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Potential protective role of ACE-inhibitors and AT1 receptor blockers against levodopa-induced dyskinesias:a retrospective case-control study

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Neural Regeneration Research 2021年第12期16卷 2475-2478页

作者： Elena Contaldi Luca Magistrelli Anna VMilner Marco Cosentino Franca Marino Cristoforo Comi Movement Disorders Centre Neurology UnitDepartment of Translational MedicineUniversity of Piemonte OrientaleNovaraItaly PhD Program in Medical Sciences and Biotechnology University of Piemonte OrientaleNovaraItaly PhD Program in Clinical and Experimental Medicine and Medical Humanities University of InsubriaVareseItaly Center of Research in Medical Pharmacology University of InsubriaVareseItaly Center for Research in Neuroscience University of InsubriaVareseItaly

Growing evidence has highlighted that angiotensin-converting enzyme(ACE)-inhibitors(ACEi)/AT1 receptor blockers(ARBs)may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway,thus affecting the development of levodopa-induced dyskinesia in Parkinson’s disease(PD).In the present study,we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia,using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital“Maggiore della Carità”.We conducted a retrospective case-control study identifying PD patients with dyskinesias(PwD;n=47)as *** each PwD we selected a non-dyskinetic control(NoD),nearly perfectly matched according to sex,Unified Parkinson’s Disease Rating Scale(UPDRS)part III score,and duration of antiparkinsonian *** logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs ***-four PD patients were included,aged 72.18±9 years,with an average disease duration of 10.20±4.8 years and 9.04±4.9 years of antiparkinsonian *** mean UPDRS part III score was 18.87±7.6 and the median HY stage was *** the NoD group,25(53.2%)were users and 22(46.8%)non-users of ACEi/***,in the PwD group,11(23.4%)were users and 36 non-users(76.6%)of this drug class(Pearson chi-square=8.824,P=0.003).Concerning general medication,there were no other statistically significant differences between *** controlling for tremor dominant phenotype,levodopa equivalent daily dose,HY 3-4,and disease duration,ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia(OR=0.226,95%CI:0.080-0.636,P=0.005).Therefore,our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and,thanks to good tolerability and easy management,represent a feasible choice when dealing with the treatment of hypertension in PD patients.

关键词： angiotensin-converting enzyme inhibitors AT1 receptor blockers dyskinesias hypertension levodopa motor complications neuroinflammation Parkinson’s disease renin-angiotensin system

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Targeting protein-protein interaction interfaces with antiviral N protein inhibitor in SARS-CoV-2

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Biophysical Journal 2024年第4期123卷 478-488页

作者： Hong, Jhen-Yi Lin, Shih-Chao Kehn-Hall, Kylene Zhang, Kai-Min Luo, Shun-Yuan Wu, Hung-Yi Chang, Sui-Yuan Hou, Ming-Hon Institute of Genomics and Bioinformatics and Department of Life Sciences National Chung Hsing University Taichung Taiwan Bachelor Degree Program in Marine Biotechnology College of Life Sciences National Taiwan Ocean University Keelung Taiwan Department of Biomedical Sciences and Pathobiology Virginia-Maryland College of Veterinary Medicine Virginia Polytechnic Institute and State University Blacksburg VA United States Center for Emerging Zoonotic and Arthropod-borne Pathogens Virginia Polytechnic Institute and State University Blacksburg VA United States Department of Chemistry National Chung Hsing University Taichung Taiwan Graduate Institute of Veterinary Pathobiology College of Veterinary Medicine National Chung Hsing University. Taichung Taiwan Department of Clinical Laboratory Sciences and Medical Biotechnology College of Medicine National Taiwan University Taipei Taiwan PhD Program in Medical Biotechnology National Chung Hsing University Taichung Taiwan Biotechnology Center National Chung Hsing University Taichung Taiwan

