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Open Biology Oct 2020RNA editing is a post-transcriptional process increasing transcript diversity, thereby regulating different biological processes. We recently observed that mutations... (Review)
Review
RNA editing is a post-transcriptional process increasing transcript diversity, thereby regulating different biological processes. We recently observed that mutations resulting from RNA editing due to hydrolytic deamination of adenosine increase during the development of mesothelioma, a rare cancer linked to chronic exposure to asbestos. This review gathers information from the published literature and public data mining to explore several aspects of RNA editing and their possible implications for cancer growth and therapy. We address possible links between RNA editing and particular types of mesothelioma genetic and epigenetic alterations and discuss the relevance of an edited substrate in the context of current chemotherapy or immunotherapy.
Topics: Adenosine Deaminase; Animals; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Genomic Instability; Humans; Interferon Type I; Mesothelioma; Protein Binding; RNA Editing; RNA Processing, Post-Transcriptional; RNA-Binding Proteins
PubMed: 33050791
DOI: 10.1098/rsob.200112 -
International Journal of Molecular... Aug 2023Endothelial cells are a preferential target for SARS-CoV-2 infection. Previously, we have reported that vascular adenosine deaminase 1 (ADA1) may serve as a biomarker of...
Endothelial cells are a preferential target for SARS-CoV-2 infection. Previously, we have reported that vascular adenosine deaminase 1 (ADA1) may serve as a biomarker of endothelial activation and vascular inflammation, while ADA2 plays a critical role in monocyte and macrophage function. In this study, we investigated the activities of circulating ADA isoenzymes in patients 8 weeks after mild COVID-19 and related them to the parameters of inflammation and microvascular/endothelial function. Post-COVID patients revealed microvascular dysfunction associated with the changes in circulating parameters of endothelial dysfunction and inflammatory activation. Interestingly, serum total ADA and ADA2 activities were diminished in post-COVID patients, while ADA1 remained unchanged in comparison to healthy controls without a prior diagnosis of SARS-CoV-2 infection. While serum ADA1 activity tended to positively correspond with the parameters of endothelial activation and inflammation, sICAM-1 and TNFα, serum ADA2 activity correlated with IL-10. Simultaneously, post-COVID patients had lower circulating levels of ADA1-anchoring protein, CD26, that may serve as an alternative receptor for virus binding. This suggests that after the infection CD26 is rather maintained in cell-attached form, enabling ADA1 complexing. This study points to the possible role of ADA isoenzymes in cardiovascular complications after mild COVID-19.
Topics: Humans; Adenosine Deaminase; COVID-19; Dipeptidyl Peptidase 4; Endothelial Cells; Inflammation; Isoenzymes; SARS-CoV-2; Vascular Diseases
PubMed: 37685949
DOI: 10.3390/ijms241713140 -
Frontiers in Immunology 2019Specialized receptors that recognize molecular patterns such as double stranded RNA duplexes-indicative of viral replication-are potent triggers of the innate immune... (Review)
Review
Specialized receptors that recognize molecular patterns such as double stranded RNA duplexes-indicative of viral replication-are potent triggers of the innate immune system. Although their activation is beneficial during viral infection, RNA transcribed from endogenous mobile genetic elements may also act as ligands potentially causing autoimmunity. Recent advances indicate that the adenosine deaminase ADAR1 through RNA editing is involved in dampening the canonical antiviral RIG-I-like receptor-, PKR-, and OAS-RNAse L pathways to prevent autoimmunity. However, this inhibitory effect must be overcome during viral infections. In this review we discuss ADAR1's critical role in balancing immune activation and self-tolerance.
Topics: Adenosine Deaminase; Animals; Cell Cycle Checkpoints; Cytoplasm; DEAD Box Protein 58; Disease Susceptibility; Endoribonucleases; Humans; Immunity, Innate; Interferons; RNA Editing; RNA-Binding Proteins; Signal Transduction; eIF-2 Kinase
PubMed: 31404141
DOI: 10.3389/fimmu.2019.01763 -
Ideggyogyaszati Szemle May 2023
In our study, we aimed to evaluate inflammation by measuring serum Adenosine deaminase and dipeptidyl peptidase IV levels of individuals diagnosed with autism...
BACKGROUND AND PURPOSE
In our study, we aimed to evaluate inflammation by measuring serum Adenosine deaminase and dipeptidyl peptidase IV levels of individuals diagnosed with autism spectrum disorder and to determine its relationship with the Childhood Autism Rating Scale.
