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ATP functions as a pathogen-associated molecular pattern to activate the E3 ubiquitin ligase RNF213

Nature Communications 2025年第1期16卷 1-19页

作者： Ahel, Juraj Balci, Arda Faas, Victoria Grabarczyk, Daniel B. Harmo, Roosa Squair, Daniel R. Zhang, Jiazhen Roitinger, Elisabeth Lamoliatte, Frederic Mathur, Sunil Deszcz, Luiza Bell, Lillie E. Lehner, Anita Williams, Thomas L. Sowar, Hanna Meinhart, Anton Wood, Nicola T. Clausen, Tim Virdee, Satpal Fletcher, Adam J. Research Institute of Molecular Pathology (IMP) Vienna BioCenter Vienna Austria MRC University of Glasgow Centre for Virus Research University of Glasgow Glasgow United Kingdom Vienna Biocenter PhD Program a Doctoral School of the University of Vienna and the Medical University of Vienna Vienna Austria MRC Protein Phosphorylation and Ubiquitylation Unit School of Life Sciences University of Dundee Dundee United Kingdom Institute of Molecular Biotechnology (IMBA) Vienna BioCenter Vienna Austria Vienna BioCenter Core Facilities Vienna BioCenter Vienna Austria Medical University of Vienna Vienna Austria

The giant E3 ubiquitin ligase RNF213 is a conserved component of mammalian cell-autonomous immunity, limiting the replication of bacteria, viruses and parasites. To understand how RNF213 reacts to these unrelated pathogens, we employ chemical and structural biology to find that ATP binding to its ATPases Associated with diverse cellular Activities (AAA) core activates its E3 function. We develop methodology for proteome-wide E3 activity profiling inside living cells, revealing that RNF213 undergoes a reversible switch in E3 activity in response to cellular ATP abundance. Interferon stimulation of macrophages raises intracellular ATP levels and primes RNF213 E3 activity, while glycolysis inhibition depletes ATP and downregulates E3 activity. These data imply that ATP bears hallmarks of a danger/pathogen associated molecular pattern, coordinating cell-autonomous defence. Furthermore, quantitative labelling of RNF213 with E3-activity probes enabled us to identify the catalytic cysteine required for substrate ubiquitination and obtain a cryo-EM structure of the RNF213-E2-ubiquitin conjugation enzyme transfer intermediate, illuminating an unannotated E2 docking site. Together, our data demonstrate that RNF213 represents a new class of ATP-dependent E3 enzyme, employing distinct catalytic and regulatory mechanisms adapted to its specialised role in the broad defence against intracellular pathogens. © The Author(s) 2025.

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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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Fate and state transitions during human blood vessel organoid development

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Cell 2025年

作者： Nikolova, Marina T. He, Zhisong Seimiya, Makiko Jonsson, Gustav Cao, Wuji Okuda, Ryo Wimmer, Reiner A. Okamoto, Ryoko Penninger, Josef M. Camp, J. Gray Treutlein, Barbara Department of Biosystems Science and Engineering ETH Zurich Basel Switzerland Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna Austria Vienna BioCenter PhD Program Doctoral School of the University of Vienna and Medical University of Vienna Vienna 1030 Austria Roche Pharma Research and Early Development Roche Innovation Center Basel Switzerland Department of Medical Genetics Life Science Institute University of British Columbia Vancouver V6T 1Z3 BC Canada Department of Laboratory Medicine Medical University of Vienna Vienna Austria Helmholtz Centre for Infection Research Braunschweig Germany Institute of Human Biology Roche Pharma Research and Early Development Roche Innovation Center Basel Basel Switzerland Biozentrum University of Basel Basel Switzerland

Human blood vessel organoids (hBVOs) have emerged as a system to model human vascular development and disease. Here, we use single-cell multi-omics together with genetic and signaling pathway perturbations to reconstruct hBVO development. Mesodermal progenitors bifurcate into endothelial and mural fates in vitro, and xenografted BVOs acquire definitive arteriovenous endothelial cell specification. We infer a gene regulatory network and use single-cell genetic perturbations to identify transcription factors (TFs) and receptors involved in cell fate specification, including a role for MECOM in endothelial and mural specification. We assess the potential of BVOs to generate organotypic states, identify TFs lacking expression in hBVOs, and find that induced LEF1 overexpression increases brain vasculature specificity. Finally, we map vascular disease-associated genes to hBVO cell states and analyze an hBVO model of diabetes. Altogether, we provide a comprehensive cell state atlas of hBVO development and illuminate the power and limitation of hBVOs for translational research. © 2025 The Authors