Coronaviruses not only pose significant global public health threats but also cause extensive damage to livestock-based industries. Previous studies have shown that 5-benzyloxygramine (P3) targets the Middle East respiratory syndrome coronavirus (MERS-CoV) nucleocapsid (N) protein N-terminal domain (N-NTD), inducing non-native protein-protein interactions (PPIs) that impair N protein function. Moreover, P3 exhibits broad-spectrum antiviral activity against CoVs. The sequence similarity of N proteins is relatively low among CoVs, further exhibiting notable variations in the hydrophobic residue responsible for non-native PPIs in the N-NTD. Therefore, to ascertain the mechanism by which P3 demonstrates broad-spectrum anti-CoV activity, we determined the crystal structure of the SARS-CoV-2 N-NTD:P3 complex. We found that P3 was positioned in the dimeric N-NTD via hydrophobic contacts. Compared with the interfaces in MERS-CoV N-NTD, P3 had a reversed orientation in SARS-CoV-2 N-NTD. The Phe residue in the MERS-CoV N-NTD:P3 complex stabilized both P3 moieties. However, in the SARS-CoV-2 N-NTD:P3 complex, the Ile residue formed only one interaction with the P3 benzene ring. Moreover, the pocket in the SARS-CoV-2 N-NTD:P3 complex was more hydrophobic, favoring the insertion of the P3 benzene ring into the complex. Nevertheless, hydrophobic interactions remained the primary stabilizing force in both complexes. These findings suggested that despite the differences in the sequence, P3 can accommodate a hydrophobic pocket in N-NTD to mediate a non-native PPI, enabling its effectiveness against various CoVs. © 2024 Biophysical Society

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Seasonal shift in gut microbiome diversity in wild Sichuan takin (Budorcas tibetanus) and environmental adaptation

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Computational and Structural biotechnology Journal 2023年 21卷 1283-1291页

作者： Guan, Tian-Pei Teng, Jade L.L Fong, Jordan Y.H Lau, Susanna K.P Woo, Patrick C.Y Institute of Qinghai-Tibetan Plateau Southwest Minzu University Chengdu610225 China Faculty of Dentistry The University of Hong Kong Hong Kong Department of Microbiology School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong PhD Program in Translational Medicine and Department of Life Sciences National Chung Hsing University Taichung 402 Taiwan The iEGG and Animal Biotechnology Research Center National Chung Hsing University Taichung 402 Taiwan

In this study, we investigated the change in microbiome composition of wild Sichuan takin (Budorcas tibetanus) during winter and spring and analyzed the physiological implications for such changes. Diversity analyses of the microbiome (average 15,091 high-quality reads per sample) in 24 fecal samples (15 from winter, 9 from spring) revealed that spring samples had higher species diversity and were compositionally different from winter samples (P © 2023 The Authors

关键词： Biodiversity

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Chlorine-containing polyacetoxybriarane diterpenoids from the octocoral Junceella fragilis

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RSC Advances 2024年第24期14卷 17195-17201页

作者： Do, Hai Nhat Chen, Yu-Ta Chien, Su-Ying Chen, You-Ying Zhang, Mingzi M. Tsou, Lun Kelvin Chen, Jih-Jung Wen, Zhi-Hong Lo, Yi-Hao Zheng, Li-Guo Sung, Ping-Jyun Department of Marine Biotechnology and Resources National Sun Yat-sen University Kaohsiung804201 Taiwan National Museum of Marine Biology & Aquarium Pingtung944401 Taiwan Department of Family Medicine Zuoying Armed Forces General Hospital Kaohsiung813204 Taiwan Instrumentation Center National Taiwan University Taipei106319 Taiwan Institute of Molecular and Genomic Medicine National Health Research Institutes Miaoli350401 Taiwan Institute of Biotechnology and Pharmaceutical Research National Health Research Institutes Miaoli350401 Taiwan Department of Pharmacy School of Pharmaceutical Sciences National Yang Ming Chia Tung University Taipei112304 Taiwan Shu-Zen Junior College of Medicine and Management Kaohsiung821004 Taiwan Institute of Medical Science and Technology National Sun Yat-sen University Kaohsiung804201 Taiwan Doctoral Degree Program in Marine Biotechnology National Sun Yat-sen University Kaohsiung804201 Taiwan Chinese Medicine Research and Development Center China Medical University Hospital Taichung404394 Taiwan Graduate Institute of Natural Products Kaohsiung Medical University Kaohsiung807378 Taiwan PhD Program in Pharmaceutical Biotechnology Fu Jen Catholic University New Taipei City242062 Taiwan

The chemical screening of an octocoral identifed as Junceella fragilis has led to the isolation of five chlorinated briarane-type diterpenoids, including three known metabolites, gemmacolide X (1), frajunolide I (2), and fragilide F (3), along with two new analogs, 12α-acetoxyfragilide F (4) and 12α-acetoxyjunceellin (5). Single-crystal X-ray diffraction analysis was carried out to determine the absolute configurations of 1 and 2, while the structures of new compounds 4 and 5 were ascertained with 2D NMR experiments. Briaranes 1 and 3-5 were active in enhancing alkaline phosphatase (ALP) activity. © 2024 The Royal Society of Chemistry.

