- Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function. [Journal Article]
- Neutrophil extracellular traps contribute to lung injury in cystic fibrosis and asthma, but the mechanisms are poorly understood. We sought to understand the impact of human NETs on barrier function in primary human bronchial epithelial and a human airway epithelial cell line. We demonstrate that NETs disrupt airway epithelial barrier function by decreasing transepithelial electrical resistance a…
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- COVID-19 Pathology Sheds Further Light on Balance between Neutrophil Proteases and Their Inhibitors. [Review]
- Excessive neutrophil influx and activation in lungs during infections, such as manifest during the ongoing SARS CoV-2 pandemic, have brought neutrophil extracellular traps (NETs) and the concomitant release of granule contents that damage surrounding tissues into sharp focus. Neutrophil proteases, which are known to participate in NET release, also enable the binding of the viral spike protein to…
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- Human Alpha-1 Antitrypsin Attenuates ENaC and MARCKS and Lowers Blood Pressure in Hypertensive Diabetic db/db Mice. [Journal Article]
- Hypertension may develop before or after the onset of diabetes and it is known to increase the risk of developing diabetic nephropathy. Alpha-1 antitrypsin (AAT) is a multi-functional protein with beneficial effects in various diseases but its role in reducing blood pressure in the diabetic kidney has not been thoroughly studied. Like blood pressure, epithelial sodium channels (ENaC) and its adap…
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- Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis. [Journal Article]Cell Chem Biol. 2023 Jan 19; 30(1):22-42.e5.CC
- Genetic variation in alpha-1 antitrypsin (AAT) causes AAT deficiency (AATD) through liver aggregation-associated gain-of-toxic pathology and/or insufficient AAT activity in the lung manifesting as chronic obstructive pulmonary disease (COPD). Here, we utilize 71 AATD-associated variants as input through Gaussian process (GP)-based machine learning to study the correction of AAT folding and functi…
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- Modeling bile duct ischemia and reoxygenation injury in human cholangiocyte organoids for screening of novel cholangio-protective agents. [Journal Article]
- CONCLUSIONS: These findings demonstrate that ICOs recapitulate ischemic cholangiopathy in vitro and enable drug assessment studies for the discovery of new therapeutics for ischemic cholangiopathies.
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- Quantitative Proteomic Analysis of Non-Tobacco Associated Oral Squamous Cell Carcinoma Reveals Deregulation of Cytoskeletal and Apoptotic Proteins. [Journal Article]Asian Pac J Cancer Prev. 2022 Dec 01; 23(12):4285-4292.AP
- CONCLUSIONS: The differentially expressed proteins are found to be involved in apoptotic signalling pathways, cytoskeletal dynamics and are known to play a critical role in oral tumorigenesis. Put together, the results provide available baseline information for understanding the development and progression of NT-OSCC. These identified proteins on further validation may be used as potential biomarkers in future for early detection and predicting therapeutic outcome of patients with NT-OSCC.
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- Recombinant Alpha-1 Antitrypsin as Dry Powder for Pulmonary Administration: A Formulative Proof of Concept. [Journal Article]
- Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder associated with pulmonary emphysema and bronchiectasis. Its management currently consists of weekly infusions of plasma-purified human AAT, which poses several issues regarding plasma supplies, possible pathogen transmission, purification costs, and parenteral administration. Here, we investigated an alternative administration strategy fo…
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- Influence of Protein Carbonylation on Human Adipose Tissue Dysfunction in Obesity and Insulin Resistance. [Journal Article]
- CONCLUSIONS: The adipose tissue carbonylome contributes to understanding the molecular mechanism driving adipocyte dysfunction and identifies possible adipose tissue carbonylated targets in obesity-associated insulin resistance.
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- Registry-based cohort study of alpha-1 antitrypsin deficiency prevalence, incidence and mortality in Denmark 2000-2018. [Journal Article]
- CONCLUSIONS: Diagnosed AATD was associated with increased mortality, especially for children. The finding for children was based on few deaths and had very wide 95% CIs.
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- Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry. [Journal Article]
- CONCLUSIONS: EARCO has recruited > 1000 individuals with AATD from 15 countries in its first 2 years. Baseline cross sectional data provide relevant information about the clinical phenotypes of the disease, the patterns of functional impairment and factors associated with poor lung function. Trial registration www.
