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Frontiers in Medicine 2024Prior investigations have indicated associations between Knee Osteoarthritis (KOA) and certain inflammatory cytokines, such as the interleukin series and tumor necrosis...
BACKGROUND
Prior investigations have indicated associations between Knee Osteoarthritis (KOA) and certain inflammatory cytokines, such as the interleukin series and tumor necrosis factor-alpha (TNFα). To further elaborate on these findings, our investigation utilizes Mendelian randomization to explore the causal relationships between KOA and 91 inflammatory cytokines.
METHODS
This two-sample Mendelian randomization utilized genetic variations associated with KOA from a large, publicly accessible Genome-Wide Association Study (GWAS), comprising 2,227 cases and 454,121 controls of European descent. The genetic data for inflammatory cytokines were obtained from a GWAS summary involving 14,824 individuals of European ancestry. Causal relationships between exposures and outcomes were primarily investigated using the inverse variance weighted method. To enhance the robustness of the research results, other methods were combined to assist, such as weighted median, weighted model and so on. Multiple sensitivity analysis, including MR-Egger, MR-PRESSO and leave one out, was also carried out. These different analytical methods are used to enhance the validity and reliability of the final results.
RESULTS
The results of Mendelian randomization indicated that Adenosine Deaminase (ADA), Fibroblast Growth Factor 5(FGF5), and Hepatocyte growth factor (HFG) proteins are protective factors for KOA (IVW: OR = 0.862, 95% CI: 0.771-0.963, = 0.008; IVW: OR = 0.850, 95% CI: 0.764-0.946, = 0.003; IVW: OR = 0.798, 95% CI: 0.642-0.991, = 0.042), while Tumor necrosis factor (TNFα), Colony-stimulating factor 1(CSF1), and Tumor necrosis factor ligand superfamily member 12(TWEAK) proteins are risk factors for KOA. (IVW: OR = 1.319, 95% CI: 1.067-1.631, = 0.011; IVW: OR = 1.389, 95% CI: 1.125-1.714, = 0.002; IVW: OR = 1.206, 95% CI: 1.016-1.431, = 0.032).
CONCLUSION
The six proteins identified in this study demonstrate a close association with the onset of KOA, offering valuable insights for future therapeutic interventions. These findings contribute to the growing understanding of KOA at the microscopic protein level, paving the way for potential targeted therapeutic approaches.
PubMed: 38863887
DOI: 10.3389/fmed.2024.1382836 -
BMC Medicine Jun 2024Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive ages. Our previous study has implicated a possible link between RNA...
BACKGROUND
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive ages. Our previous study has implicated a possible link between RNA editing and PCOS, yet the actual role of RNA editing, its association with clinical features, and the underlying mechanisms remain unclear.
METHODS
Ten RNA-Seq datasets containing 269 samples of multiple tissue types, including granulosa cells, T helper cells, placenta, oocyte, endometrial stromal cells, endometrium, and adipose tissues, were retrieved from public databases. Peripheral blood samples were collected from twelve PCOS and ten controls and subjected to RNA-Seq. Transcriptome-wide RNA-Seq data analysis was conducted to identify differential RNA editing (DRE) between PCOS and controls. The functional significance of DRE was evaluated by luciferase reporter assays and overexpression in human HEK293T cells. Dehydroepiandrosterone and lipopolysaccharide were used to stimulate human KGN granulosa cells to evaluate gene expression.
RESULTS
RNA editing dysregulations across multiple tissues were found to be associated with PCOS in public datasets. Peripheral blood transcriptome analysis revealed 798 DRE events associated with PCOS. Through weighted gene co-expression network analysis, our results revealed a set of hub DRE events in PCOS blood. A DRE event in the eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2:chr2:37,100,559) was associated with PCOS clinical features such as luteinizing hormone (LH) and the ratio of LH over follicle-stimulating hormone. Luciferase assays, overexpression, and knockout of RNA editing enzyme adenosine deaminase RNA specific (ADAR) showed that the ADAR-mediated editing cis-regulated EIF2AK2 expression. EIAF2AK2 showed a higher expression after dehydroepiandrosterone and lipopolysaccharide stimulation, triggering changes in the downstrean MAPK pathway.
CONCLUSIONS
Our study presented the first evidence of cross-tissue RNA editing dysregulation in PCOS and its clinical associations. The dysregulation of RNA editing mediated by ADAR and the disrupted target EIF2AK2 may contribute to PCOS development via the MPAK pathway, underlining such epigenetic mechanisms in the disease.