关键词： Metabolites

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Caffeic acid phenethyl ester suppresses the expression of androgen receptor variant 7 via inhibition of CDK1 and AKT

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Cancer Gene Therapy 2024年第6期31卷 807-815页

作者： Kuo, Ying-Yu Huo, Chieh Li, Chia-Yang Chuu, Chih-Pin Institute of Cellular and System Medicine National Health Research Institutes Miaoli County Taiwan Graduate Institute of Medicine College of Medicine Kaohsiung Medical University Kaohsiung Taiwan Department of Medical Research Kaohsiung Medical University Kaohsiung Taiwan PhD Program for Aging and Graduate Institute of Basic Medical Science China Medical University Taichung City Taiwan Biotechnology Center National Chung Hsing University Taichung City Taiwan Department of Life Sciences National Central University Taoyuan City Taiwan

Androgen receptor (AR) splice variant 7 (AR-V7) is capable to enter nucleus and activate downstream signaling without ligand. AR-V7 assists the tumor growth, cancer metastasis, cancer stemness, and the evolvement of therapy-resistant prostate cancer (PCa). We discovered that caffeic acid phenethyl ester (CAPE) can repress the expression and downstream signaling of AR-V7 in PCa cells. CAPE blocked the gene transcription, nuclear localization, and protein abundance of AR-V7. CAPE inhibited the expression of U2AF65, SF2 and hnRNPF, which were splicing factors for AR-V7 intron. Additionally, CAPE decreased protein stability of AR-V7 and enhanced the proteosome-degradation of AR-V7. We observed that CDK1 and AKT regulated the expression and stability of AR-V7 via phosphorylation of Ser81 and Ser213, respectively. CAPE decreased the expression of CDK1 and AKT. Overexpression of CDK1 restored the abundance of AR-V7 in CAPE-treated PCa cells. Overexpression of AR-V7, AKT or CDK1 rescued the proliferation of PCa cells under CAPE treatment. Intraperitoneal injection of 10 mg/kg CAPE retarded the growth of 22Rv1 xenografts in nude mice and suppressed the protein levels of AR-V7, CDK1 and AKT in 22Rv1 xenografts. Our study provided the rationale of applying CAPE for inhibition of AR-V7 in prostate tumors. (Figure presented.). © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

关键词： Drug development Prostate cancer

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Fipronil disturbs the antigen-specific immune responses and GABAergic gene expression in the ovalbumin-immunized BALB/c mice

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BMC Veterinary Research 2024年第1期20卷 30页

作者： Kuo, Jui-Fang Cheng, Yin-Hua Tung, Chun-Wei Wang, Chia-Chi School of Veterinary Medicine National Taiwan University Taipei Taiwan PhD Program in Toxicology Kaohsiung Medical University Kaohsiung Taiwan Institute of Biotechnology and Pharmaceutical Research National Health Research Institutes Miaoli County Taiwan

Background: Fipronil (FPN) is a broad-spectrum pesticide and commonly known as low toxicity to vertebrates. However, increasing evidence suggests that exposure to FPN might induce unexpected adverse effects in the liver, reproductive, and nervous systems. Until now, the influence of FPN on immune responses, especially T-cell responses has not been well examined. Our study is designed to investigate the immunotoxicity of FPN in ovalbumin (OVA)-sensitized mice. The mice were administered with FPN by oral gavage and immunized with OVA. Primary splenocytes were prepared to examine the viability and functionality of antigen-specific T cells ex vivo. The expression of T cell cytokines, upstream transcription factors, and GABAergic signaling genes was detected by qPCR. Results: Intragastric administration of FPN (1–10 mg/kg) for 11 doses did not show any significant clinical symptoms. The viability of antigen-stimulated splenocytes, the production of IL-2, IL-4, and IFN-γ by OVA-specific T cells, and the serum levels of OVA-specific IgG₁ and IgG_2a were significantly increased in FPN-treated groups. The expression of the GABAergic signaling genes was notably altered by FPN. The GAD67 gene was significantly decreased, while the GABAR β2 and GABAR δ were increased. Conclusion: FPN disturbed antigen-specific immune responses by affecting GABAergic genes in vivo. We propose that the immunotoxic effects of FPN may enhance antigen-specific immunity by dysregulation of the negative regulation of GABAergic signaling on T cell immunity. © 2024, The Author(s).

