Article
Biochemistry & Molecular Biology
Noor Ahmad Shaik, Najla Bint Saud Al-Saud, Thamer Abdulhamid Aljuhani, Kaiser Jamil, Huda Alnuman, Deema Aljeaid, Nasreen Sultana, Ashraf AbdulRahman El-Harouni, Zuhier Ahmed Awan, Ramu Elango, Babajan Banaganapalli
Summary: This study investigates the impact of SERPINA1 missense variants on the structural and functional characteristics of A1AT protein in Alpha-1 antitrypsin deficiency. The results suggest that these variants alter the structure, stability, and function of A1AT protein, and negatively affect its binding with NE ligand molecule.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Annelot D. Sark, Malin Fromme, Beata Olejnicka, Tobias Welte, Pavel Strnad, Sabina Janciauskiene, Jan Stolk
Summary: This study investigates the association between levels of circulating Z-AAT polymers and the severity of lung disease and liver disease. The results show that plasma Z-AAT polymer levels are correlated with liver function but not with lung function.
Article
Biochemistry & Molecular Biology
David J. Wilkinson, Adrian M. D. Falconer, Helen L. Wright, Hua Lin, Kazuhiro Yamamoto, Kathleen Cheung, Sarah H. Charlton, Maria del Carmen Arques, Sabina Janciauskiene, Ramsay Refaie, Kenneth S. Rankin, David A. Young, Andrew D. Rowan
Summary: This study identifies elastase as a novel activator of pro-MMP-13, which has relevance for cartilage collagen destruction in OA patients with synovitis. Elastase induced significant collagen destruction from human OA cartilage ex vivo in an MMP-dependent manner, and activated pro-MMP-13 more potently than MMP-3. Additionally, active MMP-13 specifically inactivated the major elastase inhibitor AAT, further implicating elastase in cartilage breakdown in OA.
Editorial Material
Biochemistry & Molecular Biology
Magdalena K. Kaneva
Summary: Cartilage maintenance relies on the delicate balance between anabolism and catabolism. In osteoarthritis, cartilage breakdown, synovial inflammation, and bone changes lead to reduced joint mobility and pain, with neutrophil elastase activating MMP-13, causing cartilage destruction. Potential treatment strategies should focus on preventing the loss of alpha-1-antitrypsin to halt osteoarthritis progression.
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
Zuzana Rabekova, Sona Frankova, Milan Jirsa, Magdalena Neroldova, Mariia Lunova, Ondrej Fabian, Martin Kveton, David Varys, Klara Chmelova, Vera Adamkova, Jaroslav A. Hubacek, Julius Spicak, Dusan Merta, Jan Sperl
Summary: The study found that patients with liver cirrhosis carrying the SERPINA1 MZ and MS genotypes have a significantly lower risk of hepatocellular carcinoma. MZ and MS heterozygotes have lower serum AAT levels. Multivariate analysis identified MZ or MS genotype carriage as a protective factor, while factors such as age, gender, BMI, and viral aetiology of cirrhosis increase the risk of HCC.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Medicine, General & Internal
David Nygren, Ulrica Molstad, Hans Thulesius, Magnus Hillman, Lars Mikael Broman, Hanan Tanash, Mona Landin-Olsson, Magnus Rasmussen, Maria Thunander
Summary: This study examined the prevalence rate of AATD among hospitalized COVID-19 patients and found that mild AATD was rare in a study setting with a high background prevalence of AATD.
INTERNATIONAL JOURNAL OF GENERAL MEDICINE
(2022)
Article
Pediatrics
Jose M. Hernandez-Perez, Mario A. Gonzalez Carracedo, Angelines Concepcion Garcia, Jose A. Perez Perez
Summary: A novel SERPINA1 defective allele, PI*S-hangzhou, was identified in this study, potentially destabilizing the structure of alpha-1-antitrypsin. Considering the frequency in East Asian populations, this finding helps explain the global prevalence of the PiS phenotype observed in China.
FRONTIERS IN PEDIATRICS
(2022)
Review
Pharmacology & Pharmacy
Kimberly E. Foil
Summary: Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene, leading to quantitative and/or qualitative changes in the AAT protein. The diverse pathogenic mutations often result in misfolding or truncating of the AAT amino acid sequence, and genetic testing should be widely offered along with genetic counseling.
THERAPEUTIC ADVANCES IN CHRONIC DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Riccardo Ronzoni, Ilaria Ferrarotti, Emanuela D'Acunto, Alice M. Balderacchi, Stefania Ottaviani, David A. Lomas, James A. Irving, Elena Miranda, Annamaria Fra
Summary: Alpha-1-antitrypsin (AAT) deficiency leads to pulmonary and liver diseases due to imbalanced protease activity and deposition of AAT variants. The new variant Bologna AAT (N186Y) shows secretion deficiency and intracellular polymer accumulation, disrupting hydrogen bonding network in the AAT shutter region. This highlights the importance of understanding structural mechanisms in AAT polymer formation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Respiratory System
Angel Gonzalez, Irene Belmonte, Alexa Nunez, Georgina Farago, Miriam Barrecheguren, Monica Pons, Gerard Orriols, Pablo Gabriel-Medina, Francisco Rodriguez-Frias, Marc Miravitlles, Cristina Esquinas
Summary: This study analyzed and located newly discovered AAT mutations using structural simulations and clinical data, providing insights into their effects on AAT protein structure and function. The results demonstrated that rare variants may be more common than expected and highlighted the utility of computational modeling in assessing the pathogenicity of rare mutations.