关键词： arteriovenous specification human blood vessel organoid human development organoid cell atlas single-cell genomics single-cell perturbation screen

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Discovery of Novel Zoanthamine-Type Alkaloids Derived from Cultured Zoanthus Kuroshio with Prominent Therapeutic Potential Against Osteoporosis

SSRN

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SSRN 2025年

作者： Pham, Ngoc-Thac Peng, Bo-Rong Le, Huong-Giang Chen, Yun-Shiuan Huynh, Thanh Hao Chen, Lo-Yun Nguyen, Le Anh Tuan Nguyen, Dang T. Su, Jui-Hsin El-Shazly, Mohamed Lee, Mei-Hsien Lai, Kuei-Hung PhD Program in Clinical Drug Development of Herbal Medicine College of Pharmacy Taipei Medical University Taipei110301 Taiwan Graduate Institute of Pharmacognosy College of Pharmacy Taipei Medical University Taipei110301 Taiwan Graduate Institute of Healthy Industry Technology Research Center for Chinese Herbal Medicine College of Human Ecology Chang Gung University of Science and Technology Taoyuan333324 Taiwan Faculty of Pharmacy Lac Hong University Dongnai Bien Hoa Viet Nam Faculty of Applied Sciences Ton Duc Thang University Ho Chi Minh City Viet Nam National Museum of Marine Biology and Aquarium Pingtung944401 Taiwan Department of Marine Biotechnology and Resources National Sun Yat-sen University Kaohsiung804201 Taiwan Department of Pharmacognosy Faculty of Pharmacy Ain-Shams University Organization of African Unity Street Abassia Cairo11566 Egypt Center for Reproductive Medicine and Sciences Taipei Medical University Hospital Taipei110301 Taiwan Traditional Herbal Medicine Research Center Taipei Medical University Hospital Taipei110301 Taiwan

Marine invertebrates are well-established as prolific sources of secondary metabolites, renowned for their remarkable chemical diversity and extensive spectrum of biological activities. Among these, Zoanthus Kuroshio (ZK) has gained significant attention due to its abundant chemical constituents, particularly alkaloids, which exhibit promising bioactivities against osteoporosis. To investigate its therapeutic potential, the extracts of cultured ZK exhibited significant anti-osteoporotic activity in vitro with MG-63 cells, leading to the integration of Global Natural Products Social Molecular Networking (GNPS) to identify fractions containing the highest amounts of alkaloids. Subsequent isolation efforts resulted in the discovery of five novel zoanthamine-type alkaloids: norzoabenzaldehyde (1), norzoazepanol (2), 11-keto-3-acetoxynorzoanthamine (3), 11-hydroxynorzoanthamide B (4), and 11-hydroxyzoanthamide B (5), alongside four previously identified compounds, including norzoanthaminone (6), 3-acetoxynorzoanthamine (7), 3-acetoxyzoanthamine (8), and 3-hydroxynorzoanthamine (9). Structural elucidation of compounds 1, 3, 4, and 5 was achieved using comprehensive spectroscopic analyses, whereas compound 2 required advanced techniques, including time-dependent density functional theory nuclear magnetic resonance (TDDFT-NMR) calculations and comparative analysis of theoretical and experimental electronic circular dichroism (ECD) data, to ascertain its absolute configuration. Bioassays evaluating alkaline phosphatase activity and mineralization demonstrated that compound 9 exhibited significant activity, with an IC50 value of 20 µM. The mechanism by which this compound operates was elucidated through network pharmacology, molecular docking and dynamics simulations, further confirming the stability of interactions between compound 9 and key protein targets, thereby emphasizing its potential as a promising lead compound for osteoporosis therapeutics. © 2025, The Authors. All

关键词： Spectroscopic analysis

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Changing life expectancy in European countries 1990–2021: a subanalysis of causes and risk factors from the Global Burden of Disease Study 2021

