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2.
PLoS One ; 15(9): e0238691, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881938

RESUMO

OBJECTIVES: This cross-sectional study aimed to investigate the influence of haplotypes, alpha-gene status and UGTA1 polymorphism on the severity of sickle cell disease in children. METHODS: This cross-sectional study was conducted between 2012 and 2014 at the Cayenne Hospital, in French Guiana. Acute clinical complications were grouped into (i) severe SCD defined by the presence of stroke and/or abnormal-transcranial Doppler (TCD), (ii) moderate SCD defined by the presence of at least three annual events requiring hospitalization and/or at least one acute chest syndrome, (iii) no severe SCD (in the absence of the precited events). RESULTS: Among the 86 patients, 33.7% were female with a median age of 10 years (range: 6-12 years). The vast majority of patients had SCA (HbSS) phenotype (74.4%; n = 64). The severe haplotype was found in 40% of patients. 30% were BEN/BEN. Analysis of α-globin gene deletions revealed that 32 patients (37.2%) were heterozygous (loss of 2 genes in 2 cases and loss of 1 gene in 30 cases) for α-thalassemia (3.7 kb deletion). Homozygous (TA) n TA7/7 was found in 24 (28%). In the multivariate analysis, the factors associated with the severity of sickle cell disease were the first vaso-occlusive crisis before one year of age (OR 25, [95% CI = 6.0-107.0], p<0.001) and a baseline MCV >80 fL (OR 0.20 [95% CI = 0.04-0.96], p = 0.04). The area of the ROC curve was 0.90. CONCLUSION: Prospective studies with greater statistical power would provide more knowledge on the relationship between UGT1A1 mutations and the clinical and hematological manifestations of SCA.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/genética , Glucuronosiltransferase/genética , Haplótipos/genética , Família Multigênica , Polimorfismo Genético , alfa-Globinas/genética , Globinas beta/genética , Criança , Feminino , Guiana Francesa , Humanos , Masculino , Análise Multivariada , Curva ROC
4.
Ann Hematol ; 99(10): 2279-2288, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32772141

RESUMO

Sickle cell disease (SCD) is a monogenic disease characterized by multisystem morbidity and highly variable clinical course. Inter-individual variability in hemoglobin F (HbF) levels is one of the main modifiers that account for the clinical heterogeneity in SCD. HbF levels are affected by, among other factors, single nucleotide polymorphisms (SNPs) at the BCL11A gene and the HBS1L-MYB intergenic region and Xmn1 gene. Our aim was to investigate HbF-enhancer haplotypes at these loci to obtain a first overview of the genetic situation of SCD patients in Egypt and its impact on the severity of the disease. The study included 100 SCD patients and 100 matched controls. Genotyping of BCL11A (rs1886868 C/T), HBS1L-MYB (rs9389268 A/G) and Xmn1 γG158 (rs7842144 C/T) SNPs showed no statistically significant difference between SCD patients and controls except for the hetero-mutant genotypes of BCL11A which was significantly higher in SCD patients compared with controls. Baseline HbF levels were significantly higher in those with co-inheritance of polymorphic genotypes of BCL11A + HSB1L-MYB and BCL11A + Xmn1. Steady-state HbF levels, used as an indicator of disease severity, were significantly higher in SCD-Sß patients having the polymorphic genotypes of HSB1L-MYB. Fold change of HbF in both patient groups did not differ between those harboring the wild and the polymorphic genotypes of the studied SNPs. In conclusion, BCL11A, HSB1L, and Xmn1 genetic polymorphisms had no positive impact on baseline HbF levels solely but had if coexisted. Discovery of the molecular mechanisms controlling HbF production could provide a more effective strategy for HbF induction.


