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1.
BMJ Case Rep ; 17(5)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38724212

RESUMO

A girl in the early adolescent age group presented with multisystem manifestations in the form of periodic fever, recurrent abdominal pain, hypertension, seizure, skin lesions over the chest and gangrene over the left ring and middle fingertips. Her condition had remained undiagnosed for 11 years. On evaluation, she had features of polyarteritis nodosa (PAN) (multiple aneurysms, symmetric sensorimotor peripheral neuropathy, superficial ulcers, digital necrosis, myalgia, hypertension and proteinuria). As childhood PAN is a phenocopy of adenosine deaminase 2 with a different management strategy, whole-exome sequencing was performed, which revealed a pathogenic variant in ADA2 gene. The child was treated with TNF alpha inhibitors and showed improvement in the Paediatric Vasculitis Activity Score. The paper highlights the gratifying consequences of correct diagnosis with disease-specific therapy that ended the diagnostic odyssey, providing relief to the patient from debilitating symptoms and to the family from the financial burden of continued out-of-pocket health expenditure.


Assuntos
Adenosina Desaminase , Poliarterite Nodosa , Humanos , Poliarterite Nodosa/diagnóstico , Poliarterite Nodosa/tratamento farmacológico , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Feminino , Diagnóstico Diferencial , Adolescente , Sequenciamento do Exoma , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Criança , Peptídeos e Proteínas de Sinalização Intercelular
2.
Medicine (Baltimore) ; 103(19): e38116, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38728474

RESUMO

RNA editing, as an epigenetic mechanism, exhibits a strong correlation with the occurrence and development of cancers. Nevertheless, few studies have been conducted to investigate the impact of RNA editing on cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). In order to study the connection between RNA editing and CESC patients' prognoses, we obtained CESC-related information from The Cancer Genome Atlas (TCGA) database and randomly allocated the patients into the training group or testing group. An RNA editing-based risk model for CESC patients was established by Cox regression analysis and least absolute shrinkage and selection operator (LASSO). According to the median score generated by this RNA editing-based risk model, patients were categorized into subgroups with high and low risks. We further constructed the nomogram by risk scores and clinical characteristics and analyzed the impact of RNA editing levels on host gene expression levels and adenosine deaminase acting on RNA. Finally, we also compared the biological functions and pathways of differentially expressed genes (DEGs) between different subgroups by enrichment analysis. In this risk model, we screened out 6 RNA editing sites with significant prognostic value. The constructed nomogram performed well in forecasting patients' prognoses. Furthermore, the level of RNA editing at the prognostic site exhibited a strong correlation with host gene expression. In the high-risk subgroup, we observed multiple biological functions and pathways associated with immune response, cell proliferation, and tumor progression. This study establishes an RNA editing-based risk model that helps forecast patients' prognoses and offers a new understanding of the underlying mechanism of RNA editing in CESC.


Assuntos
Nomogramas , Edição de RNA , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/genética , Feminino , Edição de RNA/genética , Prognóstico , Medição de Risco/métodos , Pessoa de Meia-Idade , Carcinoma de Células Escamosas/genética , Adenocarcinoma/genética , Adenosina Desaminase/genética
4.
Neoplasma ; 71(2): 180-192, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38766853

RESUMO

It has been demonstrated that calreticulin (CALR) is expressed abnormally in various tumors and is involved in the occurrence and development of tumors. In this study, CALR and EIF2AK2 expression was measured in the clinical specimens of 39 patients with melanoma. Then, we constructed knockdown and overexpression cell models of CALR and EIF2AK2 and used wound healing and Transwell assays to observe cell migration and invasion. Apoptosis, EDU, and ROS assays were used to measure cell apoptosis and proliferation, as well as ROS levels. The effect of CALR on endoplasmic reticulum stress was detected using endoplasmic reticulum fluorescent probes. Western blotting was used to detect protein levels of CALR, EIF2AK2, ADAR1, and MMP14. The results indicated that CALR and EIF2AK2 expression levels were significantly higher in human melanoma tissues than in adjacent non-tumor tissue. In addition, we found a correlation between CALR and the expression of EIF2AK2 and MMP14, and the experimental results indicated that overexpression of CALR significantly upregulated the expression of EIF2AK2, MMP14, and ADAR1, while knockdown of CALR inhibited their expression. Notably, the knockdown of EIF2AK2 in the CALR overexpression group blocked the upregulation of MMP14 and ADAR1 expression by CALR, and the knockdown of both CALR and EIF2AK2 significantly inhibited MMP14 and ADAR1 expression. In conclusion, CALR and EIF2AK2 play a promoting role in melanoma progression, and knockdown of CALR and EIF2AK2 may be an effective anti-tumor target, and its mechanism may be through MMP14, ADAR1 signaling.