RESPIRATORY RESEARCH
(2022)
Article
Medicine, General & Internal
Victoria Therese Muecke, Janett Fischer, Marcus Maximilian Muecke, Alexander Teumer, Alexander Koch, Johannes Vermehren, Malin Fromme, Stefan Zeuzem, Christian Trautwein, Christoph Sarrazin, Thomas Berg, Biaohuan Zhou, Karim Hamesch
Summary: This study found that the heterozygous Pi*Z allele is not a clinically relevant disease modifier in chronic hepatitis C infection, based on analysis of two cohorts. Further validation in larger cohorts with longitudinal follow-up is needed.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Multidisciplinary Sciences
Bryce A. Schuler, Lisa Bastarache, Janey Wang, Jing He, Sara L. Van Driest, Joshua C. Denny
Summary: This study compared the risk of liver transplantation associated with hepatitis C infection with alpha-1 antitrypsin deficiency (AATD) heterozygotes and homozygotes. The results showed that liver transplantation was more common in individuals with AATD risk alleles, and there was a gene-environment interaction between AATD and hepatitis C in relation to liver transplantation. SERPINA1 sequencing was found to increase the diagnostic yield for AATD and provide information for stratifying the risk of liver disease and managing individuals with AATD risk alleles and liver disease risk factors.
Article
Biotechnology & Applied Microbiology
Rachel D. Truong, Megan A. Bernier, James E. Dennis, Thomas J. Kean
Summary: This study has demonstrated that bFGF and SCM can enhance the growth of human chondrocytes, either individually or in combination, and increase cell proliferation rates as well as glycosaminoglycan and collagen content during redifferentiation culture.
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(2022)
Article
Critical Care Medicine
James R. Ashenhurst, Hoang Nhan, Janie F. Shelton, Shirley Wu, Joyce Y. Tung, Sarah L. Elson, James K. Stoller
Summary: Direct-to-consumer (DTC) genetic testing combined with clinical follow-up can help identify previously undiagnosed AATD patients, and the test results have a particularly positive impact on behavior change among individuals with risk variants.
Review
Biochemistry & Molecular Biology
Camilla S. A. Davan-Wetton, Emanuela Pessolano, Mauro Perretti, Trinidad Montero-Melendez
Summary: Cellular senescence, defined as an irreversible cell cycle arrest with increased cellular growth and metabolic activity, has become a focus of biomedical research. The dual nature of senescence, beneficial/detrimental, is linked to contextual aspects, with the pro-resolving model suggesting that pathology arises from incomplete senescence program. Therapeutic approaches based on senescence include induction, prevention, and clearance of senescent cells, as well as the use of senolytic and senomorphic drugs. Challenges and gaps in research need to be addressed to promote the clinical success of senescence-based therapies.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Chemistry, Medicinal
Monika Maciuszek, Almudena Ortega-Gomez, Sanne L. Maas, Mauro Perretti, Andy Merritt, Oliver Soehnlein, Timothy M. Chapman
Summary: This study used homology modeling, molecular docking, and pharmacophore studies to design a series of novel FPR2 receptor agonists and investigate their structure-activity relationships. These new compounds show promising potential to reduce neutrophil adhesion and suppress the inflammatory process, with good pharmacokinetic properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Editorial Material
Rheumatology
Mauro Perretti
Summary: Three studies published in 2020 have described phenotypic variation in synovial cells, offering a novel perspective on the potential to resolve pathology and augment treatment options for patients with RA.
NATURE REVIEWS RHEUMATOLOGY
(2021)
Article
Multidisciplinary Sciences
Tomoya Ito, Yusuke Shintani, Laura Fields, Manabu Shiraishi, Mihai-Nicolae Podaru, Satoshi Kainuma, Kizuku Yamashita, Kazuya Kobayashi, Mauro Perretti, Fiona Lewis-McDougall, Ken Suzuki
Summary: Peritoneal adhesions are a common complication after abdominal surgery. Research shows that a specific subset of F4/80(High)CD206(-) macrophages can form a protective barrier to prevent adhesion formation, which can be enhanced by IL-4 treatment or cell transfer.
NATURE COMMUNICATIONS
(2021)
Article
Immunology
Alice Hamilton, Raffaella Rizzo, Samuel Brod, Masahiro Ono, Mauro Perretti, Dianne Cooper, Fulvio D'Acquisto
Summary: Social isolation has a significant impact on the immune regulation of mice, enhancing their resistance to bacterial infection. Social housing and huddling behavior may be important factors in regulating the host immune response.