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The Lancet Public Health 2025年第3期10卷 e172-e188页

作者： Steel, Nicholas Bauer-Staeb, Clarissa Maria Mercedes Ford, John A. Abbafati, Cristiana Abdalla, Mohammed Altigani Abdelkader, Atef Abdi, Parsa Zuñiga, Roberto Ariel Abeldaño Abiodun, Olugbenga Olusola Abolhassani, Hassan Abu-Gharbieh, Eman Abukhadijah, Hana J. Abu-Zaid, Ahmed Addo, Isaac Yeboah Addolorato, Giovanni Adekanmbi, Victor Adetunji, Juliana Bunmi Adeyeoluwa, Temitayo Esther Agardh, Emilie E. Agyemang-Duah, Williams Ahmad, Danish Ahmed, Ayman Ahmed, Syed Anees Akinosoglou, Karolina Akkaif, Mohammed Ahmed Al Awaidy, Salah Al Hasan, Syed Mahfuz Al Zaabi, Omar Ali Mohammed Aldridge, Robert W. Algammal, Abdelazeem M. Al-Gheethi, Adel Ali Saeed Ali, Abid Ali, Mohammed Usman Ali, Syed Shujait Ali, Waad Alicandro, Gianfranco Alif, Sheikh Mohammad Al-Jumaily, Adel Allebeck, Peter Alrawashdeh, Ahmad Al-Rifai, Rami H. Alsabri, Mohammed A. Alshahrani, Najim Z. Aluh, Deborah Oyine Al-Wardat, Mohammad Al-Zyoud, Walid A. Amiri, Sohrab Anderlini, Deanna Andrei, Catalina Liliana Anil, Abhishek Anvari, Saeid Anyasodor, Anayochukwu Edward Appiah, Seth Christopher Yaw Aquilano, Michele Arabloo, Jalal Arafat, Mosab Areda, Demelash Aremu, Abdulfatai Armani, Keivan Armocida, Benedetta Ärnlöv, Johan Asaduzzaman, Muhammad Astell-Burt, Thomas Aujayeb, Avinash Ausloos, Marcel Azadnajafabad, Sina Aziz, Shahkaar Azzam, Ahmed Y. Babu, Giridhara Rathnaiah Badache, Andreea Corina Badiye, Ashish D. Bahramian, Saeed Baig, Atif Amin Baker, Jennifer L. Bansal, Hansi Bärnighausen, Till Winfried Barone, Mark Thomaz Ugliara Barrow, Amadou Barteit, Sandra Bashir, Shahid Bashiru, Hameed Akande Basso, João Diogo Bastan, Mohammad-Mahdi Basu, Sanjay Batra, Kavita Bauckneht, Matteo Baune, Bernhard T. Beghi, Massimiliano Beiranvand, Maryam Béjot, Yannick Bell, Michelle L. Bello, Olorunjuwon Omolaja Belo, Luis Beloukas, Apostolos Beneke, Alice A. Bettencourt, Paulo J.G. Bhagavathula, Akshaya Srikanth Bhala, Neeraj Bhaskar, Sonu Bisulli, Francesca Bjørge, Tone Bodunrin, Aadam Olalekan Carvajal, Alejandro Botero Bouaoud, Souad Brayne, Carol Brenner, H Department of Primary Care and Public Health University of East Anglia Norwich United Kingdom Office for Health Improvement and Disparities Department of Health and Social Care London United Kingdom Department of Legal and Economic Studies La Sapienza University Rome Italy Rome Italy Hull York Medical School University of Hull Hull United Kingdom Department of Mathematics and Sciences Ajman University Ajman United Arab Emirates Department of Medicine Memorial University St. John's NL Canada Postgraduate Department University of Sierra Sur Miahuatlan de Porfirio Diaz Mexico Yhteiskuntadatatieteen keskus (Centre for Social Data Science) Helsinki Finland Department of Internal Medicine Federal Medical Centre Abuja Nigeria Research Center for Immunodeficiencies Tehran University of Medical Sciences Tehran Iran Department of Medical Biochemistry and Biophysics Karolinska Institutet (Karolinska Institute) Stockholm Sweden Department of Clinical Sciences University of Sharjah Sharjah United Arab Emirates Department of Biopharmaceutics and Clinical Pharmacy University of Jordan Amman Jordan Medical Research Center Hamad Medical Corporation Doha Qatar Department of Biochemistry and Molecular Medicine Alfaisal University Riyadh Saudi Arabia College of Graduate Health Sciences University of Tennessee Memphis TN United States School of Medicine Sydney NSW Australia Centre for Social Research in Health University of New South Wales Sydney NSW Australia Internal Medicine and Alcohol Related Disease Unit Fondazione Policlinico Universitario A. Gemelli IRCCS Rome Italy Department of Medical and Surgical Sciences Università Cattolica di Roma (Catholic University of Rome) Rome Italy Department of Obstetrics and Gynecology University of Texas Medical Branch Galveston TX United States Department of Biochemistry Osun State University Osogbo Nigeria Department of Pharmacology and Therapeutics University of Medical Sciences Ondo Ondo Nigeria Department of Veteri