Assuntos
Anemia Falciforme/genética , DNA Intergênico/genética , Hemoglobina Fetal/análise , Proteínas de Ligação ao GTP/genética , Genes myb , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Proteínas Repressoras/genética , gama-Globinas/genética , Adolescente , Alelos , Anemia Falciforme/sangue , Anemia Falciforme/etnologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Desoxirribonucleases de Sítio Específico do Tipo II , Egito , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Fragmento de Restrição , Adulto Jovem
6.
Niger Postgrad Med J ; 27(3): 190-195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687118

RESUMO

Background: Haemoglobin (Hb) disorders are among the most common blood genetic disorders worldwide, and they constitute an important cause of morbidity and mortality, especially in Nigeria. Despite the clinical significance of early diagnosis, newborn screening for these conditions is not routinely done in Nigeria. Objective: This study was undertaken to document the pattern of Hb phenotypes of newborn babies at the National Hospital Abuja and highlight the relevance of neonatal screening for early diagnosis of abnormal Hb phenotypes in Nigeria. Subjects and Methods: A prospective study of eligible newborn babies delivered in the hospital at the study site was undertaken following parental informed consent. Venous blood was collected from the babies into an ethylenediaminetetraacetic acid sample bottles. The samples were analysed using high-performance liquid chromatography (HPLC) techniques, and the Hb phenotypes obtained were documented. Data were analysed using the Statistical Package for Social Sciences (SPSS) version 20 (IBM-SPSS, Armonk, NY, USA). Results: Three hundred and eleven newborns (male = 173, female = 138) aged 0-28 days were recruited. Two hundred and thirty-six (75.9%) babies had Hb AA (FA) phenotype, 63 (20.3%) Hb AS (FAS), 6 (1.9%) Hb SS (FS), 4 (1.3%) Hb AC (FAC) and 2 (0.6%) had abnormal HbA variants. The overall prevalence of abnormal Hb phenotype was 24.1%. The results showed a significant association of sex (P = 0.003) and ethnicity (P = 0.047) with Hb phenotype. Conclusion: There is a wide spectrum of abnormal Hb phenotypes in Nigeria, and these phenotypes can easily be detected at birth using HPLC. We, therefore, recommend routine neonatal screening for sickle cell disease by HPLC in Nigeria.


Assuntos
Anemia Falciforme/sangue , Cromatografia Líquida de Alta Pressão/métodos , Hemoglobinas Anormais/análise , Hemoglobinas/análise , Recém-Nascido/sangue , Traço Falciforme/sangue , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano , Anemia Falciforme/epidemiologia , Anemia Falciforme/genética , Criança , Pré-Escolar , Hemoglobina Falciforme , Hemoglobinas/classificação , Hemoglobinas Anormais/genética , Humanos , Lactente , Nigéria/epidemiologia , Fenótipo , Prevalência , Estudos Prospectivos , Adulto Jovem
7.
BMC Med Genet ; 21(1): 125, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503527

RESUMO

BACKGROUND: Sickle cell disease (SCD) is a blood disorder caused by a point mutation on the beta globin gene resulting in the synthesis of abnormal hemoglobin. Fetal hemoglobin (HbF) reduces disease severity, but the levels vary from one individual to another. Most research has focused on common genetic variants which differ across populations and hence do not fully account for HbF variation. METHODS: We investigated rare and common genetic variants that influence HbF levels in 14 SCD patients to elucidate variants and pathways in SCD patients with extreme HbF levels (≥7.7% for high HbF) and (≤2.5% for low HbF) in Tanzania. We performed targeted next generation sequencing (Illumina_Miseq) covering exonic and other significant fetal hemoglobin-associated loci, including BCL11A, MYB, HOXA9, HBB, HBG1, HBG2, CHD4, KLF1, MBD3, ZBTB7A and PGLYRP1. RESULTS: Results revealed a range of genetic variants, including bi-allelic and multi-allelic SNPs, frameshift insertions and deletions, some of which have functional importance. Notably, there were significantly more deletions in individuals with high HbF levels (11% vs 0.9%). We identified frameshift deletions in individuals with high HbF levels and frameshift insertions in individuals with low HbF. CHD4 and MBD3 genes, interacting in the same sub-network, were identified to have a significant number of pathogenic or non-synonymous mutations in individuals with low HbF levels, suggesting an important role of epigenetic pathways in the regulation of HbF synthesis. CONCLUSIONS: This study provides new insights in selecting essential variants and identifying potential biological pathways associated with extreme HbF levels in SCD interrogating multiple genomic variants associated with HbF in SCD.