BRAIN BEHAVIOR AND IMMUNITY
(2022)
Editorial Material
Biochemistry & Molecular Biology
Magdalena K. Kaneva
Summary: Cartilage maintenance relies on the delicate balance between anabolism and catabolism. In osteoarthritis, cartilage breakdown, synovial inflammation, and bone changes lead to reduced joint mobility and pain, with neutrophil elastase activating MMP-13, causing cartilage destruction. Potential treatment strategies should focus on preventing the loss of alpha-1-antitrypsin to halt osteoarthritis progression.
Article
Medicine, General & Internal
Kimberly Pistorius, Lucy Ly, Patricia R. Souza, Esteban A. Gomez, Duco S. Koenis, Ana R. Rodriguez, Julie Foster, Jane Sosabowski, Mark Hopkinson, Vinothini Rajeeve, Bernd W. Spur, Andrew Pitsillides, Costantino Pitzalis, Jesmond Dalli
Summary: In patients with rheumatoid arthritis, the concentration of MCTR3 in plasma is negatively correlated with joint disease activity and severity. Research shows that MCTR3 can confer enduring joint protective properties by reprogramming monocytes and its anti-arthritic and tissue reparative activities are mediated in part by Arg-1.
Article
Cell Biology
Tatiana Paula Teixeira Ferreira, Fernanda Verdini Guimaraes, Yago Amigo Pinho Jannini Sa, Natalia Barreto da Silva Ribeiro, Ana Carolina Santos de Arantes, Vinicius de Frias Carvalho, Lirlandia Pires Sousa, Mauro Perretti, Marco Aurelio Martins, Patricia Machado Rodrigues Silva
Summary: The study found that the peptide Ac2-26 and its derivative AnxA1 regulate the inflammatory response in allergic asthma triggered by house dust mite extract. The peptide Ac2-26 decreased eosinophil infiltration, fibrosis, and mucus exacerbation caused by the allergen challenge and also inhibited airway hyperreactivity and mediator production. These findings suggest that Ac2-26 or similar compounds could be potential therapeutic candidates for allergic asthma treatment.
Review
Cell Biology
Andreas Margraf, Mauro Perretti
Summary: This article discusses the importance of inflammation for immune response and its potential role in chronic diseases and organ damage. The mechanisms triggering, hindering, or resolving inflammation have been studied, but precise therapeutic interventions are not yet fully understood. The article highlights the role of cellular phenotypes, particularly neutrophils, macrophages, and platelets, in inflammation research and suggests implications for diagnostics and therapeutics.
Review
Pharmacology & Pharmacy
Cheng Xue Qin, Lucy Norling, Elizabeth A. Vecchio, Eoin P. Brennan, Lauren T. May, Denise Wootten, Catherine Godson, Mauro Perretti, Rebecca H. Ritchie
Summary: This article discusses the pharmacology of formylpeptide receptor 2 (FPR2) and its complex biology. The authors propose that understanding FPR2 could lead to innovative treatments for chronic inflammatory conditions.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Cell Biology
Simone de Araujo, Victor R. de Melo Costa, Franciele M. Santos, Carla D. Ferreira de Sousa, Thaiane P. Moreira, Matheus R. Goncalves, Franciel B. Felix, Celso M. Queiroz-Junior, Gabriel H. Campolina-Silva, Mauricio Lacerda Nogueira, Michelle A. Sugimoto, Caio S. Bonilha, Mauro Perretti, Danielle G. Souza, Vivian V. Costa, Mauro M. Teixeira
Summary: This study investigated the role of the AnxA1-FPR2/ALX pathway during CHIKV infection. The results showed that genetic deletion of AnxA1 or its receptor enhanced inflammatory responses driven by CHIKV and led to more severe tissue damage. Conversely, treatment with the AnxA1 mimetic peptide reduced inflammation and alleviated pain and edema caused by CHIKV infection.
Review
Immunology
Serena Bert, Suchita Nadkarni, Mauro Perretti
Summary: Neutrophils, while being fundamental in combating infection and injury, are now recognized as key modulators of adaptive immune responses. This review explores the novel properties of neutrophils and redefines their pathophysiological functions, highlighting their role in mediating acute inflammatory responses and regulating adaptive immunity to maintain immune tolerance.
IMMUNOLOGICAL REVIEWS
(2023)
Article
Immunology
Jianmin Chen, Shani Austin-Williams, Caroline Elizabeth O'Riordan, Pol Claria-Ribas, Michelle A. Sugimoto, Lucy V. Norling, Christoph Thiemermann, Mauro Perretti
Summary: Using a humanized FPR2 mouse model, this study found that deficiency of FPR2 in myeloid cells exacerbates cardiac dysfunction and worsens clinical outcome in polymicrobial sepsis. The FPR2 agonist annexin A1 improved cardiac function in FPR2-competent septic mice but had limited beneficial effects in mice lacking FPR2.
JOURNAL OF INNATE IMMUNITY
(2023)