Background: Decades of steady improvements in life expectancy in Europe slowed down from around 2011, well before the COVID-19 pandemic, for reasons which remain disputed. We aimed to assess how changes in risk factors and cause-specific death rates in different European countries related to changes in life expectancy in those countries before and during the COVID-19 pandemic. Methods: We used data and methods from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 to compare changes in life expectancy at birth, causes of death, and population exposure to risk factors in 16 European Economic Area countries (Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, the Netherlands, Norway, Portugal, Spain, and Sweden) and the four UK nations (England, Northern Ireland, Scotland, and Wales) for three time periods: 1990–2011, 2011–19, and 2019–21. Changes in life expectancy and causes of death were estimated with an established life expectancy cause-specific decomposition method, and compared with summary exposure values of risk factors for the major causes of death influencing life expectancy. Findings: All countries showed mean annual improvements in life expectancy in both 1990–2011 (overall mean 0·23 years [95% uncertainty interval [UI] 0·23 to 0·24]) and 2011–19 (overall mean 0·15 years [0·13 to 0·16]). The rate of improvement was lower in 2011–19 than in 1990–2011 in all countries except for Norway, where the mean annual increase in life expectancy rose from 0·21 years (95% UI 0·20 to 0·22) in 1990–2011 to 0·23 years (0·21 to 0·26) in 2011–19 (difference of 0·03 years). In other countries, the difference in mean annual improvement between these periods ranged from –0·01 years in Iceland (0·19 years [95% UI 0·16 to 0·21] vs 0·18 years [0·09 to 0·26]), to –0·18 years in England (0·25 years [0·24 to 0·25] vs 0·07 years [0·06 to 0·08]). In 2019–21, there was an overall decrease in mean annual life expectancy a

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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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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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Enhanced IGF-IIRα Expression Exacerbates Lipopolysaccharide-Induced Cardiac Inflammation, Hypertrophy, and Apoptosis Through Calcineurin Activation

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Environmental Toxicology 2024年第11期39卷 5173-5186页

作者： Boonha, Khwanchit Kuo, Wei-Wen Tsai, Bruce Chi-Kang Hsieh, Dennis Jine-Yuan Lin, Kuan-Ho Lu, Shang-Yeh Kuo, Chia-Hua Yang, Liang-Yo Huang, Chih-Yang Graduate Institute of Biomedical Sciences China Medical University Taichung Taiwan Cardiovascular and Mitochondrial Related Disease Research Center Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Hualien Taiwan Faculty of Tropical Medicine Mahidol University Bangkok Thailand Department of Biological Science and Technology College of Life Sciences China Medical University Taichung Taiwan PhD Program for Biotechnology Industry China Medical University Taichung Taiwan School of Pharmacy China Medical University Taichung Taiwan Department of Medical Laboratory and Biotechnology Chung Shan Medical University Taichung Taiwan Clinical Laboratory Chung Shan Medical University Hospital Taichung Taiwan Department of Emergency Medicine China Medical University Hospital Taichung Taiwan College of Medicine China Medical University Taichung Taiwan Division of Cardiovascular Medicine Department of Internal Medicine China Medical University Hospital Taichung Taiwan Laboratory of Exercise Biochemistry University of Taipei Taipei Taiwan Institute of Sports Sciences University of Taipei Taipei Taiwan Department of Kinesiology and Health Science College of William and Mary WilliamsburgVA United States School of Physical Education and Sports Science Soochow University Suzhou China Department of Physiology School of Medicine College of Medicine China Medical University Taichung Taiwan Laboratory for Neural Repair China Medical University Hospital Taichung Taiwan Department of Medical Research China Medical University Hospital China Medical University Taichung Taiwan Department of Medical Laboratory Science and Biotechnology Asia University Taichung Taiwan Center of General Education Buddhist Tzu Chi Medical Foundation Tzu Chi University of Science and Technology Hualien Taiwan