Assuntos
Adenosina Desaminase , Calreticulina , Proliferação de Células , Metaloproteinase 14 da Matriz , Melanoma , Proteínas de Ligação a RNA , Transdução de Sinais , eIF-2 Quinase , Humanos , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Melanoma/patologia , Melanoma/metabolismo , Melanoma/genética , eIF-2 Quinase/metabolismo , eIF-2 Quinase/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Calreticulina/genética , Calreticulina/metabolismo , Linhagem Celular Tumoral , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 14 da Matriz/genética , Movimento Celular , Apoptose , Estresse do Retículo Endoplasmático , Feminino , Progressão da Doença , Masculino , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade
5.
J Clin Immunol ; 44(5): 118, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38758417

RESUMO

Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies. A type I interferon (IFN) gene signature is associated with DADA2 though its association with immune dysregulation is unclear.


Assuntos
Adenosina Desaminase , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Feminino , Doenças Hereditárias Autoinflamatórias
6.
Commun Biol ; 7(1): 594, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760406

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2-/-/GluR-BR/R mice (ADAR2 KO) mice are fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibit protection against HFD-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice display reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigates excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibits hepatic gluconeogenesis via the AMPK/CREB pathway and promotes glycogen synthesis by activating the AMPK/GSK3ß pathway. These results provide evidence that ADAR2 KO protects against NAFLD progression through the activation of AMPK signaling pathways.


Assuntos
Adenosina Desaminase , Dieta Hiperlipídica , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica , Proteínas de Ligação a RNA , Transdução de Sinais , Animais , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Adenosina Desaminase/deficiência , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/etiologia , Dieta Hiperlipídica/efeitos adversos , Masculino , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Resistência à Insulina , Camundongos Obesos , Obesidade/metabolismo , Obesidade/genética , Camundongos Endogâmicos C57BL , Fígado/metabolismo
7.
BMC Pulm Med ; 24(1): 241, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750432

RESUMO

BACKGROUND: Pleural fluid is one of the common complications of thoracic diseases, and tuberculous pleural effusion (TPE) is the most common cause of pleural effusion in TB-endemic areas and the most common type of exudative pleural effusion in China. In clinical practice, distinguishing TPE from pleural effusion caused by other reasons remains a relatively challenging issue. The objective of present study was to explore the clinical significance of the pleural fluid lactate dehydrogenase/adenosine deaminase ratio (pfLDH/pfADA) in the diagnosis of TPE. METHODS: The clinical data of 618 patients with pleural effusion were retrospectively collected, and the patients were divided into 3 groups: the TPE group (412 patients), the parapneumonic pleural effusion (PPE) group (106 patients), and the malignant pleural effusion (MPE) group (100 patients). The differences in the ratios of pleural effusion-related and serology-related indicators were compared among the three groups, and receiver operating characteristic curves were drawn to analyze the sensitivity and specificity of the parameter ratios of different indicators for the diagnosis of TPE. RESULTS: The median serum ADA level was higher in the TPE group (13 U/L) than in the PPE group (10 U/L, P < 0.01) and MPE group (10 U/L, P < 0.001). The median pfADA level in the TPE group was 41 (32, 52) U/L; it was lowest in the MPE group at 9 (7, 12) U/L and highest in the PPE group at 43 (23, 145) U/L. The pfLDH level in the PPE group was 2542 (1109, 6219) U/L, which was significantly higher than that in the TPE group 449 (293, 664) U/L. In the differential diagnosis between TPE and non-TPE, the AUC of pfLDH/pfADA for diagnosing TPE was the highest at 0.946 (0.925, 0.966), with an optimal cutoff value of 23.20, sensitivity of 93.9%, specificity of 87.0%, and Youden index of 0.809. In the differential diagnosis of TPE and PPE, the AUC of pfLDH/pfADA was the highest at 0.964 (0.939, 0.989), with an optimal cutoff value of 24.32, sensitivity of 94.6%, and specificity of 94.4%; this indicated significantly better diagnostic efficacy than that of the single index of pfLDH. In the differential diagnosis between TPE and MPE, the AUC of pfLDH/pfADA was 0.926 (0.896, 0.956), with a sensitivity of 93.4% and specificity of 80.0%; this was not significantly different from the diagnostic efficacy of pfADA. CONCLUSIONS: Compared with single biomarkers, pfLDH/pfADA has higher diagnostic value for TPE and can identify patients with TPE early, easily, and economically.