Topics: Humans; Polycystic Ovary Syndrome; Female; RNA Editing; eIF-2 Kinase; Adult; HEK293 Cells; Gene Expression Profiling; Clinical Relevance
PubMed: 38853264
DOI: 10.1186/s12916-024-03434-8 -
Virus Research Aug 2024The conversion of Adenosine (A) to Inosine (I), by Adenosine Deaminases Acting on RNA or ADARs, is an essential post-transcriptional modification that contributes to...
The conversion of Adenosine (A) to Inosine (I), by Adenosine Deaminases Acting on RNA or ADARs, is an essential post-transcriptional modification that contributes to proteome diversity and regulation in metazoans including humans. In addition to its transcriptome-regulating role, ADARs also play a major part in immune response to viral infection, where an interferon response activates interferon-stimulated genes, such as ADARp150, in turn dynamically regulating host-virus interactions. A previous report has shown that infection from reoviruses, despite strong activation of ADARp150, does not influence the editing of some of the major known editing targets, while likely editing others, suggesting a potentially nuanced editing pattern that may depend on different factors. However, the results were based on a handful of selected editing sites and did not cover the entire transcriptome. Thus, to determine whether and how reovirus infection specifically affects host ADAR editing patterns, we analyzed a publicly available deep-sequenced RNA-seq dataset, from murine fibroblasts infected with wild-type and mutant reovirus strains that allowed us to examine changes in editing patterns on a transcriptome-wide scale. To the best of our knowledge, this is the first transcriptome-wide report on host editing changes after reovirus infection. Our results demonstrate that reovirus infection induces unique nuanced editing changes in the host, including introducing sites uniquely edited in infected samples. Genes with edited sites are overrepresented in pathways related to immune regulation, cellular signaling, metabolism, and growth. Moreover, a shift in editing targets has also been observed, where the same genes are edited in infection and control conditions but at different sites, or where the editing rate is increased for some and decreased for other differential targets, supporting the hypothesis of dynamic and condition-specific editing by ADARs.
Topics: Animals; Mice; Fibroblasts; Transcriptome; RNA Editing; Inosine; Adenosine Deaminase; Adenosine; Reoviridae Infections; Host-Pathogen Interactions; RNA-Binding Proteins; Reoviridae
PubMed: 38848818
DOI: 10.1016/j.virusres.2024.199413 -
PLoS Pathogens Jun 2024Although lack of ADAR (adenosine deaminase acting on RNA) orthologs, genome-wide A-to-I editing occurs specifically during sexual reproduction in a number of filamentous... (Review)
Review
Although lack of ADAR (adenosine deaminase acting on RNA) orthologs, genome-wide A-to-I editing occurs specifically during sexual reproduction in a number of filamentous ascomycetes, including Fusarium graminearum and Neurospora crassa. Unlike ADAR-mediated editing in animals, fungal A-to-I editing has a strong preference for hairpin loops and U at -1 position, which leads to frequent editing of UAG and UAA stop codons. Majority of RNA editing events in fungi are in the coding region and cause amino acid changes. Some of these editing events have been experimentally characterized for providing heterozygote and adaptive advantages in F. graminearum. Recent studies showed that FgTad2 and FgTad3, 2 ADAT (adenosine deaminase acting on tRNA) enzymes that normally catalyze the editing of A34 in the anticodon of tRNA during vegetative growth mediate A-to-I mRNA editing during sexual reproduction. Stage specificity of RNA editing is conferred by stage-specific expression of short transcript isoforms of FgTAD2 and FgTAD3 as well as cofactors such as AME1 and FIP5 that facilitate the editing of mRNA in perithecia. Taken together, fungal A-to-I RNA editing during sexual reproduction is catalyzed by ADATs and it has the same sequence and structural preferences with editing of A34 in tRNA.
Topics: RNA Editing; Adenosine Deaminase; Fungal Proteins; Ascomycota; RNA, Fungal; Adenosine; Inosine; Fusarium; Neurospora crassa
PubMed: 38843141
DOI: 10.1371/journal.ppat.1012238 -
Veterinarni Medicina May 2024At present, the assessment of pig welfare quality has gained significant importance, prompting the exploration of novel biomarkers for this purpose. Traditionally,... (Review)
Review
At present, the assessment of pig welfare quality has gained significant importance, prompting the exploration of novel biomarkers for this purpose. Traditionally, these biomarkers have been monitored in the blood; however, blood sampling is considered an invasive procedure. Currently, non-invasive methods for collecting samples are emerging as viable alternatives for assessing these biomarkers. This article aims to present the current knowledge regarding the use of non-invasive methods for analysing pig welfare biomarkers, specifically focusing on the saliva, hair, faeces, and urine as matrices to determine these biomarkers. The saliva analysis encompasses various biomarkers, such as cortisol, alpha-amylase, chromogranin A, the total esterase, oxytocin, acute phase proteins, adenosine deaminase, immunoglobulins and parameters of redox homeostasis. Cortisol, a specific biomarker, can be determined in the hair, urine and faeces, while urine samples allow for the analysis of catecholamines as non-invasive markers of pig welfare.
