Article
Hematology
Julie Riis, Borge G. Nordestgaard, Shoaib Afzal
Summary: The study revealed an association between the alpha(1)-antitrypsin Z genetic variant and an increased risk of venous thromboembolism, with hazard ratios of 2.2 for homozygotes and 1.1 for heterozygotes. The absolute risk of venous thromboembolism associated with alpha(1)-antitrypsin ZZ homozygosity was 7.8%.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Biochemistry & Molecular Biology
Connie Fung, Brendan Wilding, Ralf B. Schittenhelm, Robert J. Bryson-Richardson, Phillip I. Bird
Summary: Individuals with the Pi*Z allele of SERPINA1 are prone to lung and liver diseases due to insufficient alpha 1-antitrypsin secretion and compromised protein folding. Transgenic zebrafish expressing human ZAAT show no hepatic accumulation but exhibit serum insufficiency. Suppressed cholesterol biosynthesis in the liver of ZAAT-expressing zebrafish was observed, and ER protein quality control factors were found to play a role in ZAAT processing. Manipulation of these factors improved ZAAT secretion without causing hepatic accumulation, providing potential therapeutic targets for the disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Nicoleta Cazacu, Claudia G. Chilom
Summary: This study investigated the interaction between the A1AT protein and the flavonoid luteolin using multi-spectroscopic methods and molecular docking. The results showed that luteolin quenched the intrinsic fluorescence of A1AT through a static mechanism, bound to one site of the protein, and affected the stability of its structure.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
John Liddle, Andrew C. Pearce, Christopher Arico-Muendel, Svetlana Belyanskaya, Andrew Brewster, Murray Brown, Chun-wa Chung, Alexis Denis, Nerina Dodic, Anthony Dossang, Peter Eddershaw, Diana Klimaszewska, Imran Haq, Duncan S. Holmes, Alistair Jagger, Toral Jakhria, Emilie Jigorel, Ken Lind, Jeff Messer, Margaret Neu, Allison Olszewski, Riccardo Ronzoni, James Rowedder, Martin Rudiger, Steve Skinner, Kathrine J. Smith, Lionel Trottet, Iain Uings, Zhengrong Zhu, James A. Irving, David A. Lomas
Summary: α1-antitrypsin deficiency is characterized by misfolding and intracellular polymerization of mutant α1-antitrypsin protein in hepatocytes. Small molecules that stabilize Z α1-antitrypsin were identified through a DNA-encoded library screen. Subsequent structure-based optimization yielded a series of highly potent, selective, and cellular active α1-antitrypsin correctors.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Multidisciplinary Sciences
Joseph E. Chambers, Nikita Zubkov, Marketa Kubankova, Jonathon Nixon-Abell, Ioanna Mela, Susana Abreu, Max Schwiening, Giulia Lavarda, Ismael Lopez-Duarte, Jennifer A. Dickens, Tomas Torres, Clemens F. Kaminski, Liam J. Holt, Edward Avezov, James A. Huntington, Peter St George-Hyslop, Marina K. Kuimova, Stefan J. Marciniak
Summary: This study investigates the mechanism of protein misfolding in alpha(1)-antitrypsin deficiency, leading to cirrhosis. The researchers find that alpha(1)-antitrypsin polymers undergo a phase transition, forming a protein matrix that hinders the mobility of ER proteins. This phase transition is promoted by ER stress and facilitated by the ER chaperone calreticulin. The study also reveals that immobilization of ER chaperones within the polymer matrix contributes to ER dysfunction. These findings provide insights into proteinopathies and suggest ER chaperones as potential therapeutic targets.
Article
Gastroenterology & Hepatology
David A. Rudnick, Jiansheng Huang, Tunda Hidvegi, Andrew S. Chu, Pamela Hale, Admire Munanairi, Dennis J. Dietzen, Paul F. Cliften, Eric Tycksen, Andrew J. Lutkewitte, Brian N. Finck, Stephen C. Pak, Gary A. Silverman, David H. Perlmutter
Summary: Insulin signaling exacerbates hepatic proteotoxicity in PiZ mice with alpha 1-antitrypsin deficiency, and PGC1 alpha is identified as a novel therapeutic target.
Article
Cell Biology
Adriana Ordonez, Heather P. Harding, Stefan J. Marciniak, David Ron
Summary: The study explored the cellular factors affecting the secretion of circulating polymers of alpha 1-antitrypsin, finding that cargo receptors LMAN1 and SURF4 are crucial for polymer secretion. Disruption of these receptors leads to a defect in alpha 1-antitrypsin secretion, particularly polymers, indicating their important role in regulating the process.