Cardiovascular disease is one of the leading causes of death worldwide and has a high prevalence. Insulin-like growth factor-II receptor α (IGF-IIRα) acts as a stress-inducible negative regulator. This study focused on the substantial impact of heightened expression of IGF-IIRα in cardiac myoblasts and its association with the exacerbation of cardiac dysfunction. Using lipopolysaccharide (LPS)-induced H9c2 cardiac myoblasts as a model for sepsis, we aimed to elucidate the molecular interactions between IGF-IIRα and LPS in exacerbating cardiac injury. Our findings demonstrated a synergistic induction of cardiac inflammation and hypertrophy by LPS stimulation and IGF-IIRα overexpression, leading to decreased cell survival. Excessive calcineurin activity, triggered by this combined condition, was identified as a key factor exacerbating the negative effects on cell survival. Cellular changes such as cell enlargement, disrupted actin filaments, and upregulation of hypertrophy-related and inflammation-related proteins contributed to the overall hypertrophic and inflammatory responses. Overexpression of IGF-IIRα also exacerbated apoptosis induced by LPS in H9c2 cardiac myoblasts. Inhibiting calcineurin in LPS-treated H9c2 cardiac myoblasts with IGF-IIRα overexpression effectively reversed the detrimental effects, reducing cell damage and mitigating apoptosis-related cardiac mechanisms. Our study suggests that under sepsis-like conditions in the heart with IGF-IIRα overexpression, hyperactivation of calcineurin worsens cardiac damage. Suppressing IGF-IIRα and calcineurin expression could be a potential intervention to alleviate the impact of the illness and improve cardiac function. © 2024 Wiley Periodicals LLC.

关键词： Heart

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Bat organoids reveal antiviral responses at epithelial surfaces

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Nature Immunology 2025年 1-13页

作者： Max J. Kellner Patrick Zelger Masahiro Onji Josef M. Penninger Vanessa M. Monteil Ali Mirazimi Gang Pei Anca Dorhoi Jie Jiao Komal Nayak Matthias Zilbauer Anne Balkema-Buschmann Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) Vienna BioCenter (VBC) Vienna Austria Vienna BioCenter PhD Program Doctoral School of the University of Vienna and Medical University of Vienna Vienna Austria Department of Laboratory Medicine Medical University of Vienna Vienna Austria Helmholtz Centre for Infection Research Braunschweig Germany Department of Medical Genetics Life Sciences Institute University of British Columbia Vancouver British Columbia Canada Division of Clinical Microbiology Department of Laboratory Medicine Karolinska Institute and Karolinska University Hospital Stockholm Sweden Public Health Agency of Sweden Solna Sweden National Veterinary Institute Uppsala Sweden Institute of Immunology Friedrich-Loeffler-Institut Greifswald-Insel Riems Germany Faculty of Mathematics and Natural Sciences University of Greifswald Greifswald Germany Wellcome – MRC Cambridge Stem Cell Institute University of Cambridge Cambridge UK Department of Paediatrics University of Cambridge Cambridge UK Institute of Novel and Emerging Infectious Diseases Friedrich-Loeffler-Institut Greifswald-Insel Riems Germany

Bats can host viruses of pandemic concern without developing disease. The mechanisms underlying their exceptional resilience to viral infections are largely unresolved, necessitating the development of physiologically relevant and genetically tractable research models. Here, we developed respiratory and intestinal organoids that recapitulated the cellular diversity of the in vivo epithelium present inRousettus aegyptiacus, the natural reservoir for the highly pathogenic Marburg virus (MARV). In contrast to human counterparts, bat organoids and mucosal tissue exhibited elevated constitutive expression of innate immune effectors, including type I interferon-ε (IFNε) and IFN-stimulated genes (ISGs). Upon infection with diverse zoonotic viruses, including MARV, bat organoids strongly induced type I and III IFN responses, which conferred robust antiviral protection. Type III IFNλ3 additionally displayed virus-independent self-amplification, acting as an ISG to enhance antiviral immunity. Our organoid platform reveals key features of bat epithelial antiviral immunity that may inform therapeutic strategies for viral disease resilience.