关键词： Antigen-specific immune responses Fipronil GABAergic signaling Immunotoxicity Ovalbumin

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The difference between dacomitinib and afatinib in effectiveness and safety in first-line treatment of patients with advanced EGFR-mutant non-small cell lung cancer: a real-world observational study

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BMC Cancer 2024年第1期24卷 1页

作者： Cheng, Wen-Chien Lin, Chi-Chien Liao, Wei-Chih Lin, Yu-Chao Chen, Chia-Hung Chen, Hung-Jen Tu, Chih-Yen Hsia, Te-Chun Division of Pulmonary and Critical Care Department of Internal Medicine China Medical University Hospital Taichung Taiwan School of Medicine College of Medicine China Medical University Taichung Taiwan Department of Life Science National Chung Hsing University Taichung Taiwan PhD Program in Translational Medicine National Chung Hsing University Taichung Taiwan Rong Hsing Research Center for Translational Medicine National Chung Hsing University Taichung Taiwan Institute of Biomedical Science the iEGG and Animal Biotechnology Center Advanced Plant and Food Crop Biotechnology Center National Chung-Hsing University Taichung Taiwan Department of Pharmacology College of Medicine Kaohsiung Medical University Kaohsiung Taiwan Department of Medical Research Taichung Veterans General Hospital Taichung Taiwan

Objectives: The irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) afatinib and dacomitinib are approved for first-line treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and dacomitinib in this setting. Materials and methods: Between September 2020 and March 2023, we retrospectively recruited patients diagnosed with advanced-stage EGFR-mutant NSCLC who were treated with first-line irreversible EGFR-TKIs. The enrolled patients were assigned to two groups based on whether they received afatinib or dacomitinib. Results: A total of 101 patients were enrolled in the study (70 to afatinib and 31 to dacomitinib). The partial response rates (PR) for first-line treatment with afatinib and dacomitinib were 85.7 and 80.6% (p = 0.522). The median progression-free survival (PFS) (18.9 vs. 16.3 months, p = 0.975) and time to treatment failure (TTF) (22.7 vs. 15.9 months, p = 0.324) in patients with afatinib and dacomitinib treatment were similar. There was no significant difference observed in the median PFS (16.1 vs. 18.9 months, p = 0.361) and TTF (32.5 vs. 19.6 months, p = 0.182) between patients receiving the standard dose and those receiving the reduced dose. In terms of side effects, the incidence of diarrhea was higher in the afatinib group (75.8% vs. 35.5%, p < 0.001), while the incidence of paronychia was higher in the dacomitinib group (58.1% vs. 31.4%, p = 0.004). The PFS (17.6 vs. 24.9 months, p = 0.663) and TTF (21.3 vs. 25.1 months, p = 0.152) were similar between patients younger than 75 years and those older than 75 years. Conclusion: This study showed that afatinib and dacomitinib had similar effectiveness and safety profiles. However, they have slightly different side effects. Afatinib and dacomitinib can be safely administered to patients across different age groups with appropriate dose reductions. © The Author(s) 2024.

关键词： Afatinib Dacomitinib Epidermal growth factor receptor (EGFR) Non-small cell lung cancer (NSCLC)

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Structural insights into the molecular mechanism of phytoplasma immunodominant membrane protein

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IUCrJ 2024年第PT 3期11卷 384-394页

作者： Chang Yi Liu Han Pin Cheng Chan Pin Lin Yi Ting Liao Tzu Ping Ko Shin Jen Lin Shih Shun Lin Hao Ching Wang The PhD Program for Translational Medicine College of Medical Science and Technology Taipei Medical University and Academia Sinica Taipei Taiwan. Institute of Biotechnology National Taiwan University Taipei Taiwan. Institute of Biological Chemistry Academia Sinica Taipei Taiwan. International Center for the Scientific Development of Shrimp Aquaculture National Cheng Kung University Tainan Taiwan.

Immunodominant membrane protein (IMP) is a prevalent membrane protein in phytoplasma and has been confirmed to be an F-actin-binding protein. However, the intricate molecular mechanisms that govern the function of IMP require further elucidation. In this study, the X-ray crystallographic structure of IMP was determined and insights into its interaction with plant actin are provided. A comparative analysis with other proteins demonstrates that IMP shares structural homology with talin rod domain-containing protein 1 (TLNRD1), which also functions as an F-actin-binding protein. Subsequent molecular-docking studies of IMP and F-actin reveal that they possess complementary surfaces, suggesting a stable interaction. The low potential energy and high confidence score of the IMP-F-actin binding model indicate stable binding. Additionally, by employing immunoprecipitation and mass spectrometry, it was discovered that IMP serves as an interaction partner for the phytoplasmal effector causing phyllody 1 (PHYL1). It was then shown that both IMP and PHYL1 are highly expressed in the S2 stage of peanut witches' broom phytoplasma-infected Catharanthus roseus. The association between IMP and PHYL1 is substantiated through in vivo immunoprecipitation, an in vitro cross-linking assay and molecular-docking analysis. Collectively, these findings expand the current understanding of IMP interactions and enhance the comprehension of the interaction of IMP with plant F-actin. They also unveil a novel interaction pathway that may influence phytoplasma pathogenicity and host plant responses related to PHYL1. This discovery could pave the way for the development of new strategies to overcome phytoplasma-related plant diseases.

