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.

New Frontiers or the Treatment of Interstitial Cystitis/Bladder Pain Syndrome - Focused on Stem Cells, Platelet-Rich Plasma, and Low-Energy Shock Wave

Chih-Chieh Lin,Yun-Ching Huang,Wei-Chia Lee,Yao-Chi Chuang 대한배뇨장애요실금학회 2020 International Neurourology Journal Vol.24 No.3

Interstitial cystitis/bladder pain syndrome (IC/BPS), which is characterized by bladder pain and irritative voiding symptoms, is a frustrating disease without effective treatment. The cause is still largely not understood, although urothelium ischemia/hypoxia, apoptosis, denudation, and infiltration of inflammatory cells are common histopathological findings. The current uncertainty regarding the etiology and pathology of IC/BPS has a negative impact on its timely and successful treatment; therefore, the development of new treatment modalities is urgently needed. Herein, we present advances in our knowledge on this topic and review the potential application of regenerative medicine for the treatment of IC/BPS. This article provides information on the basic characteristics and clinical evidence of stem cells, platelet-rich plasma (PRP), and low-energy shock waves (LESWs) based on a literature review with a search strategy for articles related to IC/BPS, stem cells, PRP, and LESW published in MEDLINE and PubMed. Stem cells, PRP, and LESW, which modulate inflammatory processes and promote tissue repair, have been proven to improve bladder regeneration, relieve bladder pain, inhibit bladder inflammation, and increase bladder capacity in some preclinical studies. However, clinical studies are still in their infancy. Based on the mechanisms of action of stem cells, PRP, and LESW documented in many preclinical studies, the potential applications of regenerative medicine for the treatment of IC/BPS is an emerging frontier of interest. However, solid evidence from clinical studies remains to be obtained.

Comparative Study Between Behavior Therapy and Behavior Therapy Plus Mirabegron 50 mg in Sexually Active Men With Bothersome Overactive Bladder Symptoms – A Multicenter, Randomized Study

Chih-Chieh Lin,Hann-Chorng Kuo,Jian-Ri Li,Yao-Chi Chuang 대한배뇨장애요실금학회 2023 International Neurourology Journal Vol.27 No.3

Purpose: We evaluated the therapeutic effects on overactive bladder (OAB) symptoms and sexual function of behavioral therapy with or without mirabegron in sexually active male patients with OAB. Mirabegron, a selective β3 adrenoceptor agonist for the treatment of OAB, has been shown to induce corpus cavernosum relaxation. Methods: In this 4-site, randomized controlled trial, 150 sexually active men with OAB were enrolled between June 2020 and May 2022. Participants were randomly allocated (1:2) into 2 treatment groups: (1) behavioral therapy alone (n=50) and (2) a combination of mirabegron 50 mg daily and behavioral therapy (n=100). The evaluation was based on the overactive bladder symptoms score (OABSS), the International Index of Erectile Function, the ejaculatory domain short form, the International Prostate Symptom Score, patient perception of bladder condition, quality of life, and urodynamic parameters. The therapeutic outcomes were assessed at baseline, 4 weeks, and 12 weeks. Results: There were 65 patients (65%) in the combination subgroup and 36 patients in the behavioral therapy who completed all 12 weeks of treatment. Both groups had a statistically significant improvement in OABSS after 12 weeks of treatment. The combination therapy group achieved a statistically significant improvement in all 4 subscores of OABSS, however, the urinary frequency (P=0.120) and urinary incontinence (P=0.234) subscores in the behavioral therapy only group did not show a significant change. Additionally, the combination group had a significant improvement in functional bladder capacity, which was not seen in the behavioral therapy group. However, both groups did not have a significant change in erectile or ejaculatory function. Conclusions: Behavioral therapy combined with mirabegron had more significant impact on the improvement of OAB than behavior therapy alone. However, both groups did not have significant changes in erectile or ejaculatory function.