Assuntos
Adenosina Desaminase , L-Lactato Desidrogenase , Derrame Pleural , Curva ROC , Sensibilidade e Especificidade , Tuberculose Pleural , Humanos , Adenosina Desaminase/análise , Adenosina Desaminase/sangue , Adenosina Desaminase/metabolismo , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Derrame Pleural/diagnóstico , L-Lactato Desidrogenase/análise , Tuberculose Pleural/diagnóstico , Adulto , Idoso , China , Diagnóstico Diferencial , Derrame Pleural Maligno/diagnóstico , Biomarcadores/análise , Biomarcadores/sangue , Relevância Clínica
8.
Int Immunopharmacol ; 134: 112177, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38696908

RESUMO

BACKGROUND: Ferroptosis, characterized by excessive iron ions and lipid peroxides accumulation, contributes to Nonalcoholic Fatty Liver Disease (NAFLD) development. The role of ADAR1, crucial for lipid metabolism and immune regulation, in ferroptosis-related NAFLD remains unexplored. METHODS: In this study, we analyzed the expression of ADAR1 in NAFLD patients using the GSE66676 database. Subsequently, We investigated the effects of ADAR1 knockdown on mitochondrial membrane potential (MMP), Fe2+ levels, oxidation products, and ferroptosis in NAFLD cells through in vitro and in vivo experiments. Additionally, RNA-seq analysis was performed following ADAR1 depletion in an NAFLD cell model. Overlapping and ferroptosis-related genes were identified using a Venn diagram, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted as well. Furthermore, a protein-protein interaction (PPI) network was constructed to identify hub genes associated with ferroptosis. RESULTS: We found the expression level of ADAR1 was downregulated in NAFLD patients and 22 ferroptosis-associated genes were differentially expressed in a NAFLD cell model upon ADAR1 knockdown. Based on PPI network, we identified NOS2, PTGS2, NOX4, ALB, IL6, and CCL5 as the central genes related to ferroptosis. ADAR1 deletion-related NAFLD was found to be involved in the ferroptosis signaling pathway. NOS2, PTGS2, ALB, and IL6 can serve as potential biomarkers. These findings offer new insights and expanded targets for NAFLD prevention and treatment. CONCLUSION: These findings provide new strategies and potential targets for preventing and treating NAFLD. NOS2, PTGS2, ALB, and IL6 may serve as biomarkers for ADAR1 deletion-related NAFLD, which could help for developing its new diagnostic and therapeutic strategies.


Assuntos
Adenosina Desaminase , Ferroptose , Hepatopatia Gordurosa não Alcoólica , Proteínas de Ligação a RNA , Ferroptose/genética , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Animais , Camundongos , RNA-Seq , Masculino , Camundongos Endogâmicos C57BL , Mapas de Interação de Proteínas
9.
Commun Biol ; 7(1): 615, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38777862