Article
Biotechnology & Applied Microbiology
Jonathan B. Rosenberg, P. De Bishnu, Alessandria Greco, Nicholas Gorman, Vikrum Kooner, Alvin Chen, Melissa Yost-Bido, Carlos Munoz-Zuluaga, Stephen M. Kaminsky, Mahboubeh Rostami, Sebastien Monette, Ronald G. Crystal, Dolan Sondhi
Summary: Alpha 1-antitrypsin (AAT) deficiency is a common hereditary disorder with a risk of early-onset emphysema. AAT, produced in the liver, protects the lungs from protease damage, but deficiency leads to lung tissue destruction. Oxidative damage to AAT prevents it from inhibiting target proteases. In this study, the safety of intravenous administration of an engineered AAT variant, AAV8hAAT(AVL), was evaluated in mice. The study showed that AAV8hAAT(AVL) is safe with no significant adverse effects, demonstrating its potential for further clinical studies.
HUMAN GENE THERAPY
(2023)
Article
Biochemistry & Molecular Biology
Hana Im, Jaeyeon Lim
Summary: This study evaluated the potential application of antioxidant response signaling pathway and antioxidants to cope with oxidative stress induced by Z-type alpha(1)-antitrypsin. The results showed that cellular antioxidant capacity is crucial for protection against misfolded Z-type alpha(1)-antitrypsin. These findings are important for preventing oxidative stress caused by misfolded proteins associated with degenerative diseases.
PROTEIN AND PEPTIDE LETTERS
(2022)
Article
Respiratory System
Tomoyuki Nakagiri, Sabine Wrenger, Kokilavani Sivaraman, Fabio Ius, Tobias Goecke, Patrick Zardo, Veronika Grau, Tobias Welte, Axel Haverich, Ann-Kathrin Knofel, Sabina Janciauskiene
Summary: Therapy with AAT suppresses acute rejection after LuTx in a mouse model, with beneficial effects involving anti-protease and immunomodulatory activities of AAT.
RESPIRATORY RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Zixuan Wang, Stefano Martellucci, Alicia Van Enoo, Dana Austin, Cohava Gelber, Wendy M. Campana
Summary: SP16, derived from AAT, is a bioactive peptide that can increase neurite length and regenerative gene expression in sensory neurons. It activates the Akt and ERK1/2 cell-signaling pathways in an LRP1-dependent manner. SP16 shows efficacy in attenuating nociceptive, inflammatory, and neuropathic pain in three different pain models, and also inhibits inflammatory cell recruitment and satellite cell activation.
Article
Biochemistry & Molecular Biology
Katarzyna Kucwaj-Brysz, Anna Dela, Sabina Podlewska, Marek Bednarski, Agata Siwek, Grzegorz Satala, Kinga Czarnota, Jadwiga Handzlik, Katarzyna Kiec-Kononowicz
Summary: Several studies have shown the reciprocal interactions between adrenergic and serotoninergic systems and their impact on anxiety pathogenesis. Finding chemical agents with a multifunctional pharmacodynamic profile may lead to effective therapy for CNS disorders. This study provides structural insights into hydantoin-arylpiperazine compounds and their serotonin/alpha-adrenergic activity, suggesting compounds 12 and 14 as potential candidates for anxiolytic agents.
Article
Multidisciplinary Sciences
Haiping Ke, Kevin P. Guay, Terence R. Flotte, Lila M. Gierasch, Anne Gershenson, Daniel N. Hebert
Summary: This study analyzed the production efficiency of α1-antitrypsin (AAT) in Chinese hamster ovary cells and myoblasts, and compared it to liver hepatocytes. The study found that AAT secretion and maturation were most efficient in hepatocytes, while myoblasts had the lowest expression efficiency. Treatment with a specific drug significantly enhanced the secretion of active AAT in myoblasts. These findings may have implications for enhancing the efficacy of gene therapy approaches for AAT and the production of proteins from mRNA vaccines.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Chemistry, Multidisciplinary
Amit Amar, Eli Lewis, Daniel Kaplan, Sabri El-Saied
Summary: Glucocorticoids can block inflammation but do not promote inflammatory resolution or tissue repair. Steroids are used in otolaryngology to prevent excessive inflammation and preserve hearing and vestibular function. Alpha 1-Antitrypsin is a molecule that regulates inflammation and promotes tissue repair. Treating with AAT, either alone or in combination with glucocorticoids, addresses unmet medical needs in otolaryngology.
APPLIED SCIENCES-BASEL
(2022)
Article
Immunology
Ranjeet Maurya, Pallavi Mishra, Aparna Swaminathan, Varsha Ravi, Sheeba Saifi, Akshay Kanakan, Priyanka Mehta, Priti Devi, Shaista Praveen, Sandeep Budhiraja, Bansidhar Tarai, Shimpa Sharma, Rajesh J. Khyalappa, Meghnad G. Joshi, Rajesh Pandey
Summary: In this study, a comprehensive analysis of mutation distribution among COVID-19 recovered and mortality patients was conducted. It was found that mutations in recovered patients were regionally limited, while mutations in mortality patients had a broader global distribution and may contribute to enhanced viral characteristics. Molecular dynamics simulations revealed the impact of certain mutations on protein structure and stability. This study provides valuable insights into the clinical features and viral spread influenced by mutations in the COVID-19 pandemic.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)