PubMed: 38841131
DOI: 10.17221/17/2024-VETMED -
BMC Biology Jun 2024ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is thought to play a significant role both in tumor suppression and tumor initiation, which is highly...
BACKGROUND
ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is thought to play a significant role both in tumor suppression and tumor initiation, which is highly dependent upon context. Previous studies have suggested that ARID1A deficiency may contribute to cancer development. The specific mechanisms of whether ARID1A loss affects tumorigenesis by RNA editing remain unclear.
RESULTS
Our findings indicate that the deficiency of ARID1A leads to an increase in RNA editing levels and alterations in RNA editing categories mediated by adenosine deaminases acting on RNA 1 (ADAR1). ADAR1 edits the CDK13 gene at two previously unidentified sites, namely Q113R and K117R. Given the crucial role of CDK13 as a cyclin-dependent kinase, we further observed that ADAR1 deficiency results in changes in the cell cycle. Importantly, the sensitivity of ARID1A-deficient tumor cells to SR-4835, a CDK12/CDK13 inhibitor, suggests a promising therapeutic approach for individuals with ARID1A-mutant tumors. Knockdown of ADAR1 restored the sensitivity of ARID1A deficient cells to SR-4835 treatment.
CONCLUSIONS
ARID1A deficiency promotes RNA editing of CDK13 by regulating ADAR1.
Topics: Adenosine Deaminase; RNA-Binding Proteins; Humans; Transcription Factors; RNA Editing; DNA-Binding Proteins; Cyclin-Dependent Kinases; Cell Line, Tumor; CDC2 Protein Kinase
PubMed: 38835016
DOI: 10.1186/s12915-024-01927-9 -
Frontiers in Endocrinology 2024The aim of this study was to identify potential causal cytokines in thymic malignancies and benign tumors from the FinnGen database using Mendelian randomization (MR).
OBJECTIVE
The aim of this study was to identify potential causal cytokines in thymic malignancies and benign tumors from the FinnGen database using Mendelian randomization (MR).
METHODS
In this study, data from genome-wide association studies (GWAS) of 91 cytokines were used as exposure factors, and those of thymic malignant tumors and thymic benign tumors were the outcome variables. Two methods were used to determine the causal relationship between exposure factors and outcome variables: inverse variance weighting (IVW) and MR-Egger regression. Sensitivity analysis was performed using three methods, namely, the heterogeneity test, the pleiotropy test, and the leave-one-out test.
RESULTS
There was a causal relationship between the expression of fibroblast growth factor 5, which is a risk factor for thymic malignant tumors, and thymic malignant tumors. C-C motif chemokine 19 expression, T-cell surface glycoprotein CD5 levels, and interleukin-12 subunit beta levels were causally related to thymic malignant tumors and were protective. Adenosine deaminase levels, interleukin-10 receptor subunit beta expression, tumor necrosis factor (TNF)-related apoptosis-inducing ligand levels, and TNF-related activation-induced cytokine levels showed a causal relationship with thymic benign tumors, which are its risk factors. Caspase 8 levels, C-C motif chemokine 28 levels, interleukin-12 subunit beta levels, latency-associated peptide transforming growth factor beta 1 levels, and programmed cell death 1 ligand 1 expression showed a causal relationship with thymic benign tumors, which are protective factors. Sensitivity analysis showed no heterogeneity.
CONCLUSION
Cytokines showed a causal relationship with benign and malignant thymic tumors. Interleukin-12 subunit beta is a common cytokine that affects malignant and benign thymic tumors.
Topics: Humans; Mendelian Randomization Analysis; Cytokines; Thymus Neoplasms; Proteomics; Genome-Wide Association Study; Biomarkers, Tumor; Risk Factors
PubMed: 38828408
DOI: 10.3389/fendo.2024.1390140 -
The Journal of Biological Chemistry May 2024Adenosine deaminase (ADA) catalyzes the irreversible deamination of adenosine (ADO) to inosine and regulates ADO concentration. ADA ubiquitously expresses in various...