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Demethoxymurrapanine, an indole-naphthoquinone alkaloid, inhibits the proliferation of oral cancer cells without major side effects on normal cells

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Environmental Toxicology 2024年第3期39卷 1221-1234页

作者： Chuang, Ya-Ting Yen, Ching-Yu Shiau, Jun-Ping Chang, Fang-Rong Duh, Chang-Yih Sung, Ping-Jyun Chen, Kuan-Liang Tsai, Yi-Hong Tang, Jen-Yang Jeng, Jiiang-Huei Sheu, Jyh-Horng Chang, Hsueh-Wei Department of Biomedical Science and Environmental Biology PhD Program in Life Sciences College of Life Science Kaohsiung Medical University Kaohsiung Taiwan School of Dentistry Taipei Medical University Taipei Taiwan Department of Oral and Maxillofacial Surgery Chi-Mei Medical Center Tainan Taiwan Division of Breast Oncology and Surgery Department of Surgery Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Taiwan Graduate Institute of Natural Products Kaohsiung Medical University Kaohsiung Taiwan Department of Marine Biotechnology and Resources National Sun Yat-sen University Kaohsiung Taiwan National Museum of Marine Biology and Aquarium Pingtung Taiwan Department of Pharmacy and Master Program College of Pharmacy and Health Care Tajen University Pingtung Taiwan School of Post-Baccalaureate Medicine Kaohsiung Medical University Kaohsiung Taiwan Department of Radiation Oncology Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Taiwan School of Dentistry College of Dental Medicine Kaohsiung Medical University Kaohsiung Taiwan Department of Dentistry Kaohsiung Medical University Hospital Kaohsiung Taiwan Department of Dentistry National Taiwan University Hospital Taipei Taiwan Department of Medical Research China Medical University Hospital China Medical University Taichung Taiwan Department of Medical Research Kaohsiung Medical University Hospital Kaohsiung Taiwan Center for Cancer Research Kaohsiung Medical University Kaohsiung Taiwan

Antioral cancer drugs need a greater antiproliferative impact on cancer than on normal cells. Demethoxymurrapanine (DEMU) inhibits proliferation in several cancer cells, but an in-depth investigation was necessary. This study evaluated the proliferation-modulating effects of DEMU, focusing on oral cancer and normal cells. DEMU (0, 2, 3, and 4 μg/mL) at 48 h treatments inhibited the proliferation of oral cancer cells (the cell viability (%) for Ca9-22 cells was 100.0 ± 2.2, 75.4 ± 5.6, 26.0 ± 3.8, and 15.4 ± 1.4, and for CAL 27 cells was 100.0 ± 9.4, 77.2 ± 5.9, 57.4 ± 10.7, and 27.1 ± 1.1) more strongly than that of normal cells (the cell viability (%) for S-G cells was 100.0 ± 6.6, 91.0 ± 4.6, 95.0 ± 2.6, and 95.8 ± 5.5), although this was blocked by the antioxidant N-acetylcysteine. The presence of oxidative stress was evidenced by the increase of reactive oxygen species and mitochondrial superoxide and the downregulation of the cellular antioxidant glutathione in oral cancer cells, but these changes were minor in normal cells. DEMU also caused greater induction of the subG1 phase, extrinsic and intrinsic apoptosis (annexin V and caspases 3, 8, and 9), and DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) in oral cancer than in normal cells. N-acetylcysteine attenuated all these DEMU-induced changes. Together, these data demonstrate the preferential antiproliferative function of DEMU in oral cancer cells, with the preferential induction of oxidative stress, apoptosis, and DNA damage in these cancer cells, and low cytotoxicity toward normal cells. © 2023 Wiley Periodicals LLC.

关键词： Oxidative stress

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