关键词： X-ray crystallography actin-binding proteins immunodominant membrane proteins phytoplasma protein structure α-helix bundles

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Commentary on small-volume biopsy of follicular lymphoma: Practical issues in the molecular era

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Cancer cytopathology 2024年第3期132卷 136-138页

作者： Chien-Chin Chen Department of Pathology Ditmanson Medical Foundation Chia-Yi Christian Hospital Chiayi Taiwan. Department of Biotechnology and Bioindustry Sciences College of Bioscience and Biotechnology National Cheng Kung University Tainan Taiwan. Department of Cosmetic Science Chia Nan University of Pharmacy and Science Tainan Taiwan. PhD Program in Translational Medicine Rong Hsing Research Center for Translational Medicine National Chung Hsing University Taichung Taiwan.

Follicular lymphoma (FL) is a common subtype of non-Hodgkin lymphoma derived from germinal center B-cells. Small-volume biopsies (SVBs), including fine-needle aspiration, needle core biopsy, and cell blocks, are often used for the assessment of patients with FL. Recently, Fitzpatrick et al. found that additional biopsies were frequently needed to supplement SVB for the initial diagnosis of FL. However, regardless of the type of SVB used, additional biopsies were usually not necessary for assessments for transformed or recurrent FL. Their multi-institutional study reflects the fact that SVB may be sufficient for clinical decision-making in these medical settings, although surgical excision is the gold standard for a definitive diagnosis of FL. With ancillary tests and advances in molecular testing, SVB has become increasingly popular and helpful, although there are practical limitations.

关键词： biopsy core needle fine-needle aspiration follicular lymphoma hematology lymphoma

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Introducing Triplex Forming Oligonucleotide into Loop-Mediated Isothermal Amplification for Developing a Lateral Flow Biosensor for Streptococci Detection

Biosensors

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Biosensors 2024年第5期14卷 257页

作者： Chang, Wei Chou, Po-Hao Wu, Cai-Tong Song, Jheng-Da Tsai, Kun-Nan Chiou, Chiuan-Chian Master and PhD Program in Biotechnology Industry College of Medicine Chang Gung University Taoyuan33302 Taiwan Delta Research Center Delta Electronics Inc Taipei114501 Taiwan College of Biological Science and Technology National Yang Ming Chiao Tung University Hsinchu City300093 Taiwan Department of Medical Biotechnology and Laboratory Science College of Medicine Chang Gung University Taoyuan33302 Taiwan Department of Laboratory Medicine Chang Gung Memorial Hospital Taoyuan33302 Taiwan

Loop-mediated isothermal amplification (LAMP) technology is extensively utilized for the detection of infectious diseases owing to its rapid processing and high sensitivity. Nevertheless, conventional LAMP signaling methods frequently suffer from a lack of sequence specificity. This study integrates a triplex-forming oligonucleotide (TFO) probe into the LAMP process to enhance sequence specificity. This TFO-LAMP technique was applied for the detection of Group B Streptococcus (GBS). The TFO probe is designed to recognize a specific DNA sequence, termed the TFO targeting sequence (TTS), within the amplified product, facilitating detection via fluorescent instrumentation or lateral flow biosensors. A screening method was developed to identify TFO sequences with high affinity to integrate TFO into LAMP, subsequently incorporating a selected TTS into an LAMP primer. In the TFO-LAMP assay, a FAM-labeled TFO is added to target the TTS. This TFO can be captured by an anti-FAM antibody on lateral flow test strips, thus creating a nucleic acid testing biosensor. The efficacy of the TFO-LAMP assay was confirmed through experiments with specimens spiked with varying concentrations of GBS, demonstrating 85% sensitivity at 300 copies and 100% sensitivity at 30,000 copies. In conclusion, this study has successfully developed a TFO-LAMP technology that offers applicability in lateral flow biosensors and potentially other biosensor platforms. © 2024 by the authors.

关键词： Biosensors

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