Sofosbuvir/Ledipasvir in the Treatment of Chronic Hepatitis C - A Subgroup Analysis from A Nationwide Real-World HCV Registry Program (TACR) in Taiwan

( Ming-Lung Yu ),( Chi-Yi Chen ),( Kuo-Chih Tseng ),( Ching-Chu Lo ),( Pin-Nan Cheng ),( Cheng-Yuan Peng ),( Ming-Jong Bair ),( Chih-Lang Lin ),( Chi-Ming Tai ),( Chi-Chieh Yang ),( Chih-Wen Lin ),( C 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: TASL HCV Registry (TACR) is a nationwide registry program organized and supervised by Taiwan Association for the Study of the Liver (TASL), which aims to setup the database and biobank of patients with chronic hepatitis C (CHC) in Taiwan. The present study aimed to evaluate the treatment outcome of sofosbuvir (SOF)/ledipasvir (LDV) in Taiwanese CHC patients in TACR. Methods: By May 2020, 19 tertiary hospitals, 23 community hospitals and one primary care clinic join the TACR program. The baseline characteristics, prior liver and non-liver related medical history, DAA regimens, laboratory results, treatment course and outcome were recorded. The primary objective was sustained virological response, defined as undetectable HCV RNA 3 months after end-of-treatment (SVR12). Results: A total of 4742 SOF/LDV+ ribavirin treated CHC patients with available SVR12 data from 39 sites were enrolled in the current analysis. The mean age was 61.3 years, and female accounted for 54.8% of the population. The dominant viral genotypes were GT1b (52.6%) and GT2 (35.6%). 1354 (28.6%) patients had liver cirrhosis, including 156 (3.3%) with liver decompensation, 552 (11.6%) had preexisting hepatocellular carcinoma (HCC) before DAAs treatment and 413 (8.7%) had hepatitis B virus dual infections. The overall SVR12 rate was 98.5%, with 98.5%, 98.2%, 99.7% and 98.6% in treatment- naïve non-cirrhotics, treatment-naïve cirrhotics, treatment- experienced non-cirrhotics and treatment-experienced cirrhotics patients, respectively. While patients were stratified by HCV genotype, the SVR12 was 98.5%, 98.4% and 98.5% among those with GT1, GT2 and GT6 infection, respectively. The strongest factor independent associated with treatment failure was DAA adherence < 60% (odds ratio [OR]/95% confidence intervals [CI]: 125.4/25.7-612.4, P<0.0001), followed by active HCC (OR/CI: 6.20/2.57-14.97, P<0.0001), HIV co-infection (OR/CI: 3.01/1.14-7.92, P=0.026), and male gender (OR/ CI: 1.85/1.09-3.13, P=0.023). The eGFR decreased significantly at the end of treatment (EOT) (89.3 ml/min/1.73㎡ vs. 93.2 ml/min/1.73㎡, P< 0.001) and remained stable 3 months after EOT (89.3 ml/min/1.73㎡). However, the decreased eGFR was observed only in patients whose baseline eGFR > 90 ml/ min/1.73㎡. Instead, patients with chronic kidney diseases whose pretreatment eGFR < 60 ml/min/1.73㎡ had improved eGFR after SOF/LDV. Conclusions: SOF/LDV is highly effective in treating CHC patients in real-world setting of Taiwan. The satisfactory result could be explicitly generalized to patients with different viral genotypes and liver disease severities.

New Three-Level PWM DC/DC Converter - Analysis, Design and Experiments

Lin, Bor-Ren,Chen, Chih-Chieh The Korean Institute of Power Electronics 2014 JOURNAL OF POWER ELECTRONICS Vol.14 No.1

This paper studies a new three-level pulse-width modulation (PWM) resonant converter for high input voltage and high load current applications. In order to use high frequency power MOSFETs for high input voltage applications, a three-level DC converter with two clamped diodes and a flying capacitor is adopted in the proposed circuit. For high load current applications, the secondary sides of the proposed converter are connected in parallel to reduce the size of the magnetic core and copper windings and to decrease the current rating of the rectifier diodes. In order to share the load current and reduce the switch counts, three resonant converters with the same active switches are adopted in the proposed circuit. Two transformers with a series connection in the primary side and a parallel connection in the secondary side are adopted in each converter to balance the secondary side currents. To overcome the drawback of a wide range of switching frequencies in conventional series resonant converters, the duty cycle control is adopted in the proposed circuit to achieve zero current switching (ZCS) turn-off for the rectifier diodes and zero voltage switching (ZVS) turn-on for the active switches. Finally, experimental results are provided to verify the effectiveness of the proposed converter.