Assuntos
Anemia Falciforme/genética , Hemoglobina Fetal/genética , Variação Genética , Adolescente , Criança , Pré-Escolar , Redes Reguladoras de Genes , Humanos , Mutação com Perda de Função/genética , Tanzânia , Adulto Jovem
8.
J Pediatr ; 223: 178-182.e2, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32586619

RESUMO

OBJECTIVE: To evaluate awareness of and attitudes toward preimplantation genetic testing (PGT) for sickle cell disease (SCD) among parents of children with SCD. STUDY DESIGN: Parents of children with SCD were given an educational handbook on PGT before a routine SCD clinic visit. After their clinic visit, parents were asked to complete an anonymous survey. RESULTS: Of 83 patents approached, 67 (81%) completed the survey. Only 16 of the 67 parents (24%) were previously aware of PGT for SCD. After our clinic-based education, 65 of the 67 parents (97%) indicated that it was important or very important for parents of children with SCD to know about PGT. Among parents interested in having more children, 29 of 32 (91%) would personally consider using PGT if covered by insurance. CONCLUSIONS: Parents of children with SCD are generally not aware of PGT. When educated in clinic, parents viewed information on PGT as valuable. Pediatricians and other health care professionals should inform parents of children with SCD about this reproductive option.


Assuntos
Anemia Falciforme/diagnóstico , Testes Genéticos/métodos , Pais , Cuidados Pré-Operatórios/métodos , Transplante de Células-Tronco , Adulto , Anemia Falciforme/genética , Criança , Feminino , Humanos , Masculino , Inquéritos e Questionários
9.
Ann Hematol ; 99(9): 2065-2072, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32572524

RESUMO

Sickle hepatopathy is a severe and not rare complication of sickle cell disease (SCD), showing mainly a cholestatic pattern. So far, no effective approaches to prevent or treat this condition have been recognized. We conducted a single-center observational study in 68 adult sickle cell patients, encompassing 17 with sickle cell anemia (SCA), 38 with sickle cell thalassemia (HbS/ß-Thal), and 13 with HbSC disease. The aim of our study was to assess liver damage in the three main forms of SCD, through the evaluation of clinical, laboratory, and imaging findings. In our population, the role of hepatotropic viruses, high BMI, and alcohol consumption in liver damage was ruled out. SCA and HbS/ß-Thal patients with lower Hb (p < 0.001), higher HbS (p < 0.001), and frequent vaso-occlusive crises showed functional (GGT values: SCA and HbS/ß-Thal vs HbSC p = 0.047 and p = 0.009, respectively) and structural liver abnormalities, defined by abdominal ultrasound and vibration-controlled transient elastography (liver stiffness values: SCA and HbS/ß-Thal vs HbSC p 0.022 and p 0.19, respectively), more severe than HbSC patients. Through univariate and multivariate analyses, male sex, SCA genotype, lower HbF, frequent transfusions, increased GGT values, and abnormal liver ultrasound and stiffness were identified as potentially early markers of sickle hepatopathy.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/diagnóstico por imagem , Genótipo , Hepatopatias/sangue , Hepatopatias/diagnóstico por imagem , Adulto , Anemia Falciforme/genética , Feminino , Humanos , Hepatopatias/genética , Masculino , Pessoa de Meia-Idade , Fatores de Risco
10.
PLoS One ; 15(5): e0232721, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379790

RESUMO

BACKGROUND: Pain in sickle cell disease (SCD) is severe and multifaceted resulting in significant differences in its frequency and intensity among individuals. In this study, we examined the influence of S100B gene single nucleotide polymorphisms (SNP) on acute and chronic pain variability in SCD. METHODS: Composite pain index (CPI) scores captured chronic pain. Painful crisis related emergency care utilization recorded acute pain incidence. Genotyping was performed using MassARRAY iPLEX platform. RESULTS: Regression analysis revealed associations of increased CPI with rs9722 A allele in additive (p = 0.005) and dominant (p = 0.005) models. Rs1051169 G allele on the other hand was associated with decreased CPI in additive (p = 0.001), and dominant (p = 0.005) models. Sex-specific analysis found that these associations were significant in females but not males in this cohort. Linkage analysis identified two haploblocks. Block 1 (rs9983698-rs9722) haplotype T-A was associated with increased CPI (p = 0.002) while block 2 (rs1051169-rs11911834) haplotype G-G was associated with decreased CPI (p = 0.001). Both haplotypic associations were only significant in females. No association of S100B SNPs with utilization reached statistical significance. CONCLUSIONS: S100B SNPs and haplotypes are associated with chronic pain in female, but not male, patients with SCD, implicating a potential role of S100B polymorphism in SCD pain heterogeneity in a sex-dependent manner.