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- New variants of alpha-1-antitrypsin: structural simulations and clinical expression. [Journal Article]
- CONCLUSIONS: The results characterize five variants, four of them previously unknown, of the SERPINA1 gene, which define new alleles contributing to the deficiency of AAT. Rare variants might be more frequent than expected, and therefore, in discordant cases, standardized screening of the S and Z alleles needs complementation with gene sequencing and structural approaches. The utility of computational modelling for providing supporting evidence of the pathogenicity of rare single nucleotide variations is discussed.
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- Seronegative MSM at high risk of HIV-1 acquisition show an immune quiescent profile with a normal immune response against common antigens. [Journal Article]
- Human immunodeficiency virus (HIV) infection still represents a major public health problem worldwide, and its vaccine remains elusive. The study of HIV-exposed seronegative individuals (HESN) brings important information about the natural resistance to HIV, allows a better understanding of the infection, and opens doors for new preventive and therapeutic strategies. Among HESN groups, there are …
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- Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity. [Journal Article]
- Individuals homozygous for the "Z" mutation in alpha-1 antitrypsin deficiency are known to be at increased risk for liver disease. It has also become clear that some degree of risk is similarly conferred by the heterozygous state. A lack of model systems that recapitulate heterozygosity in human hepatocytes has limited the ability to study the impact of a single Z alpha-1 antitrypsin (ZAAT) allel…
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- A randomized controlled pilot trial of etanercept and alpha-1 antitrypsin to improve autologous islet engraftment. [Randomized Controlled Trial]
- CONCLUSIONS: Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment.
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- [Clinical-neurobiological correlations in young depressive patients with a history of suicidal attempts]. [Journal Article]Zh Nevrol Psikhiatr Im S S Korsakova. 2022; 122(11):105-109.ZN
- CONCLUSIONS: The structure of clinical-neurobiological correlations in the examined patients indicates the involvement of neuroinflammation processes in the pathogenesis of their condition. The results make it possible to clarify the neurobiological factors of the pathogenesis of suicidal behavior in young depressive patients.
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- Frequency of alpha-1 antitrypsin deficiency and unexpected results in COPD patients in Turkey; rare variants are common. [Journal Article]Turk J Med Sci. 2022 Oct; 52(5):1478-1485.TJ
- CONCLUSIONS: In this study, which investigated the genotypic α1-AT variant frequency in COPD patients for the first time in our country, we found that the percentage of homozygous Pi*ZZ patients was 0.51%, but when heterozygous α1-AT gene variant and single point mutation were included, the frequency was 7.1%. At the same time, while the Pi*S variant was never detected, rare variants were found more frequently than expected.
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- Optimizing the screening of alpha-1 antitrypsin deficiency using serum protein electrophoresis. [Journal Article]Clin Chem Lab Med. 2023 Feb 23; 61(3):427-434.CC
- CONCLUSIONS: The V8 Nexus α1 band 2 was the best predictor of A1AT deficiency, probably owing to a better resolution. The use of SPE was however unable to predict each phenotype. Phenotype or genotype studies are therefore still advisable in case of A1AT deficiency.
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- Proteolysis and Deficiency of α1-Proteinase Inhibitor in SARS-CoV-2 Infection. [Journal Article]
- The SARS-CoV-2 pandemic had stimulated the emergence of numerous publications on the α1-proteinase inhibitor (α1-PI, α1-antitrypsin), especially when it was found that the regions of high mortality corresponded to the regions with deficient α1-PI alleles. By analogy with the data obtained in the last century, when the first cause of the genetic deficiency of α1-antitrypsin leading to elastase act…
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- Modifying a bacterial tyrosinase zymogen for use in protease activity assays. [Journal Article]
- Current clinical laboratory assays are not sufficient for determining the activity of many specific human proteases yet. In this study, we developed a general approach that enables the determination of activities of caspase-3 based on the proteolytic activation of the engineered zymogen of the recombinant tyrosinase from Verrucomicrobium spinosum (Vs-tyrosinase) by detecting the diphenolase activ…
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- [Alpha-1 antitrypsin deficiency]. [Journal Article]Rev Med Suisse. 2022 Nov 16; 18(804):2169-2174.RM
- Alpha-1 antitrypsin deficiency (DAAT) is a rare autosomal recessive genetic disorder caused by mutations in the Serpina1 gene. The role of alpha-1 antitrypsin (A1AT) is to maintain homeostasis in the acute phase of inflammation. DAAT manifests itself primarily in carriers of the Z allele, especially in the homozygous state, as emphysema and chronic liver disease. Although the diagnostic strategy …