Study molded part quality of plastic injection process by melt viscosity evaluation

Lin, Chung-Chih,Wu, Chieh-Liang Techno-Press 2014 Advances in materials research Vol.3 No.2

A study that demonstrates how to investigate the molded part quality and the consistency of injection process based on the rheological concept is proposed. It is important for plastic material whose melt viscosity is variable with respect to the processing condition. The formulations to couple the melt viscosity with injection pressure and fill time are derived first. Taking calculations of the measured pressure and the time by using these formulations, the melt viscosity in injection process can be determined on machine. As the relation between the injection speed and the melt viscosity is constructed, the influences of the setting parameter of injection machine on the molded part quality can be investigated through evaluating the state of the melt viscosity. In addition, a pressure sensor bushing (PSB) designed with a quick installation feature is also provided and validated. The results show that a higher injection speed improves the tensile strength of the molded part but also the consistency of the molded part quality. This work provides an alternative to evaluate the molding quality scientifically.

Analysis, Design and Implementation of an Interleaved DC/DC Converter with Series-Connected Transformers

Lin, Bor-Ren,Chen, Chih-Chieh The Korean Institute of Power Electronics 2012 JOURNAL OF POWER ELECTRONICS Vol.12 No.4

An interleaved DC/DC converter with series-connected transformers is presented to implement the features of zero voltage switching (ZVS), load current sharing and ripple current reduction. The proposed converter includes two half-bridge converter cells connected in series to reduce the voltage stress of the switches at one-half of the input voltage. The output sides of the two converter cells with interleaved pulse-width modulation are connected in parallel to reduce the ripple current at the output capacitor and to achieve load current sharing. Therefore, the size of the output chokes and the capacitor can be reduced. The output capacitances of the MOSFETs and the resonant inductances are resonant at the transition instant to achieve ZVS turn-on. In addition, the switching losses on the power switches are reduced. Finally, experiments on a laboratory prototype (24V/40A) are provided to demonstrate the performance of the proposed converter.

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.

Iatrogenic Subclavian Artery Perforation Rescued by Operator-Modified Graft Sent

Chih-Hung Lai,Wen-Lieng Lee,Chung-Lin Tsai,Wei-Chun Chang,Chieh-Shou Su 연세대학교의과대학 2017 Yonsei medical journal Vol.58 No.2

Subclavian artery (SCA) perforation is a rare complication while performing SCA intervention. In our present report, a 73-year-old female, with stenosis of the left SCA and situs inversus, presented with exercise-induced left arm weakness. The SCA stenosis was treated with direct stenting with a balloon-expansible Express LD 10×25 mm stent. However, it caused iatrogenic SCA perforationand hemothorax. The perforation was sealed by endovascular repair with operator-modified Endurant II graft stent, which complicated with occlusion of left common carotid artery. And, the carotid artery was rescued by another stent. The graft stent, which was originally designed for abdominal aortic aneurysm, can be modified to suitable length and take as a rescue stent of large vessel with iatrogenic perforation. Due to strong radial force of graft stent, preservation of large side branches should been watched out.

Analysis of an Interleaved Resonant Converter for High Voltage and High Current Applications

Lin, Bor-Ren,Chen, Chih-Chieh The Korean Institute of Electrical Engineers 2014 Journal of Electrical Engineering & Technology Vol.9 No.5

This paper presents an interleaved resonant converter to reduce the voltage stress of power MOSFETs and achieve high circuit efficiency. Two half-bridge converters are connected in series at high voltage side to limit MOSFETs at $V_{in}/2$ voltage stress. Flying capacitor is used between two series half-bridge converters to balance two input capacitor voltages in each switching cycle. Variable switching frequency scheme is used to control the output voltage. The resonant circuit is operated at the inductive load. Thus, the input current of the resonant circuit is lagging to the fundamental input voltage. Power MOSFETs can be turn on under zero voltage switching. Two resonant circuits are connected in parallel to reduce the current stress of transformer windings and rectifier diodes at low voltage side. Interleaved pulse-width modulation is adopted to decrease the output ripple current. Finally, experiments are presented to demonstrate the performance of the proposed converter.