Assuntos
Anemia Falciforme/genética , Dor Crônica/genética , Polimorfismo de Nucleotídeo Único , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Adulto , Afro-Americanos/genética , Anemia Falciforme/complicações , Dor Crônica/complicações , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
11.
Ann Hematol ; 99(7): 1453-1463, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32447424

RESUMO

Fetal hemoglobin (HbF) ameliorates clinical severity of sickle cell anemia (SCA). The major loci regulating HbF levels are HBB cluster, BCL11A, and HMIP-2 (HBS1L-MYB). However, the impact of noncoding single-nucleotide polymorphisms (SNPs) in these loci on clinical outcomes and their functional role on regulating HbF levels should be better elucidated. Therefore, we performed comprehensive association analyses of 14 noncoding SNPs in five loci with HbF levels and with clinical outcomes in a cohort of 250 children with SCA from Southeastern Brazil, and further performed functional annotation of these SNPs. We found SNPs independently associated with HbF levels: rs4671393 in BCL11A (ß-coefficient = 0.28), rs9399137 in HMIP-2A (ß-coefficient = 0.16), and rs4895441 in HMIP-2B (ß-coefficient = 0.15). Patients carrying minor (HbF-boosting) alleles for rs1427407, rs93979137, rs4895441, rs9402686, and rs9494145 showed reduced count of reticulocytes (p < 0.01), while those carrying the T allele of rs9494145 showed lower white blood cell count (p = 0.002). Carriers of the minor allele for rs9402686 showed higher peripheral saturation of oxygen (p = 0.002). Patients carrying minor alleles in BCL11A showed lower risk of transfusion incidence rate ratio (IRR ≥ 1.3; p < 0.0001). This effect was independent of HbF effect (p = 0.005). Carriers of minor alleles for rs9399137 and rs9402686 showed lower risk of acute chest syndrome (IRR > 1.3; p ≤ 0.01). Carriers of the reference allele for rs4671393 showed lower risk of infections (IRR = 1.16; p = 0.01). In conclusion, patients carrying HbF-boosting alleles of BCL11A and HMIP-2 were associated with milder clinical phenotypes. Higher HbF concentration may underlie this effect.


Assuntos
Anemia Falciforme/diagnóstico , Anemia Falciforme/genética , Hemoglobina Fetal/metabolismo , Proteínas de Ligação ao GTP/genética , Genes myb , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Alelos , Anemia Falciforme/sangue , Anemia Falciforme/epidemiologia , Brasil/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hemoglobina Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Retrospectivos
12.
Ann Hematol ; 99(6): 1225-1230, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32363415

RESUMO

Sickle cell anemia (SCA) is the most severe form of sickle cell disease caused by homozygosity of the ßS-gene (S/S or ßSßS) and has worldwide distribution. Six polymorphic sites in the ß-globin gene cluster were analyzed from a sample of 56 chromosomes of patients with SCA from the state of Maranhão, northeastern Brazil. PCR-RFLP showed that the CAR haplotype was predominant with a frequency of 64.28%, followed by the BEN haplotype (28.57%). Atypical haplotypes were identified at a frequency of 7.15%. Genotypes CAR/CAR, BEN/BEN, and CAR/BEN were present in 46.43%, 10.71%, and 35.71% of patients, respectively. ß-Globin haplotype determination is important not only for the monitoring and prognosis of patients with SCA, but it also serves to inform anthropological studies that contribute to elucidating any peculiarities associated with African influences that contributed to the ethnological, economic, cultural, and social formation of Brazil. The high frequency of the CAR/CAR and CAR/BEN haplotypes in this study, which are associated with low levels of fetal hemoglobin, may ultimately reflect a severe clinical course and poor prognosis in patients with SCA in Maranhão.