RESUMO

Deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity caused by loss-of-function mutations in the adenosine deaminase 2 (ADA2) gene. Clinical manifestations of DADA2 include vasculopathy and immuno-hematological abnormalities, culminating in bone marrow failure. A major gap exists in our knowledge of the regulatory functions of ADA2 during inflammation and hematopoiesis, mainly due to the absence of an ADA2 orthologue in rodents. Exploring these mechanisms is essential for understanding disease pathology and developing new treatments. Zebrafish possess two ADA2 orthologues, cecr1a and cecr1b, with the latter showing functional conservation with human ADA2. We establish a cecr1b-loss-of-function zebrafish model that recapitulates the immuno-hematological and vascular manifestations observed in humans. Loss of Cecr1b disrupts hematopoietic stem cell specification, resulting in defective hematopoiesis. This defect is caused by induced inflammation in the vascular endothelium. Blocking inflammation, pharmacological modulation of the A2r pathway, or the administration of the recombinant human ADA2 corrects these defects, providing insights into the mechanistic link between ADA2 deficiency, inflammation and immuno-hematological abnormalities. Our findings open up potential therapeutic avenues for DADA2 patients.


Assuntos
Adenosina Desaminase , Hematopoese , Células-Tronco Hematopoéticas , Inflamação , Peixe-Zebra , Animais , Peixe-Zebra/genética , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Adenosina Desaminase/deficiência , Células-Tronco Hematopoéticas/metabolismo , Inflamação/genética , Inflamação/metabolismo , Hematopoese/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Humanos , Transdução de Sinais , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(5): 591-595, 2024 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-38684307

RESUMO

OBJECTIVE: To explore the clinical characteristics and genetic etiology for a Chinese pedigree affected with Dyschromatosis symmetrica hereditaria (DSH) in conjunct with developmental delay. METHODS: A child who had presented at the First Affiliated Hospital of Zhengzhou University on May 28 2021 for abnormal skin pigmentation of the extremities and growth retardation for over 2 years was selected as the study subject. Clinical data of the child and his pedigree (11 individuals from three generations) was collected. The child was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing. RESULTS: The child, a two-year-and-seven-month-old male, had hyper- and hypopigmentation on his hands, feet and face, in addition with delayed development. All members of his pedigree had typical presentation of DSH. A heterozygous c.2657G>A variant was found in exon 8 of the ADAR gene in the child, his mother, and elder sister. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted as likely pathogenic (PM1+PM2_Supporting+PP1+PP3). CONCLUSION: The c.2657G>A variant of the ADAR gene probably underlay the DSH in this pedigree.


Assuntos
Adenosina Desaminase , Deficiências do Desenvolvimento , Linhagem , Transtornos da Pigmentação , Proteínas de Ligação a RNA , Adulto , Pré-Escolar , Feminino , Humanos , Masculino , Adenosina Desaminase/genética , China , Deficiências do Desenvolvimento/genética , População do Leste Asiático/genética , Sequenciamento do Exoma , Mutação , Transtornos da Pigmentação/genética , Transtornos da Pigmentação/congênito , Proteínas de Ligação a RNA/genética
11.
BMC Neurol ; 24(1): 130, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38632524

RESUMO

BACKGROUND: Monogenic autoinflammatory disorders result in a diverse range of neurological symptoms in adults, often leading to diagnostic delays. Despite the significance of early detection for effective treatment, the neurological manifestations of these disorders remain inadequately recognized. METHODS: We conducted a systematic review searching Pubmed, Embase and Scopus for case reports and case series related to neurological manifestations in adult-onset monogenic autoinflammatory diseases. Selection criteria focused on the four most relevant adult-onset autoinflammatory diseases-deficiency of deaminase 2 (DADA2), tumor necrosis factor receptor associated periodic fever syndrome (TRAPS), cryopyrin associated periodic fever syndrome (CAPS), and familial mediterranean fever (FMF). We extracted clinical, laboratory and radiological features to propose the most common neurological phenotypes. RESULTS: From 276 records, 28 articles were included. The median patient age was 38, with neurological symptoms appearing after a median disease duration of 5 years. Headaches, cranial nerve dysfunction, seizures, and focal neurological deficits were prevalent. Predominant phenotypes included stroke for DADA2 patients, demyelinating lesions and meningitis for FMF, and meningitis for CAPS. TRAPS had insufficient data for adequate phenotype characterization. CONCLUSION: Neurologists should be proactive in diagnosing monogenic autoinflammatory diseases in young adults showcasing clinical and laboratory indications of inflammation, especially when symptoms align with recurrent or chronic meningitis, small vessel disease strokes, and demyelinating lesions.


