RÉSUMÉ
Sickle cell disease is a growing health burden afflicting millions around the world. Clinical observation and laboratory studies have shown that the severity of sickle cell disease is ameliorated in individuals who have elevated levels of fetal hemoglobin. Additional pharmacologic agents to induce sufficient fetal hemoglobin to diminish clinical severity is an unmet medical need. We recently found that up-regulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) can induce fetal hemoglobin synthesis in human primary erythroblasts. Here, we report that a small molecule, SR-18292, increases PGC-1α leading to enhanced fetal hemoglobin expression in human erythroid cells, ß-globin yeast artificial chromosome mice, and sickle cell disease mice. In SR-18292-treated sickle mice, sickled red blood cells are significantly reduced, and disease complications are alleviated. SR-18292, or agents in its class, could be a promising additional therapeutic for sickle cell disease.
Sujet(s)
Drépanocytose , Antidrépanocytaires , Hémoglobine foetale , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes , Drépanocytose/traitement médicamenteux , Drépanocytose/métabolisme , Drépanocytose/anatomopathologie , Hémoglobine foetale/métabolisme , Hémoglobine foetale/génétique , Animaux , Humains , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes/métabolisme , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes/génétique , Souris , Antidrépanocytaires/pharmacologie , Antidrépanocytaires/usage thérapeutique , Modèles animaux de maladie humaine , Globines bêta/génétique , Globines bêta/métabolismeRÉSUMÉ
In a previous study, heart xenografts from 10-gene-edited pigs transplanted into two human decedents did not show evidence of acute-onset cellular- or antibody-mediated rejection. Here, to better understand the detailed molecular landscape following xenotransplantation, we carried out bulk and single-cell transcriptomics, lipidomics, proteomics and metabolomics on blood samples obtained from the transplanted decedents every 6 h, as well as histological and transcriptomic tissue profiling. We observed substantial early immune responses in peripheral blood mononuclear cells and xenograft tissue obtained from decedent 1 (male), associated with downstream T cell and natural killer cell activity. Longitudinal analyses indicated the presence of ischemia reperfusion injury, exacerbated by inadequate immunosuppression of T cells, consistent with previous findings of perioperative cardiac xenograft dysfunction in pig-to-nonhuman primate studies. Moreover, at 42 h after transplantation, substantial alterations in cellular metabolism and liver-damage pathways occurred, correlating with profound organ-wide physiological dysfunction. By contrast, relatively minor changes in RNA, protein, lipid and metabolism profiles were observed in decedent 2 (female) as compared to decedent 1. Overall, these multi-omics analyses delineate distinct responses to cardiac xenotransplantation in the two human decedents and reveal new insights into early molecular and immune responses after xenotransplantation. These findings may aid in the development of targeted therapeutic approaches to limit ischemia reperfusion injury-related phenotypes and improve outcomes.
Sujet(s)
Transplantation cardiaque , Hétérogreffes , Transplantation hétérologue , Humains , Animaux , Suidae , Mâle , Femelle , Rejet du greffon/immunologie , Rejet du greffon/génétique , Protéomique , Métabolomique , Agranulocytes/métabolisme , Agranulocytes/immunologie , Transcriptome , Analyse de profil d'expression de gènes , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Lipidomique , Lésion d'ischémie-reperfusion/immunologie , Lésion d'ischémie-reperfusion/génétique , Lésion d'ischémie-reperfusion/métabolisme , Multi-omiqueRÉSUMÉ
BACKGROUND: Diabetes mellitus is a chronic disease characterized by a wide range of metabolic problems. The current study sought to assess nutritional habits of Saudi patients with type 2 diabetes (T2D) and to propose recommendations to improve these patients' dietary habits and delay possible disease complications. METHODS: Over a period of three years, (2017-2019) 577 patients with T2D attending the outpatient's diabetic clinics at King Fahd Hospital of the University, Al Khobar, Saudi Arabia were invited to participate in this study. Data of dietary intake were collected by trained nurses using a pretested structured validated semi quantitative food frequency questionnaire. The dietary data were collected using 7-day dietary recall questionnaire. A modified score system that associates dietary habits with glycemic control and lipid profile was used. RESULTS: Overall, a high healthful plant-based diet score was associated with a significant (P = 0.018) reduction in triglycerides (TG) level (mean difference - 3.78%; 95% CI, -0.65% to -6.81%) and a statistically non-significant (P = 0.06) increase in high density lipoprotein (HDL) levels (mean difference 1.87%; 95% CI -0.06-3.84%) in T2D patients from the Eastern Province of Saudi Arabia. Additionally, in our patient group, the prevalence of coronary artery disease, stroke, peripheral artery disease, and chronic kidney disease in T2D patients was 11.3%, 6.2%, 3.3%, and 8.4%, respectively and were higher when compared to the prevalence in the general population. CONCLUSION: The present study showed that adherence to a healthful plant-based diet, when compared to high glycemic index diet, is associated with a favorable outcome in glycemic control and lipid profile in T2D patients. Prior assessment of total diet quality may be beneficial when giving nutritional advice to T2D patients with the possibility of improving glycemic control and lipid profile.