Adenosine deaminase (ADA) catalyzes the irreversible deamination of adenosine (ADO) to inosine and regulates ADO concentration. ADA ubiquitously expresses in various tissues to mediate ADO-receptor signaling. A significant increase in plasma ADA activity has been shown to be associated with the pathogenesis of type 2 diabetes mellitus. Here, we show that elevated plasma ADA activity is a compensated response to high level of ADO in type 2 diabetes mellitus and plays an essential role in the regulation of glucose homeostasis. Supplementing with more ADA, instead of inhibiting ADA, can reduce ADO levels and decrease hepatic gluconeogenesis. ADA restores a euglycemic state and recovers functional islets in db/db and high-fat streptozotocin diabetic mice. Mechanistically, ADA catabolizes ADO and increases Akt and FoxO1 phosphorylation independent of insulin action. ADA lowers blood glucose at a slower rate and longer duration compared to insulin, delaying or blocking the incidence of insulinogenic hypoglycemia shock. Finally, ADA suppresses gluconeogenesis in fasted mice and insulin-deficient diabetic mice, indicating the ADA regulating gluconeogenesis is a universal biological mechanism. Overall, these results suggest that ADA is expected to be a new therapeutic target for diabetes.
PubMed: 38823639
DOI: 10.1016/j.jbc.2024.107425 -
International Immunopharmacology Jul 2024Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-editing enzyme that significantly impacts cancer progression and various biological processes. The expression of...
BACKGROUND
Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-editing enzyme that significantly impacts cancer progression and various biological processes. The expression of ADAR1 mRNA has been examined in multiple cancer types using The Cancer Genome Atlas (TCGA) dataset, revealing distinct patterns in kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and liver hepatocellular carcinoma (LIHC) compared to normal controls. However, the reasons for these differential expressions remain unclear.
METHODS
In this study, we performed RT-PCR and western blotting (WB) to validate ADAR1 expression patterns in clinical tissue samples. Survival analysis and immune microenvironment analysis (including immune score and stromal score) were conducted using TCGA data to determine the specific cell types associated with ADAR1, as well as the key genes in those cell types. The relationship between ADAR1 and specific cell types' key genes was verified by immunohistochemistry (IHC), using clinical liver and kidney cancer samples.
RESULTS
Our validation analysis revealed that ADAR1 expression was downregulated in KICH, KIRC, and KIRP, while upregulated in LIHC compared to normal tissues. Notably, a significant correlation was found between ADAR1 mRNA expression and patient prognosis, particularly in KIRC, KIRP, and LIHC. Interestingly, we observed a positive correlation between ADAR1 expression and stromal scores in KIRC, whereas a negative correlation was observed in LIHC. Cell type analysis highlighted distinct relationships between ADAR1 expression and the two stromal cell types, blood endothelial cells (BECs) and lymphatic endothelial cells (LECs), and further determined the signature gene claudin-5 (CLDN5), in KIRC and LIHC. Moreover, ADAR1 was inversely related with CLDN5 in KIRC (n = 26) and LIHC (n = 30) samples, verified via IHC.
CONCLUSIONS
ADAR1 plays contrasting roles in LIHC and KIRC, associated with the enrichment of BECs and LECs within tumors. This study sheds light on the significant roles of stromal cells within the complex tumor microenvironment (TME) and provides new insights for future research in tumor immunotherapy and precision medicine.
Topics: Adenosine Deaminase; Humans; Tumor Microenvironment; Liver Neoplasms; Carcinoma, Hepatocellular; Kidney Neoplasms; Carcinoma, Renal Cell; RNA-Binding Proteins; Prognosis; Gene Expression Regulation, Neoplastic; Female; Male; Biomarkers, Tumor; Middle Aged
PubMed: 38820962
DOI: 10.1016/j.intimp.2024.112340 -
Placenta Aug 2024Chorioamnionitis (CAM) involves infection and inflammation of the chorion and amniotic membrane, but there are still no effective diagnostic biomarkers for CAM.
INTRODUCTION
Chorioamnionitis (CAM) involves infection and inflammation of the chorion and amniotic membrane, but there are still no effective diagnostic biomarkers for CAM.
METHODS
We investigated the correlation between RNA editing enzyme Adenosine deaminase family acting on RNA 1 (ADAR1) and CAM in chorion and amniotic membrane specimens derived from premature rupture of the membrane (PROM), CAM (pathologically diagnosed), and clinical CAM (clinically diagnosed) patients using reverse transcription polymerase chain reaction (RT-PCR).
RESULTS
ADAR1 was upregulated in the chorion and amniotic membrane specimens of CAM and clinical CAM patients (p < 0.001 and p = 0.005). ADAR1 had a significantly higher area under the curve (AUC) (0.735 and 0.828) than markers of inflammation characteristics in diagnosing CAM and clinical CAM patients. ADAR1 also had significantly higher AUC (0.701 and 0.837) than clinical characteristics for CAM and clinical CAM patients.
DISCUSSION
ADAR1 can be a useful diagnostic biomarker in CAM patients.
Topics: Humans; Adenosine Deaminase; Female; Pregnancy; Chorioamnionitis; Biomarkers; Adult; RNA-Binding Proteins; Fetal Membranes, Premature Rupture
PubMed: 38820942
DOI: 10.1016/j.placenta.2024.05.133