Assuntos
Síndromes Periódicas Associadas à Criopirina , Febre Familiar do Mediterrâneo , Doenças Hereditárias Autoinflamatórias , Meningite , Adulto Jovem , Humanos , Adulto , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Neurologistas , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Febre Familiar do Mediterrâneo/genética , Síndromes Periódicas Associadas à Criopirina/genética , Febre , Fenótipo
12.
Sci Rep ; 14(1): 8315, 2024 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-38594375

RESUMO

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by autoantibodies against insulin producing pancreatic beta cells and initial lack of need for insulin treatment. The aim of the present study was to investigate if individuals with LADA have an altered gut microbiota relative to non-diabetic control subjects, individuals with type 1 diabetes (T1D), and individuals with type 2 diabetes (T2D). Bacterial community profiling was performed with primers targeting the variable region 4 of the 16S rRNA gene and sequenced. Amplicon sequence variants (ASVs) were generated with DADA2 and annotated to the SILVA database. The gut virome was sequenced, using a viral particle enrichment and metagenomics approach, assembled, and quantified to describe the composition of the viral community. Comparison of the bacterial alpha- and beta-diversity measures revealed that the gut bacteriome of individuals with LADA resembled that of individuals with T2D. Yet, specific genera were found to differ in abundance in individuals with LADA compared with T1D and T2D, indicating that LADA has unique taxonomical features. The virome composition reflected the stability of the most dominant order Caudovirales and the families Siphoviridae, Podoviridae, and Inoviridae, and the dominant family Microviridae. Further studies are needed to confirm these findings.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Intolerância à Glucose , Diabetes Autoimune Latente em Adultos , Adulto , Humanos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Autoimune Latente em Adultos/genética , Microbioma Gastrointestinal/genética , Adenosina Desaminase , RNA Ribossômico 16S/genética , Peptídeos e Proteínas de Sinalização Intercelular , Insulina
13.
Bioorg Med Chem ; 104: 117700, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38583236

RESUMO

Adenosine Deaminases Acting on RNA (ADARs) catalyze the deamination of adenosine to inosine in double-stranded RNA (dsRNA). ADARs' ability to recognize and edit dsRNA is dependent on local sequence context surrounding the edited adenosine and the length of the duplex. A deeper understanding of how editing efficiency is affected by mismatches, loops, and bulges around the editing site would aid in the development of therapeutic gRNAs for ADAR-mediated site-directed RNA editing (SDRE). Here, a SELEX (systematic evolution of ligands by exponential enrichment) approach was employed to identify dsRNA substrates that bind to the deaminase domain of human ADAR2 (hADAR2d) with high affinity. A library of single-stranded RNAs was hybridized with a fixed-sequence target strand containing the nucleoside analog 8-azanebularine that mimics the adenosine deamination transition state. The presence of this nucleoside analog in the library biased the screen to identify hit sequences compatible with adenosine deamination at the site of 8-azanebularine modification. SELEX also identified non-duplex structural elements that supported editing at the target site while inhibiting editing at bystander sites.


Assuntos
Adenosina Desaminase , Nucleosídeos de Purina , Ribonucleosídeos , Humanos , Adenosina , Adenosina Desaminase/metabolismo , Sequência de Bases , RNA de Cadeia Dupla , RNA Guia de Sistemas CRISPR-Cas
14.
Indian J Tuberc ; 71(2): 170-178, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38589121

