Virtual Screening and Testing of GSK-3 Inhibitors Using Human SH-SY5Y Cells Expressing Tau Folding Reporter and Mouse Hippocampal Primary Culture under Tau Cytotoxicity

Lin Chih-Hsin,Hsieh Yu-Shao,Sun Ying-Chieh,Huang Wun-Han,Chen Shu-Ling,Weng Zheng-Kui,Lin Te-Hsien,Wu Yih-Ru,Chang Kuo-Hsuan,Huang Hei-Jen,Lee Guan-Chiun,Hsieh-Li Hsiu Mei,Lee-Chen Guey-Jen 한국응용약물학회 2023 Biomolecules & Therapeutics(구 응용약물학회지) Vol.31 No.1

Glycogen synthase kinase-3β (GSK-3β) is an important serine/threonine kinase that implicates in multiple cellular processes and links with the neurodegenerative diseases including Alzheimer’s disease (AD). In this study, structure-based virtual screening was performed to search database for compounds targeting GSK-3β from Enamine’s screening collection. Of the top-ranked compounds, 7 primary hits underwent a luminescent kinase assay and a cell assay using human neuroblastoma SH-SY5Y cells expressing Tau repeat domain (TauRD) with pro-aggregant mutation ΔK280. In the kinase assay for these 7 compounds, residual GSK-3β activities ranged from 36.1% to 90.0% were detected at the IC50 of SB-216763. In the cell assay, only compounds VB-030 and VB-037 reduced Tau aggregation in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. In SH-SY5Y cells expressing ΔK280 TauRD, neither VB-030 nor VB-037 increased expression of GSK-3α Ser21 or GSK-3β Ser9. Among extracellular signal-regulated kinase (ERK), AKT serine/threonine kinase 1 (AKT), mitogen-activated protein kinase 14 (P38) and mitogenactivated protein kinase 8 (JNK) which modulate Tau phosphorylation, VB-037 attenuated active phosphorylation of P38 Thr180/ Tyr182, whereas VB-030 had no effect on the phosphorylation status of ERK, AKT, P38 or JNK. However, both VB-030 and VB-037 reduced endogenous Tau phosphorylation at Ser202, Thr231, Ser396 and Ser404 in neuronally differentiated SH-SY5Y expressing ΔK280 TauRD. In addition, VB-030 and VB-037 further improved neuronal survival and/or neurite length and branch in mouse hippocampal primary culture under Tau cytotoxicity. Overall, through inhibiting GSK-3β kinase activity and/or p-P38 (Thr180/Tyr182), both compounds may serve as promising candidates to reduce Tau aggregation/cytotoxicity for AD treatment.

Trough Melatonin Levels Differ between Early and Late Phases of Alzheimer Disease

Chieh-Hsin Lin,Chih-Chiang Chiu,Hsien-Yuan Lane 대한정신약물학회 2021 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.19 No.1

Objective: Melatonin has been considered to have an essential role in the pathophysiology of Alzheimer’s disease (AD) for its regulatory function on circadian rhythm and interaction with glutamate for the modulation of learning and memory. Previous studies revealed that melatonin levels decreased in patients with AD. However, melatonin supplement didn’t show promising efficacy for AD. This study compared trough melatonin levels among elderly people with different severities of cognitive deficits. Methods: We enrolled 270 elder individuals (consisting four groups: healthy elderly, amnestic mild cognitive impairment [MCI], mild AD, and moderate-severe AD) in the learning cohort. Trough melatonin levels in plasma were measured using ELISA. Cognitive function was evaluated by Clinical Dementia Rating Scale (CDR) and Mini-Mental State Examination (MMSE). An independent testing cohort, also consisting of four groups, was enrolled for ascertainment. Results: In the learning cohort, trough melatonin levels decreased in the MCI group but elevated in the mild and moderate to severe AD groups. Trough melatonin levels were associated with CDR and MMSE in MCI or AD patients significantly. In the testing cohort, the results were similar to those in the learning cohort. Conclusion: This study demonstrated that trough melatonin levels in the peripheral blood were decreased in MCI but increased with the severity of AD. The finding supports the trials indicating that melatonin showed efficacy only in MCI but not in AD. Whether trough melatonin level has potential to be a treatment response biomarker for AD, especially its early phase needs further studies.

Book Review: Shuenn-Der Yu ed., Food Cultures and Technologies. Taipei: The Institute of Ethnology, Academia Sinica, 2022. 297 pp.

