3f/f;Cre/+ mice. These data suggested that under HFD feeding, SIRT3 deficiency in beta cells not only regulates insulin secretion but also modulates hepatic lipid metabolism via the release of 5-HT.

Wei-Yu Chen,1 Yi-Hsien Cheng,2 Nan-Hung Hsieh,3 Bo-Chun Wu,2 Wei-Chun Chou,4 Chia-Chi Ho,4 Jen-Kun Chen,5 Chung-Min Liao,2,* Pinpin Lin4,* 1Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 2Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, 3Institute of Labor, Occupational Safety and Health, Ministry of Labor, New Taipei City, 4National Institute of Environmental Health Sciences, 5Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan *These authors contributed equally tothis work Abstract: Zinc oxide nanoparticles (ZnO NPs) have been widely used in consumer products, therapeutic agents, and drug delivery systems. However, the fate and behavior of ZnO NPs in living organisms are not well described. The purpose of this study was to develop a physiologically based pharmacokinetic model to describe the dynamic interactions of 65ZnO NPs in mice. We estimated key physicochemical parameters of partition coefficients and excretion or elimination rates, based on our previously published data quantifying the biodistributions of 10nm and 71nm 65ZnO NPs and zinc nitrate (65Zn(NO3)2) in various mice tissues. The time-dependent partition coefficients and excretion or elimination rates were used to construct our physiologically based pharmacokinetic model. In general, tissue partition coefficients of 65ZnO NPs were greater than those of 65Zn(NO3)2, particularly the lung partition coefficient of 10nm 65ZnO NPs. Sensitivity analysis revealed that 71nm 65ZnO NPs and 65Zn(NO3)2 were sensitive to excretion and elimination rates in the liver and gastrointestinal tract. Although the partition coefficient of the brain was relative low, it increased time-dependently for 65ZnO NPs and 65Zn(NO3)2. The simulation of 65Zn(NO3)2 was well fitted with the experimental data. However, replacing partition coefficients of 65ZnO NPs with those of 65Zn(NO3)2 after day 7 greatly improved the fitness of simulation, suggesting that ZnO NPs might decompose to zinc ion after day 7. In this study, we successfully established a potentially predictive dynamic model for slowly decomposed NPs. More caution is suggested for exposure to 65ZnO NPs

Purpose: To determine the effect of the secondary metabolites from Penicillium sp. H9318 on cytotoxicity and cell cycle progression.Methods: A yeast PP1 inhibitory screening system was carried out to confirm the presence of anti-PP1c activity in crude acetone extracts of strain H9318. The extracts were fractionated and identified as Fraction S1 and Citrinin 9318 (CTN9318). Various cancer cell lines were used to test for the toxicity of the crude acetone extracts, Fraction S1 and Citrinin 9318, using MTT viability assay.Results: It was found that a colorectal cancer cell line, HT-29, was susceptible to Fraction S1 and Citrinin 9318. A propidium iodide (PI)-incorporated DNA assay was used to show that there was G2/M arrest in HT-29 by Citrinin 9318.Conclusion: Citrinin 9318 inhibits the viability of HT-29 via mitotic block. The results suggest that Citrinin 9318 is capable of exerting cytotoxicity and mitotic arrest in a colon cancer cell line, HT29.Keywords: Citrinin, Fraction S1, G2/M, HT-29, H9318, Protein phosphatase 1

We reviewed 4 cases of high-grade transitional-cell carcinoma (TCC) of the urinary tract with solitary pulmonary metastases that were studied by transthoracic needle aspiration biopsy cytology. There were two grade II and two grade III TCCs. The two grade II tumors yielded, in needle aspirates, syncytial tumor-cell clusters showing ill-defined, granular cytoplasm and slightly pleomorphic nuclei with inconspicuous nucleoli. In one case the tumor-cell cluster showed a focal acinar arrangement, mimicking cells of an adenocarcinoma. In both cases the electron microscopy (EM) study of aspirated tumor cells revealed epithelial cells with well-formed cell junctions, intracytoplasmic vesicles, apical short microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial neoplasm. The two grade III TCCs yielded, in needle aspirates, pleomorphic malignant cells singly and in small clusters, showing well-defined, granular cytoplasm and pleomorphic nuclei containing prominent nucleoli, suggesting a poorly differentiated adenocarcinoma or an anaplastic large-cell carcinoma. By EM examination the aspirated tumor cells from one case revealed well-formed cell junctions, intracytoplasmic vesicles, poorly formed microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial differentiation. In the other case the tumor cells were pleomorphic cells with occasional cell junctions and no ultrastructural features as seen in the other 3 cases of TCC. The tumor cells from the two grade II TCCs showed strong immunopositive reaction with keratin 7 antibody and weakly positive reaction with carcinoembryonic antigen antibody (CEAA), while those of the two grade III TCCs displayed only a weak and focal immunopositive staining with keratin 7 antibody and strong reaction with CEAA.

The aim was to evaluate the practice of hiding the needle prior to dental anesthesia administration to children. Fourteen 5 and 6 year olds received dental treatment in two sessions. The needle was shown in one session and hidden in the other. Eleven children were cooperative and 3 uncooperative irrespective of approach. The children's behavior correlated with fears expressed by the mothers. Our initial findings do not support the practice of hiding the needle.