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- Self-Amplifying RNA Approach for Protein Replacement Therapy. [Review]
- Messenger RNA (mRNA) technology has already been successfully tested preclinically and there are ongoing clinical trials for protein replacement purposes; however, more effort has been put into the development of prevention strategies against infectious diseases. Apparently, mRNA vaccine approval against coronavirus disease 2019 (COVID-19) is a landmark for opening new opportunities for managing …
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- The Search for Associations of Serum Proteins with the Presence of Unstable Atherosclerotic Plaque in Coronary Atherosclerosis. [Journal Article]
- To study the associations of blood proteins with the presence of unstable atherosclerotic plaques in the arteries of patients with coronary atherosclerosis using quantitative proteomics. The studies involved two groups of men with coronary atherosclerosis (group 1 (St) had only stable atherosclerotic plaques; group 2 (Ns) had only unstable atherosclerotic plaques, according to histological analys…
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- Rosa26-LSL-dCas9-VPR: a versatile mouse model for tissue specific and simultaneous activation of multiple genes for drug discovery. [Journal Article]
- Transgenic animals with increased or abrogated target gene expression are powerful tools for drug discovery research. Here, we developed a CRISPR-based Rosa26-LSL-dCas9-VPR mouse model for targeted induction of endogenous gene expression using different Adeno-associated virus (AAV) capsid variants for tissue-specific gRNAs delivery. To show applicability of the model, we targeted low-density lipo…
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- Influence of SERPINA1 Gene Polymorphisms on Anemia and Chronic Obstructive Pulmonary Disease. [Journal Article]
- CONCLUSIONS: Based on the current findings, we suggest that the SERPINA1 gene has a positive correlation with anemia as well as COPD, and the increase in altitude also influences the diseased conditions in a positive manner.
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- Reactive Centre Loop Mutagenesis of SerpinB3 to Target TMPRSS2 and Furin: Inhibition of SARS-CoV-2 Cell Entry and Replication. [Journal Article]
- The SARS-CoV-2 virus can utilize host cell proteases to facilitate cell entry, whereby the Spike (S) protein is cleaved at two specific sites to enable membrane fusion. Furin, transmembrane protease serine 2 (TMPRSS2), and cathepsin L (CatL) are the major proteases implicated, and are thus targets for anti-viral therapy. The human serpin (serine protease inhibitor) alpha-1 antitrypsin (A1AT) show…
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- Human Alpha 1 Antitrypsin Suppresses NF-κB Activity and Extends Lifespan in Adult Drosophila. [Journal Article]
- Human alpha 1 antitrypsin (hAAT) is a multifunctional protein that has been shown to have anti-inflammatory and cellular protective properties. While previous studies demonstrated the antiaging potential of hAAT, the mechanism(s) underlying the antiaging effect remain elusive. In this study, we performed a detailed analysis of transcriptomic data that indicated that NF-κB-targeted genes and NF-κB…
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- Lung cancer risk in workers occupationally exposed to polycyclic aromatic hydrocarbons with emphasis on the role of DNA repair gene. [Journal Article]Int Arch Occup Environ Health. 2022 Oct 26 [Online ahead of print]IA
- CONCLUSIONS: Therefore, we conclude that aluminum workers may be at a potential risk of lung cancer development due to PAHs exposure. Although PAHs concentrations in air were within the permissible limits, yet evidence of DNA damage was present as expressed by high BPDE-albumin adduct level in exposed workers. Also, elevation of tumor markers (SCCAg and CCNB1) in exposed workers points to the importance of periodic biological monitoring of such workers to protect them from cancer risk.
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- Domino hepatocyte transplantation using explanted human livers with metabolic defects attenuates D-GalN/LPS-induced acute liver failure. [Journal Article]
- CONCLUSIONS: Explanted livers from patients with inheritable metabolic disorders can serve as a viable cell source for cell-based therapies. Domino HT using hepatocytes with certain metabolic defects has the potential to be a novel therapeutic strategy for ALF.
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- Characterization of hepatic inflammatory changes in a C57BL/6J mouse model of alpha1-antitrypsin deficiency. [Journal Article]Am J Physiol Gastrointest Liver Physiol. 2022 12 01; 323(6):G594-G608.AJ
- Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by a hepatic accumulation of mutant alpha-1 antitrypsin (ZAAT). Individuals with AATD are prone to develop a chronic liver disease that remains undiagnosed until late stage of the disease. Here, we sought to characterize the liver pathophysiology of a human transgenic mouse model for AATD with a manifestation of liver disease compa…
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