.METHODS
37 children aged 2-12 years with a diagnosis of autism spectrum disorder and 27 children aged 2-12 years without any psychiatric disease were included in the study. Psychiatric examination and clinical evaluation according to DSM-5 diagnostic criteria for the diagnosis of autism spectrum disorder were performed on the children included in the study. The Childhood Autism Rating Scale was filled in by the researcher by interviewing the parents of the children diagnosed with autism spectrum disorder. 5 ml of venous blood samples were taken from the children in both groups in the morning on a full stomach.
.RESULTS
There was no statistically significant difference between the groups in terms of age, gender, and sociodemographic data. While serum adenosine deaminase levels were found to be statistically significantly higher in the group with autism spectrum disorder, serum dipeptidyl peptidase IV levels were found to be significantly lower. A positive correlation was found between dipeptidyl peptidase IV and Childhood Autism Rating Scale.
.CONCLUSION
We think that inflammation may play a role in the etiology of autism spectrum disorder due to altered adenosine deaminase and dipeptidyl peptidase IV levels in children with autism spectrum disorder.
.Topics: Child; Humans; Autism Spectrum Disorder; Dipeptidyl Peptidase 4; Adenosine Deaminase; Inflammation
PubMed: 37294021
DOI: 10.18071/isz.76.0212 -
Journal of Investigational Allergology... Feb 2021Deficiency of adenosine deaminase 2 (DADA2) is a rare disease with varying phenotypes and disease outcomes. We evaluated the treatment of DADA2 and explored the factors... (Review)
Review
OBJECTIVES
Deficiency of adenosine deaminase 2 (DADA2) is a rare disease with varying phenotypes and disease outcomes. We evaluated the treatment of DADA2 and explored the factors associated with disease outcome.
METHODS
A systemic literature review of DADA2 was conducted. Cases were included if they had documented detailed genotypes, phenotypes, treatment protocols, and outcomes. Patients were categorized as having uncontrolled and controlled disease. Factors associated with disease outcome were analyzed using logistic regression models.
RESULTS
The study population comprised 242 DADA2 patients with data on treatment protocols and responses, of whom 17 required no treatment. Tumor necrosis factor a inhibitors (TNFi) were effective in 78.6% (103/131). Hematological abnormalities and increased acute phase reactants are independently associated with the effectiveness of TNFi (OR, 0.21 [95%CI, 0.07-0.661; P=.007] and 9.62 [95%CI, 2.31-40.00; P=.002, respectively). Among the 225 patients requiring active treatment, 157 (69.8%) had controlled disease and 68 (30.2%) uncontrolled disease. Neither age of disease onset nor genotype was associated with disease outcome. Increased acute phase reactant values, constitutional symptoms, neurological symptoms, and treatment with TNFi were independently associated with disease control, while recurrent infections and severe vascular events were the main causes of mortality (10/21 and 6/21, respectively).
CONCLUSION
In patients requiring treatment, symptoms of systemic inflammation and vasculitis and treatment with TNFi are associated with disease control. Recurrent infections and severe vascular events should be treated intensively, as they are the main causes of death. Hematological abnormalities should be monitored, as they decrease the effectiveness of TNFi.
Topics: Adenosine Deaminase; Humans; Intercellular Signaling Peptides and Proteins; Phenotype; Primary Immunodeficiency Diseases; Treatment Outcome; Vasculitis
PubMed: 34489224
DOI: 10.18176/jiaci.0748 -
Journal of Clinical Immunology Oct 2023Deficiency of adenosine deaminase-2 (DADA2) is an autosomal recessive autoinflammatory disease with an extremely variable disease presentation. This paper provides a... (Review)
Review
Deficiency of adenosine deaminase-2 (DADA2) is an autosomal recessive autoinflammatory disease with an extremely variable disease presentation. This paper provides a comprehensive overview of the Dutch DADA2 cohort. We performed a retrospective cohort study in 29 ADA2-deficient patients from 23 families with a median age at inclusion of 26 years. All patients had biallelic pathogenic variants in the ADA2 gene. The most common clinical findings included cutaneous involvement (79.3%), (hepato)splenomegaly (70.8%) and recurrent infections (58.6%). Stroke was observed in 41.4% of the patients. The main laboratory abnormalities were hypogammaglobulinemia and various cytopenias. Patients presented most often with a mixed phenotype involving vasculopathy, immunodeficiency and hematologic manifestations (62.1%). In this cohort, malignancies were reported in eight patients (27.6%), of whom five presented with a hematologic malignancy and two with a basal cell carcinoma. Four patients developed hemophagocytic lymphohistiocytosis (HLH) or an HLH-like episode, of whom three passed away during or shortly after the occurrence of HLH. TNF-inhibitors (TNFi) were effective in treating vasculopathy-associated symptoms and preventing stroke, but were hardly effective in the treatment of hematologic manifestations. Three patients underwent hematopoietic cell transplantation and two of them are doing well with complete resolution of DADA2-related symptoms. The overall mortality in this cohort was 17.2%. In conclusion, this cohort describes the clinical, genetic and laboratory findings of 29 Dutch DADA2 patients. We describe the occurrence of HLH as a life-threatening disease complication and report a relatively high incidence of malignancies and mortality.