Assuntos
Anemia Falciforme/epidemiologia , Anemia Falciforme/genética , Haplótipos/genética , Adolescente , Adulto , Anemia Falciforme/diagnóstico , Brasil/epidemiologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Adulto Jovem
13.
Exp Hematol ; 84: 1-6.e1, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32243995

RESUMO

Sickle cell disease (SCD) is a monogenic disorder estimated to affect more than three million people worldwide. Acute systemic painful vaso-occlusive episode (VOE) is the primary reason for emergency medical care among SCD patients. VOE may also progress to acute chest syndrome (ACS), a type of acute lung injury and one of the primary reasons for mortality among SCD patients. Recently, P-selectin monoclonal antibodies were found to attenuate VOE in SCD patients and lung vaso-occlusion in transgenic humanized SCD mice, highlighting the therapeutic benefit of P-selectin inhibition in SCD. Here, we use quantitative fluorescence intravital lung microscopy (qFILM) to illustrate that tandem P-selectin-glycoprotein ligand-immunoglobulin (TSGL-Ig) fusion molecule containing four P-selectin binding sites, significantly attenuated intravenous (IV) oxyhemoglobin triggered lung vaso-occlusion in SCD mice. These findings highlight the therapeutic potential of TSGL-Ig in preventing VOE and ACS in SCD.


Assuntos
Anemia Falciforme/tratamento farmacológico , Imunoglobulinas/farmacologia , Pneumopatias/tratamento farmacológico , Selectina-P/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Doenças Vasculares/tratamento farmacológico , Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Anemia Falciforme/patologia , Animais , Feminino , Humanos , Imunoglobulinas/genética , Pneumopatias/genética , Pneumopatias/metabolismo , Pneumopatias/patologia , Masculino , Camundongos , Selectina-P/genética , Ratos , Proteínas Recombinantes de Fusão/genética , Doenças Vasculares/genética , Doenças Vasculares/metabolismo
14.
J Clin Invest ; 130(3): 1062-1072, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32118586

RESUMO

Sickle cell anemia is a unique disease dominated by hemolytic anemia and vaso-occlusive events. The latter trigger a version of ischemia/reperfusion (I/R) pathobiology that is singular in its origin, cyclicity, complexity, instability, perpetuity, and breadth of clinical consequences. Specific clinical features are probably attributable to local I/R injury (e.g., stroke syndromes) or remote organ injury (e.g., acute chest syndrome) or the systematization of inflammation (e.g., multifocal arteriopathy). Indeed, by fashioning an underlying template of endothelial dysfunction and vulnerability, the robust inflammatory systematization no doubt contributes to all sickle pathology. In this Review, we highlight I/R-targeting therapeutics shown to improve microvascular blood flow in sickle transgenic mice undergoing I/R, and we suggest how such insights might be translated into human therapeutic strategies.


Assuntos
Anemia Falciforme , Endotélio Vascular , Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Anemia Falciforme/fisiopatologia , Animais , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Inflamação/classificação , Inflamação/genética , Inflamação/metabolismo , Inflamação/fisiopatologia , Camundongos , Camundongos Transgênicos , Traumatismo por Reperfusão/classificação , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia
16.
Arterioscler Thromb Vasc Biol ; 40(5): 1220-1230, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32160775