Yi-Chieh LIN,Wan-Hsin HSIA 한국과학사학회 2023 한국과학사학회지 Vol.45 No.2

Machine Learning and Deep Learning for the Pharmacogenomics of Antidepressant Treatments

Eugene Lin,Chieh-Hsin Lin,Hsien-Yuan Lane 대한정신약물학회 2021 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.19 No.4

A growing body of evidence now proposes that machine learning and deep learning techniques can serve as a vital foundation for the pharmacogenomics of antidepressant treatments in patients with major depressive disorder (MDD). In this review, we focus on the latest developments for pharmacogenomics research using machine learning and deep learning approaches together with neuroimaging and multi-omics data. First, we review relevant pharmacogenomics studies that leverage numerous machine learning and deep learning techniques to determine treatment prediction and potential biomarkers for antidepressant treatments in MDD. In addition, we depict some neuroimaging pharmacogenomics studies that utilize various machine learning approaches to predict antidepressant treatment outcomes in MDD based on the integration of research on pharmacogenomics and neuroimaging. Moreover, we summarize the limitations in regard to the past pharmacogenomics studies of antidepressant treatments in MDD. Finally, we outline a discussion of challenges and directions for future research. In light of latest advancements in neuroimaging and multi-omics, various genomic variants and biomarkers associated with antidepressant treatments in MDD are being identified in pharmacogenomics research by employing machine learning and deep learning algorithms.

Poster Session : PS 0589 ; Psychiatry ; Holistic Care Unit Improves Access Block in Emergency Department in Taiwan

( Meng Chieh Wu ),( Hsin Kai Huang ),( Chun Cheng Zhang ),( Li Sheng Chang ),( Yung Ze Cheng ),( Chien Chin Hsu ),( Kao Chang Lin ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Background: Emergency department (ED) overcrowding is a problem in many countries including Taiwan. Access block refers to a situation where patients in the emergency department requiring inpatient care are unable to gain access to appropriate hospital beds within a reasonable time frame (more than 8 hours total time in the emergency department). Access block is one major reason of ED overcrowding. Methods: A new holistic care unit was established in our medical center in Taiwan in July 2012, with the attending physicians including internal medicine physicians and a neurologist. The patients who required hospitalized treatment were referred to internal medicine physicians in the emergency department. The new department was comprised of seven experienced medical attending physician to take care of the patients directly, with 8-hour duty work shifts within 24 hours, in collaboration with emergency physicians, radiologists, nurses, social workers and case managers to form a team. This team had similar three-shift work duty, education and training programs, and they shared medical devices and resources. If beds in the intensive care unit or ward are not available immediately, procedures and treatment can be performed in the holistic care unit. The pediatric patients were excluded from this study. Results: In total, 26,623 patients were admitting to ward from our emergency department from August 2011 to July 2012, and 23,790 patients from August 2012 to July 2013. The rate of access block decreased from 55.29% to 50.01% ( p < 0.01) after holistic care unit was established. The mean time of ED length of stay was also improved from 18.04 hours to 15.43 hours ( p < 0.01). Conclusions: The newly established holistic care unit in our hospital improved the quality of medical care, not only physiologically but also psychologically.

Max-throughput interference avoidance mechanism for indoor self-organizing small cell networks

Kuang-Hsun Lin,Cho-Hsin Tsai,Jen-Wei Chang,Yu-Chieh Chen,Hung-Yu Wei,Fu-Ming Yeh 한국통신학회 2017 ICT Express Vol.3 No.3

Since mobile traffic has been growing recently, the deployment of indoor small cells has become an attractive solution to enhance coverage. However, the increasing density of cells makes inter-cell interference more considerable. In this paper, we propose a max-throughput Interference Avoidance (MTIA) centralized algorithm to improve the system’s throughput. Based on signaling and reports, a central controller connected to each base station can properly turn off base stations that may induce a relatively strong interference, and thus increase SINR. We implemented the MTIA algorithm in an LTE TDD network simulation and showed that MTIA effectively reduces inter-cell interference and improves the system’s throughput.

Effects of Antipsychotics on Bone Mineral Density in Patients with Schizophrenia: Gender Differences

Chien-Yu Chen,Hsien-Yuan Lane,Chieh-Hsin Lin 대한정신약물학회 2016 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.14 No.3

Low bone mineral density (BMD) and osteoporosis are common in patients with schizophrenia and detrimental to illness prognosis and life quality. Although the pathogenesis is not fully clear, series of studies have revealed factors related to low BMD such as life style, psychotic symptoms, medication use and the activity of bone absorption markers. It has been known that antipsychotic- induced hyperprolactinemia plays a critical role on decreased BMD. However, it remains uncertain whether the risk factors differ between men and women. According to the effect on prolactin, antipsychotics can be classified into two groups: prolactin-sparing (PS) and prolactin-raising (PR). Our previous study has demonstrated that clozapine which is among the PS antipsychotics is beneficial for BMD when compared with PR antipsychotics in women with chronic schizophrenia. We have also found that risks factors associated with low BMD are different between men and women, suggesting that gender-specific risk factors should be considered for intervention of bone loss in patients with schizophrenia. This article reviews the effects of antipsychotics use on BMD with particular discussion for the differences on gender and age, which implicate the alterations of sex and other related hormones. In addition, currently reported protective and risk factors, as well as the effects of medication use on BMD including the combination of antipsychotics and other psychotropic agents and other potential medications are also reviewed.