RESUMO

BACKGROUND: Since, Vitamin D [1α,25(OH)2D)] enhances antimicrobial activity of Innate immunity and modulate Adaptive immune responses, simultaneously, so it play a potential role for balanced immune activity against Mycobacterium tuberculosis and restricting tissue injuries within the TB patients.(Chun et al., 2011) 9 We aimed to determine the role of adjunct Vitamin D treatment on the outcome of pulmonary tuberculosis patients and evaluated the effect of Vitamin D administration on Differential Leucocyte Count, Erythrocyte Sedimentation Rate, serum Adenosine deaminase, serum C- reactive protein, Oxygen saturation (SpO2) and Body Weight in Vitamin D deficient pulmonary tuberculosis patients. METHODS: We conducted a prospective, interventional, randomized, double blind, parallel group, active controlled clinical trial. Newly diagnosed Vitamin D deficient pulmonary tuberculosis patients were randomly assigned to intervention group (received standard anti-tubercular treatment with adjunct Vitamin D3) and control group (received standard anti-tubercular treatment without adjunct Vitamin D3). Total four doses [each dose of 2.5 mg (100000 IU)] of Vitamin D3 were given, orally. First dose was given within 7 days of starting anti-tubercular treatment and second, third, fourth dose were given at 2, 4 and 6 weeks respectively. At the time of enrollment, we measured all baseline characteristics. During follow-up, we measured the study variables and monitored adverse events at 2, 4, 6, 8 and 12 weeks. Our safety parameter was serum corrected calcium level to assess the risk of hypercalcemia. RESULTS: Total 130 pulmonary TB patients, 65 patients in each group, were analyzed. Our study results showed that decrease in Neutrophil count was statistically significant with small effect sizes at every time point of measurement and increase in Lymphocyte count was statistically significant with small and moderate effect sizes at 4, 6 and 8 week for intervention group than for control group. Decrease in erythrocyte sedimentation rate was statistically significant with small effect sizes at 6 and 8 week, decrease in serum adenosine deaminase and serum C- reactive protein was statistically significant with moderate effect sizes at 4, 6 and 8 week for intervention group than for control group. Increase in Oxygen saturation was statistically significant at 4 week with small effect size and increase in body weight was statistically significant with small effect sizes for intervention group than for control group. No case of hypercalcemia was reported. CONCLUSION: Our findings suggest a potential role of adjunctive Vitamin D3 to accelerate resolution of inflammatory responses and improvement in clinical outcomes of pulmonary TB patients. TRIAL REGISTRATION: This trial is registered with Clinical Trials Registry - INDIA (http://ctri.nic.in) with CTRI Number - CTRI/2021/11/037914. PLACE OF STUDY: Room Number 27, first floor out-patients department (OPD) and inpatient Wards, fourth floor, Department of Respiratory Medicine, Uttar Pradesh University of Medical Sciences, Saifai, Etawah (U.P.), INDIA.


Assuntos
Hipercalcemia , Tuberculose Pulmonar , Humanos , Vitamina D/uso terapêutico , Adenosina Desaminase , Estudos Prospectivos , Vitaminas/uso terapêutico , Colecalciferol/uso terapêutico , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/tratamento farmacológico , Método Duplo-Cego , Peso Corporal
15.
Nat Commun ; 15(1): 3662, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38688902

RESUMO

Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient's specific factors.


Assuntos
Adenosina Desaminase , Agamaglobulinemia , Terapia Genética , Vetores Genéticos , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Proto-Oncogene Mas , Imunodeficiência Combinada Severa , Humanos , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Terapia Genética/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/genética , Vetores Genéticos/genética , Agamaglobulinemia/terapia , Agamaglobulinemia/genética , Masculino , Retroviridae/genética
16.
Cell Rep Med ; 5(5): 101530, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38688275

RESUMO

Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR T cells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR T cells, improving migration and resistance to transforming growth factor ß1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor cell feeding. In mouse models of hepatocellular carcinoma and non-small cell lung cancer, metabolically refueled CAR T cells exhibit superior tumor reduction compared to unmodified CAR T cells. Overall, our study highlights the potential of selective inosine refueling to enhance CAR T therapy efficacy against solid tumors.


Assuntos
Adenosina Desaminase , Dipeptidil Peptidase 4 , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Animais , Adenosina Desaminase/metabolismo , Humanos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Camundongos , Imunoterapia Adotiva/métodos , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/imunologia , Linhagem Celular Tumoral , Linfócitos T/imunologia , Linfócitos T/metabolismo , Inosina , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia
17.
J Clin Immunol ; 44(5): 107, 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38676811

RESUMO

PURPOSE: Patients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified (PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi. METHODS: We report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data. RESULTS: Revcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2-3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred. CONCLUSION: Revcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data.