RÉSUMÉ
OBJECTIVES: The objectives of this study were to identify the composition of oral microbiota in a cohort of patients with sickle cell anemia (SCA) and a high mean number of decayed, missing, and filled permanent teeth (DMFT) and compare it to a cohort of patients with SCA and a low number of DMFT and elucidate the effect of fetal haemoglobin levels on the oral microbiota composition. METHODS: Patients who had been diagnosed with SCA, who were homozygous for sickling ß-globin mutation (ßS/ßS), who had Arab-Indian haplotype, and who ranged in age from 5 to 12 years were included in this study. Oral saliva from each participant (n = 100) was collected in GeneFiX™ Saliva DNA Microbiome Collection tube and DNA was extracted using GeneFiX™ DNA Isolation Kits. The composition of oral 16S rRNA from patients with SCA and high dental caries (n = 27, DMFT ≥5) and low dental caries (n = 73, DMFT ≤4) was analysed. Sequencing was performed on an Ion Personal Genome Machine using, Ion PGM Hi-Q view Sequencing 400-bp kit. RESULTS: We observed an overall increase in abundance of Proteobacteria, Chloroflexi, and Bacteroidetes in the high DMFT index group compared to those with a low DMFT index. In addition, there was an overall increased abundance of microbiota from Proteobacteria, Fusobacteria, Firmicutes, and Bacteroidetes in the patients with SCA with low fetal haemoglobin compared to those with high fetal haemoglobin (P < .05). Enterobacteriaceae species were the most significant abundant species of bacteria found in both the high DMFT index group and low fetal haemoglobin cohort (P < .05). CONCLUSIONS: Our data indicate that SCA in Saudi patients with high DMFT have a higher predominance of pathogenic bacteria compared to those with low DMFT. Furthermore, SCA in Saudi patients with low fetal haemoglobin have a higher predominance of pathogenic bacteria compared to those with higher fetal haemoglobin.
Sujet(s)
Drépanocytose , Caries dentaires , Microbiote , Humains , Enfant d'âge préscolaire , Enfant , ARN ribosomique 16S/génétique , Arabie saoudite , Bactéries/génétique , Drépanocytose/complications , ADN , Hémoglobines , Indice DCAORÉSUMÉ
Sickle cell disease (SCD) is a genetic disorder that affects millions around the world. Enhancement of fetal γ-globin levels and fetal haemoglobin (HbF) production in SCD patients leads to diminished severity of many clinical features of the disease. We recently identified the transcriptional co-activator PGC-1α as a new protein involved in the regulation of the globin genes. Here, we report that upregulation of PGC-1α by infection with a lentivirus expressing PGC-1α or by the small-molecule PGC-1α agonist ZLN005 in human primary erythroid progenitor CD34+ cells induces both fetal γ-globin mRNA and protein expression as well as the percentage of HbF-positive cell (F cells) without significantly affecting cell proliferation and differentiation. We further found that the combination of ZLN005 and hydroxyurea (hydroxycarbamide) exhibited an additive effect on the expression of γ-globin and the generation of F cells from cultured CD34+ cells. In addition, ZLN005 induced robust expression of the murine embryonic ßh1-globin gene and to a lesser extent, human γ-globin gene expression in sickle mice. These findings suggest that activation of PGC-1α by ZLN005 might provide a new path for modulating HbF levels with potential therapeutic benefit in ß-hemoglobinopathies.