Topics: Humans; Adult; Adenosine Deaminase; Follow-Up Studies; Retrospective Studies; Intercellular Signaling Peptides and Proteins; Stroke; Lymphohistiocytosis, Hemophagocytic; Mutation
PubMed: 37277582
DOI: 10.1007/s10875-023-01521-8 -
Blood Jun 2023Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to...
Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.
Topics: Humans; Down-Regulation; Core Binding Factors; Core Binding Factor Alpha 2 Subunit; RNA Editing; Adenosine Deaminase; Leukemia, Myeloid, Acute; Adenosine
PubMed: 36796022
DOI: 10.1182/blood.2022015830 -
Trends in Genetics : TIG Dec 2019Adenosine-to-inosine (A-to-I) editing of RNA leads to deamination of adenosine to inosine. Inosine is interpreted as guanosine by the cellular machinery, thus altering... (Review)
Review
Adenosine-to-inosine (A-to-I) editing of RNA leads to deamination of adenosine to inosine. Inosine is interpreted as guanosine by the cellular machinery, thus altering the coding, folding, splicing, or transport of transcripts. A-to-I editing is tightly regulated. Altered editing has severe consequences for human health and can cause interferonopathies, neurological disorders, and cardiovascular disease, as well as impacting on cancer progression. ADAR1-mediated RNA editing plays an important role in antiviral immunity and is essential for distinguishing between endogenous and viral RNA, thereby preventing autoimmune disorders. Interestingly, A-to-I editing can be used not only to correct genomic mutations at the RNA level but also to modulate tumor antigenicity with large therapeutic potential. We highlight recent developments in the field, focusing on cancer and other human diseases.
Topics: Adenosine Deaminase; Animals; Disease Susceptibility; Drug Development; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Immunity; Isoenzymes; RNA Editing; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 31648814
DOI: 10.1016/j.tig.2019.09.004 -
Blood Aug 2022
Topics: Adenosine Deaminase; Humans; Severe Combined Immunodeficiency
PubMed: 35980680
DOI: 10.1182/blood.2022017722 -
Frontiers in Immunology 2023Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity. Furthermore, various patient populations,...
Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity. Furthermore, various patient populations, including the aged can have suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mice. Aged mice exhibited altered cellular responses, including decreased IFNγ secretion and increased TNFα and IL-4 secretion suggestive of T2-skewed responses. Aged mice exhibited decreased total binding and neutralizing antibodies in their serum but significantly increased T2-type antigen-specific IgG1 antibody compared to their young counterparts. Strategies to enhance vaccine-induced immune responses are important, especially in aged patient populations. We observed that co-immunization with plasmid-encoded adenosine deaminase (pADA)enhanced immune responses in young animals. Ageing is associated with decreases in ADA function and expression. Here, we report that co-immunization with pADA enhanced IFNγ secretion while decreasing TNFα and IL-4 secretion. pADA expanded the breadth and affinity SARS-CoV-2 spike-specific antibodies while supporting T1-type humoral responses in aged mice. scRNAseq analysis of aged lymph nodes revealed that pADA co-immunization supported a T1 gene profile and decreased FoxP3 gene expression. Upon challenge, pADA co-immunization decreased viral loads in aged mice. These data support the use of mice as a model for age-associated decreased vaccine immunogenicity and infection-mediated morbidity and mortality in the context of SARS-CoV-2 vaccines and provide support for the use of adenosine deaminase as a molecular adjuvant in immune-challenged populations.
Topics: Humans; Animals; Mice; SARS-CoV-2; COVID-19 Vaccines; Tumor Necrosis Factor-alpha; COVID-19; Interleukin-4; Adenosine Deaminase; Immunization; Antibodies, Viral; Disease Models, Animal
PubMed: 36999023
DOI: 10.3389/fimmu.2023.1138609