Assuntos
Adenosina Desaminase , Agamaglobulinemia , Terapia de Reposição de Enzimas , Imunodeficiência Combinada Severa , Animais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Agamaglobulinemia/terapia , Reconstituição Imune , Proteínas Recombinantes/uso terapêutico , Imunodeficiência Combinada Severa/terapia , Resultado do Tratamento
18.
Reumatol. clín. (Barc.) ; 20(3): 117-122, Mar. 2024. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-231122

RESUMO

Objectives: Adenosine deaminase (ADA) activity has shown good performance in diagnosing pleural, peritoneal, and meningeal tuberculosis. This meta-analysis aimed to evaluate the performance of measuring ADA activity in synovial fluid for the early diagnosis of joint tuberculosis. Methods: We searched published information in MEDLINE, Embase, Cochrane Library, Web of Science, and MedRxiv databases, as well as unpublished information in the American College of Rheumatology and European League Against Rheumatism for conference abstracts (2012–2021). We also scanned the reference lists of articles. Two reviewers independently applied the criteria for selection, assessed quality, and extracted data (PROSPERO number CRD42021284472). Results: Seven independent studies (N=305 subjects) that compared ADA activity in synovial fluid with a composite reference diagnostic method for tuberculosis were included. Overall, the risk of bias was judged low. Studies were classified as high quality (n=3; 148 subjects) and low quality (n=4; 157 subjects). Pooled sensitivity and specificity of ADA activity was 94% (95% confidence interval [CI], 0.89–98; I2=23%) and 88% (95% CI, 83–92; I2=83%), respectively. The random-effects model for pooled diagnostic Odds ratio was 67.1 (95%CI, 20.3–222.2; I2=30%). The receiver operating characteristic curve area was 0.96 (95% CI, 0.92–0.99). Meta-regression did not identify the quality of the study, country of publication, or the type of assay as a source of heterogeneity. Conclusions: Measuring ADA activity in synovial fluid demonstrates good performance for the early diagnosis of joint tuberculosis.(AU)


Objetivos: La actividad de la adenosina desaminasa (ADA) ha mostrado un buen desempeño en el diagnóstico de la tuberculosis pleural, peritoneal y meníngea. Este metaanálisis tuvo como objetivo evaluar el rendimiento de la medición de la actividad de la ADA en el líquido sinovial para el diagnóstico precoz de la tuberculosis articular. Métodos: Se realizaron búsquedas de resúmenes de congresos en la información publicada en las bases de datos MEDLINE, Embase, Cochrane Library, Web of Science y MedRxiv, así como en información no publicada en el American College of Rheumatology y la European League Against Rheumatism (2012-2021). También se escanearon las listas de referencias de los artículos. Dos revisores aplicaron de forma independiente los criterios de selección, evaluaron la calidad y extrajeron los datos (número PROSPERO CRD42021284472). Resultados: Se incluyeron siete estudios independientes (n=305 sujetos) que compararon la actividad de la ADA en el líquido sinovial con un método diagnóstico compuesto de referencia para la tuberculosis. En general, el riesgo de sesgo se consideró bajo. Los estudios se clasificaron como de alta calidad (n=3; 148 sujetos) y de baja calidad (n=4; 157 sujetos). La sensibilidad y la especificidad agrupadas de la actividad de la ADA fueron del 94% (intervalo de confianza [IC] del 95%: 0,89-98; I2=23%) y del 88% (IC95%: 83-92; I2=83%), respectivamente. El modelo de efectos aleatorios para el odds ratio diagnóstico agrupado fue de 67,1 (IC95%: 20,3-222,2; I2=30%). El área de la curva característica de operación del receptor fue de 0,96 (IC95%: 0,92-0,99). La metarregresión no identificó la calidad del estudio, el país de publicación o el tipo de ensayo como fuente de heterogeneidad.Conclusiones: La medición de la actividad de ADA en el líquido sinovial demuestra un buen rendimiento para el diagnóstico precoz de la tuberculosis articular.(AU)