Sujet(s)
Drépanocytose , Hémoglobinopathies , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes/métabolisme , Drépanocytose/traitement médicamenteux , Drépanocytose/génétique , Animaux , Hémoglobine foetale/métabolisme , Expression des gènes , Régulation de l'expression des gènes , Humains , Souris , Globines gamma/génétiqueSujet(s)
Drépanocytose/traitement médicamenteux , Antienzymes/pharmacologie , Cellules érythroïdes/métabolisme , Hémoglobine foetale/biosynthèse , Histone Demethylases/antagonistes et inhibiteurs , Cellules souches pluripotentes induites/métabolisme , Drépanocytose/métabolisme , Drépanocytose/anatomopathologie , Animaux , Antienzymes/composition chimique , Cellules érythroïdes/anatomopathologie , Histone Demethylases/métabolisme , Humains , Cellules souches pluripotentes induites/anatomopathologie , SourisRÉSUMÉ
We previously constructed a collection of fission yeast strains that express various mammalian cyclic nucleotide phosphodiesterases (PDEs) and developed a cell-based high throughput screen (HTS) for small molecule PDE inhibitors. Here we describe a compound, BC54, that is a selective inhibitor of enzymes from the cAMP-specific PDE4 and PDE7 families. Consistent with the biological effect of other PDE4 and PDE7 inhibitors, BC54 displays potent anti-inflammatory properties and is superior to a combination of rolipram (a PDE4 inhibitor) and BRL50481 (a PDE7A inhibitor) for inducing apoptosis in chronic lymphocytic leukemia (CLL) cells. We further exploited PKA-regulated growth phenotypes in fission yeast to isolate two mutant alleles of the human PDE4B2 gene that encode enzymes possessing single amino acid changes that confer partial resistance to BC54. We confirm this resistance to both BC54 and rolipram via yeast-based assays and, for PDE4B2T407A, in vitro enzyme assays. Thus, we are able to use this system for both chemical screens to identify biologically-active PDE inhibitors and molecular genetic studies to characterize the interaction of these molecules with their target enzymes. Based on its potency, selectivity, and effectiveness in cell culture, BC54 should be a useful tool to study biological processes regulated by PDE4 and PDE7 enzymes.
Sujet(s)
Anti-inflammatoires non stéroïdiens/pharmacologie , Cyclic Nucleotide Phosphodiesterases, Type 4/métabolisme , Cyclic Nucleotide Phosphodiesterases, Type 7/antagonistes et inhibiteurs , Cyclohexanes/pharmacologie , Pyridines/pharmacologie , Pyrimidines/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , AMP cyclique/métabolisme , Évaluation préclinique de médicament , Humains , Leucémie chronique lymphocytaire à cellules B/génétique , Leucémie chronique lymphocytaire à cellules B/anatomopathologie , Rolipram/administration et posologie , Schizosaccharomyces/effets des médicaments et des substances chimiques , Schizosaccharomyces/génétiqueRÉSUMÉ
Fetal hemoglobin (HbF) has well-known tempering effects on the symptoms of sickle cell disease and its levels vary among patients with different haplotypes of the sickle hemoglobin gene. Compared with sickle cell anemia haplotypes found in patients of African descent, HbF levels in Saudi and Indian patients with the Arab-Indian (AI) haplotype exceed that in any other haplotype by nearly twofold. Genetic association studies have identified some loci associated with high HbF in the AI haplotype but these observations require functional confirmation. Saudi patients with the Benin haplotype have HbF levels almost twice as high as African patients with this haplotype but this difference is unexplained. Hydroxyurea is still the only FDA approved drug for HbF induction in sickle cell disease. While most patients treated with hydroxyurea have an increase in HbF and some clinical improvement, 10 to 20% of adults show little response to this agent. We review the genetic basis of HbF regulation focusing on sickle cell anemia in Saudi Arabia and discuss new drugs that can induce increased levels of HbF.
Sujet(s)
Drépanocytose/sang , Drépanocytose/génétique , Hémoglobine foetale/génétique , Drépanocytose/traitement médicamenteux , Drépanocytose/métabolisme , Animaux , Sites de fixation , Hémoglobine foetale/métabolisme , Régulation de l'expression des gènes au cours du développement/effets des médicaments et des substances chimiques , Haplotypes , Hémoglobine S/génétique , Humains , microARN/génétique , microARN/métabolisme , Thérapie moléculaire ciblée , Famille multigénique , Motifs nucléotidiques , Phénotype , Liaison aux protéines , Séquences d'acides nucléiques régulatrices , Facteurs de transcription/métabolisme , Globines bêta/génétique , Globines gamma/génétiqueSujet(s)
Drépanocytose/génétique , Protéines de liaison à l'ADN/génétique , Famille multigénique , Facteurs de transcription/génétique , Globines bêta/génétique , Motifs d'acides aminés , Drépanocytose/métabolisme , Protéines de liaison à l'ADN/métabolisme , Femelle , Humains , Mâle , Facteurs de transcription/métabolisme , Globines bêta/métabolismeRÉSUMÉ
Sickle cell disease, a common single gene disorder, has a complex pathophysiology that at its root is initiated by the polymerization of deoxy sickle hemoglobin. Sickle vasoocclusion and hemolytic anemia drive the development of disease complications. In this review, we focus on the genetic modifiers of disease heterogeneity. The phenotypic heterogeneity of disease is only partially explained by genetic variability of fetal hemoglobin gene expression and co-inheritance of α thalassemia. Given the complexity of pathophysiology, many different definitions of severity are possible complicating a full understanding of its genetic foundation. The pathophysiological complexity and the interlocking nature of the biological processes underpinning disease severity are becoming better understood. Nevertheless, useful genetic signatures of severity, regardless of how this is defined, are insufficiently developed to be used for treatment decisions and for counseling.