ABSTRACT
Insulin resistance is caused by the abnormal secretion of proinflammatory cytokines in adipose tissue, which is induced by an increase in lipid accumulation in adipocytes, hepatocytes, and myocytes. The inflammatory pathway involves multiple targets such as nuclear factor kappa B, inhibitor of nuclear factor κ-B kinase, and mitogen-activated protein kinase. Vitamins are micronutrients with anti-inflammatory activities that have unclear mechanisms. The present study aimed to describe the putative mechanisms of vitamins involved in the inflammatory pathway of insulin resistance. The strategy to achieve this goal was to integrate data mining and analysis, target prediction, and molecular docking simulation calculations to support our hypotheses. Our results suggest that the multitarget activity of vitamins A, B1, B2, B3, B5, B6, B7, B12, C, D3, and E inhibits nuclear factor kappa B and mitogen-activated protein kinase, in addition to vitamins A and B12 against inhibitor of nuclear factor κ-B kinase. The findings of this study highlight the pharmacological potential of using an anti-inflammatory and multitarget treatment based on vitamins and open new perspectives to evaluate the inhibitory activity of vitamins against nuclear factor kappa B, mitogen-activated protein kinase, and inhibitor of nuclear factor κ-B kinase in an insulin-resistant context.
Subject(s)
Insulin Resistance , Molecular Docking Simulation , NF-kappa B , Vitamins , Humans , Vitamins/pharmacology , NF-kappa B/metabolism , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Mitogen-Activated Protein Kinases/metabolismABSTRACT
Bone marrow samples from children with acute lymphoblastic leukemia were analyzed for the expression of RUNX1a/b/c isoforms. Obtained patterns were associated with genetic abnormalities and the expression of the RUNX1 regulated gene BLK. RUNX1c was present in all patients, but the expected over-expression of RUNX1a was not observed. Over-expression of total RUNT domain isoforms was detected in patients with extra RUNX1 copies, and unexpectedly, in those with t(4;11). Only expression of the total RUNT domain-containing isoforms and BLK presented positive correlation. Results suggest a more complex role of RUNX1 in leukemogenesis than the proposed antagonism between the isoforms.
Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Protein-Tyrosine Kinases/genetics , Adolescent , Amino Acid Sequence , Base Sequence , Child , Child, Preschool , Core Binding Factor Alpha 2 Subunit/metabolism , Female , Gene Expression Regulation, Leukemic , Humans , Infant , Infant, Newborn , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein-Tyrosine Kinases/metabolismABSTRACT
We evaluated the prevalence of BCR/ABL, MLL, and ETV6/RUNX1 rearrangements as well as CDKN2A (alias p16) deletion in a group of Mexican children with acute lymphoblastic leukemia (ALL) to determine whether the changes coexist, and to compare the incidences found with other reports in the literature. To increase the detection of these abnormalities, we combined conventional cytogenetics and fluorescence in situ hybridization (FISH) analysis. Bone marrow samples were obtained from 59 consecutive children with ALL. FISH detected a total of 63 abnormalities with the selected probes, 34 of which were related to the conventional cytogenetic results. The most common abnormality was the p16 deletion (22.8%), followed by MLL and ETV6/RUNX1 rearrangements (8.7%), and the BCR/ABL fusion was the least frequent (2.7%). The coexistence of two recurrent abnormalities with specific prognostic significance in the same patient was not found. A lesser proportion of the p16 deletion in T-ALL patients was observed, probably related to the low prevalence of this subtype in our population. In addition, we confirmed the low frequency of the ETV6/RUNX1 fusion observed in Hispanics. Due to the different prevalence of these abnormalities in the Mexican population, similar studies should be conducted analyzing new rearrangements, to improve the adequate classification of the abnormalities and the stratification in prognostic groups.
Subject(s)
Chromosome Aberrations , In Situ Hybridization, Fluorescence/methods , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 19 , Chromosomes, Human, Pair 22 , Chromosomes, Human, Pair 9 , Core Binding Factor Alpha 2 Subunit/genetics , Female , Gene Frequency , Genes, abl , Genes, p16 , Histone-Lysine N-Methyltransferase , Humans , Infant , Infant, Newborn , Male , Mexico , Myeloid-Lymphoid Leukemia Protein/genetics , Oncogene Proteins, Fusion/geneticsSubject(s)
Leukemia, Megakaryoblastic, Acute/genetics , Translocation, Genetic , Child , Female , Humans , KaryotypingABSTRACT
RUNX1 over-representation is present in children with acute lymphoblastic leukemia. Although these cases have been related with poor outcome, not all reports describe patient follow-up. To understand its associated clinical features and prognosis, we report on 14 children with ALL and RUNX1 over-representation with laboratory data and outcomes compared to previous reports. Eighty-six children with RUNX1 over-representation have been described, including the 14 patients of this study. Most of them are between 6 and 15 years of age, have low leukocyte counts, pre-B immunophenotype, and three to eight RUNX1 copies. Of the 69 patients with follow-up data, 21 of them relapsed or died, suggesting that RUNX1 over-representation is associated to a poor outcome.
Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Gene Amplification , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Female , Follow-Up Studies , Gene Dosage , Genetic Testing , Humans , Karyotyping , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , PrognosisABSTRACT
The t(12;21) produces the gene fusion ETV6/RUNX1 and is a frequent rearrangement in childhood ALL, associated with a good prognosis. In Mexico its prevalence has not been reported. This study evaluated a group of consecutive Mexican children with newly diagnosed ALL, to detect the fusion using fluorescence in situ hybridization (FISH). Seventy-one bone marrow samples were analyzed with FISH, using ETV6/RUNX1 DNA probes. Abnormalities of ETV6, RUNX1, or both were found in 31 of the 71 (44%) patients. Six showed ETV6/RUNX1 fusion and 17, with extra RUNX1 copies, presented an additional chromosome 21 or dup(21)(q22). Five patients had structural changes in ETV6, and three patients showed extra copies of ETV6 and RUNX1 from polysomy of chromosomes 12 and 21. Our results revealed a fusion in 8.5% of the 71 cases analyzed. This frequency is lower than that observed in other populations (9.5-32%). The structural rearrangements resulting in RUNX1 extra copies were found in 9.8% of patients, which is close to the range reported (1.5-9.7%) by other authors. Due to the prevalence of RUNX1 overrepresentation in our population and its unknown prognostic significance, further studies should be conducted in consecutive children with ALL, to correlate this abnormality with the patients' follow-up.