Venous Thromboembolism Following Dantrolene Treatment for Neuroleptic Malignant Syndrome

Po-Hao Chen,Hsien-Yuan Lane,Chieh-Hsin Lin 대한정신약물학회 2016 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.14 No.4

Neuroleptic malignant syndrome (NMS) is one of the most severe iatrogenic emergencies in clinical service. The symptoms including sudden consciousness change, critical temperature elevation and electrolytes imbalance followed by mutli-organ system failure were common in NMS. In addition to aggressive interventions with intravenous fluid resuscitation and antipyretics, several antidotes have been suggested to prevent further progression of the muscle damage. Dantrolene has been reported to be one of the most effective treatments for NMS. However, the adverse effects of dantrolene treatment for NMS have not yet been evaluated thoroughly. Here we report a young male patient with bipolar I disorder who developed NMS after rapid tranquilization with haloperidol. Dantrolene was given intravenously for the treatment of NMS. However, fever accompanied with local tenderness, hardness with clear border and swelling with heat over the patient’s left forearm occurred on the sixth day of dantrolene treatment. Venous thromboembolism (VTE) over intravenous indwelling site at the patient’s forearm was noted and confirmed by Doppler ultrasound. The patient’s VTE recovered after heparin and warfarin thrombolytic therapy. To our knowledge, this is the first case report demonstrating the possible relationship between dantrolene use and VTE in a patient with antipsychotic treatment. Although the causal relationship and the underlying pathogenesis require further studies, dantrolene should be used with caution for patients with NMS.

Novel Biomarkers of Alzheimer’s Disease: Based Upon N-methyl-D-aspartate Receptor Hypoactivation and Oxidative Stress

Ting-I Chiang,Yi-Hsiang Yu,Chieh-Hsin Lin,Hsien-Yuan Lane 대한정신약물학회 2021 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.19 No.3

Early detection and prevention of Alzheimer’s disease (AD) is important. The current treatment for early AD is acetylcholine esterase inhibitors (AChEIs); however, the efficacy is poor. Besides, AChEI did not show efficacy in mild cognitive impairment (MCI). Beta-amyloid (A) deposits have been regarded to be highly related to the pathogenesis of AD. However, many clinical trials aiming at the clearance of A deposits failed to improve the cognitive decline of AD, even at its early phase. There should be other important mechanisms unproven in the course of AD and MCI. Feasible biomarkers for the diagnosis and treatment response of AD are lacking to date. The N-methyl-D-aspartate receptor (NMDAR) activation plays an important role in learning and memory. On the other hand, oxidative stress has been regarded to contribute to aging with the assumption that free radicals damage cell constituents and connective tissues. Our recent study found that an NMDAR enhancer, sodium benzoate (the pivotal inhibitor of D-amino acid oxidase [DAAO]), improved the cognitive and global function of patients with early-phase AD. Further, we found that peripheral DAAO levels were higher in patients with MCI and AD than healthy controls. We also found that sodium benzoate was able to change the activity of antioxidant. These pieces of evidence suggest that the NMDAR function is associated with anti-oxidation, and have potential to be biomarkers for the diagnosis and treatment response of AD.

Clinical Features of Patients with Esophageal and Second Primary Cancers

Tsai, Huang-Wen,Chang, Chih-Chun,Sun, Jen-Tang,Liou, Ching-Biau,Lin, Hsiu-Chen,Lin, I-Hsin,Yu, Yun-Chieh,Weng, Wei-Ling,Leong, Ka-I,Yen, Tzung-Hai,Wu, Jiann-Ming Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.22

Background: The prevalence of esophageal cancer (EC) with second primary cancers (SPC) is increasing worldwide. This study was aimed to understand the clinical features of EC patients with SPC in the Taiwanese population. Materials and Methods: Clinical and laboratory data for 180 EC patients with or without SPC were collected between January 2009 and December 2013. Information on treatment approaches, location of SPCs and ABO blood type were also collected and stratified. Results: The most common SPC in EC patients was hypopharyngeal cancer, followed by laryngeal cancer and hepatocellular carcinoma in our study. Malignancies of colon, prostate and lung were also found. There was a significant higher portion of blood type A in the EC patients with SPC compared with those without (42.4% vs 19.5%, P=0.006). Conclusions: The frequency and SPC site distribution and blood type A should be considered in clinical evaluation of EC patients with a high risk of developing SPC in the Taiwanese population.