Assuntos
Humanos , Masculino , Feminino , Artrite/diagnóstico , Adenosina Desaminase , Líquido Sinovial , Tuberculose Pleural/diagnóstico , Sensibilidade e Especificidade , Reumatologia , Doenças Reumáticas , Tuberculose/classificação
19.
FASEB J ; 38(5): e23549, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38446465

RESUMO

Apical periodontitis (AP) is a disease caused by pathogenic microorganisms and featured with the degradation of periapical hard tissue. Our recent research showed the crucial role of Z-DNA binding protein 1 (ZBP1)-mediated necroptosis and apoptosis in the pathogenesis of AP. However, the specific regulatory mechanisms of ZBP1 in AP are not fully elucidated. It was found that metformin has a regulatory role in cell necroptosis and apoptosis. But whether and how metformin regulates necroptosis and apoptosis through the ZBP1 in the context of AP remains unknown. This study provided evidence that lipopolysaccharide (LPS) promotes the synthesis of left-handed Z-nucleic acids (Z-NA), which in turn activates ZBP1. Knockout of Zbp1 by CRISPR/Cas9 technology significantly reduced LPS-induced necroptosis and apoptosis in vitro. By using Zbp1-knockout mice, periapical bone destruction was alleviated. Moreover, type I interferon induced the expression of interferon-stimulated genes (ISGs), which serve as a major source of Z-NA. In addition, the RNA-editing enzyme Adenosine Deaminase RNA specific 1 (ADAR1) prevented the accumulation of endogenous Z-NA. Meanwhile, metformin suppressed the ZBP1-mediated necroptosis by inhibiting the expression of ZBP1 and the accumulation of ISGs. Metformin also promoted mitochondrial apoptosis, which is critical for the elimination of intracellular bacterial infection. The enhanced apoptosis further promoted the healing of infected apical bone tissues. In summary, these results demonstrated that the recognition of Z-NA by ZBP1 plays an important role in AP pathogenesis. Metformin suppressed ZBP1-mediated necroptosis and promoted apoptosis, thereby contributing to the soothing of inflammation and bone healing in AP.


Assuntos
Interferon Tipo I , Metformina , Periodontite Periapical , Camundongos , Animais , Camundongos Knockout , Lipopolissacarídeos , Morte Celular , Metformina/farmacologia , RNA , Proteínas de Ligação a RNA , Adenosina Desaminase
20.
Reumatol Clin (Engl Ed) ; 20(3): 117-122, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38494302

RESUMO

OBJECTIVES: Adenosine deaminase (ADA) activity has shown good performance in diagnosing pleural, peritoneal, and meningeal tuberculosis. This meta-analysis aimed to evaluate the performance of measuring ADA activity in synovial fluid for the early diagnosis of joint tuberculosis. METHODS: We searched published information in MEDLINE, Embase, Cochrane Library, Web of Science, and MedRxiv databases, as well as unpublished information in the American College of Rheumatology and European League Against Rheumatism for conference abstracts (2012-2021). We also scanned the reference lists of articles. Two reviewers independently applied the criteria for selection, assessed quality, and extracted data (PROSPERO number CRD42021284472). RESULTS: Seven independent studies (N=305 subjects) that compared ADA activity in synovial fluid with a composite reference diagnostic method for tuberculosis were included. Overall, the risk of bias was judged low. Studies were classified as high quality (n=3; 148 subjects) and low quality (n=4; 157 subjects). Pooled sensitivity and specificity of ADA activity was 94% (95% confidence interval [CI], 0.89-98; I2=23%) and 88% (95% CI, 83-92; I2=83%), respectively. The random-effects model for pooled diagnostic Odds ratio was 67.1 (95%CI, 20.3-222.2; I2=30%). The receiver operating characteristic curve area was 0.96 (95% CI, 0.92-0.99). Meta-regression did not identify the quality of the study, country of publication, or the type of assay as a source of heterogeneity. CONCLUSIONS: Measuring ADA activity in synovial fluid demonstrates good performance for the early diagnosis of joint tuberculosis.


Assuntos
Artrite , Tuberculose Osteoarticular , Humanos , Adenosina Desaminase/análise , Líquido Sinovial/química , Sensibilidade e Especificidade
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