RESUMO

OBJECTIVE: Sickle cell anemia (SCA) causes chronic inflammation and multiorgan damage. Less understood are the arterial complications, most evident by increased strokes among children. Proteolytic mechanisms, biomechanical consequences, and pharmaceutical inhibitory strategies were studied in a mouse model to provide a platform for mechanistic and intervention studies of large artery damage due to sickle cell disease. Approach and Results: Townes humanized transgenic mouse model of SCA was used to test the hypothesis that elastic lamina and structural damage in carotid arteries increased with age and was accelerated in mice homozygous for SCA (sickle cell anemia homozygous genotype [SS]) due to inflammatory signaling pathways activating proteolytic enzymes. Elastic lamina fragmentation observed by 1 month in SS mice compared with heterozygous littermate controls (sickle cell trait heterozygous genotype [AS]). Positive immunostaining for cathepsin K, a powerful collagenase and elastase, confirmed accelerated proteolytic activity in SS carotids. Larger cross-sectional areas were quantified by magnetic resonance angiography and increased arterial compliance in SS carotids were also measured. Inhibiting JNK (c-jun N-terminal kinase) signaling with SP600125 significantly reduced cathepsin K expression, elastin fragmentation, and carotid artery perimeters in SS mice. By 5 months of age, continued medial thinning and collagen degradation was mitigated by treatment of SS mice with JNK inhibitor. CONCLUSIONS: Arterial remodeling due to SCA is mediated by JNK signaling, cathepsin proteolytic upregulation, and degradation of elastin and collagen. Demonstration in Townes mice establishes their utility for mechanistic studies of arterial vasculopathy, related complications, and therapeutic interventions for large artery damage due to SCA.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antracenos/farmacologia , Artérias Carótidas/efeitos dos fármacos , Doenças das Artérias Carótidas/prevenção & controle , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Remodelação Vascular/efeitos dos fármacos , Anemia Falciforme/enzimologia , Anemia Falciforme/genética , Anemia Falciforme/fisiopatologia , Animais , Artérias Carótidas/enzimologia , Artérias Carótidas/fisiopatologia , Doenças das Artérias Carótidas/enzimologia , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/fisiopatologia , Catepsina K/metabolismo , Colágeno/metabolismo , Modelos Animais de Doenças , Elastina/metabolismo , Hemoglobinas/genética , Homozigoto , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos Transgênicos , Mutação , Proteólise , Transdução de Sinais , Fatores de Tempo
17.
Cell ; 180(5): 819, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142671

RESUMO

Sickle cell disease (SCD) is caused by a point mutation in the ß-globin gene that creates hemoglobin S (HbS). Upon deoxygenation, HbS forms long polymers that distort the shape of red blood cells, causing hemolysis and vaso-occlusion. Voxelotor inhibits HbS polymerization, the root cause of SCD complications. To view this Bench to Bedside, open or download the PDF.


Assuntos
Anemia Falciforme/genética , Benzaldeídos/uso terapêutico , Hemoglobina Falciforme/antagonistas & inibidores , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Globinas beta/genética , Anemia Falciforme/epidemiologia , Hemoglobina Falciforme/genética , Humanos , Mutação Puntual/genética , Polimerização/efeitos dos fármacos
18.
Subcell Biochem ; 94: 297-322, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189305

RESUMO

Sickle cell hemoglobin (HbS) is an example of a genetic variant of human hemoglobin where a point mutation in the ß globin gene results in substitution of glutamic acid to valine at sixth position of the ß globin chain. Association between tetrameric hemoglobin molecules through noncovalent interactions between side chain residue of ßVal6 and hydrophobic grooves formed by ßAla70, ßPhe85 and ßLeu88 amino acid residues of another tetramer followed by the precipitation of the elongated polymer leads to the formation of sickle-shaped RBCs in the deoxygenated state of HbS. There are multiple non-covalent interactions between residues across intra- and inter-strands that stabilize the polymer. The clinical phenotype of sickling of RBCs manifests as sickle cell anemia, which was first documented in the year 1910 in an African patient. Although the molecular reason of the disease has been understood well over the decades of research and several treatment procedures have been explored to date, an effective therapeutic strategy for sickle cell anemia has not been discovered yet. Surprisingly, it has been observed that the oxy form of HbS and glutathionylated form of deoxy HbS inhibits polymerization. In addition to describe the residue level interactions in the HbS polymer that provides its stability, here we explain the mechanism of inhibition in the polymerization of HbS in its oxy state. Additionally, we reported the molecular insights of inhibition in the polymerization for glutathionyl HbS, a posttranslational modification of hemoglobin, even in its deoxy state. In this chapter we briefly consider the available treatment procedures of sickle cell anemia and propose that the elevation of glutathionylation of HbS within RBCs, without inducing oxidative stress, might be an effective therapeutic strategy for sickle cell anemia.


Assuntos
Anemia Falciforme/metabolismo , Hemoglobinas/química , Hemoglobinas/metabolismo , Anemia Falciforme/genética , Anemia Falciforme/patologia , Anemia Falciforme/terapia , Eritrócitos/química , Eritrócitos/metabolismo , Eritrócitos/patologia , Hemoglobinas/genética , Humanos , Polimerização
19.
Ann Hematol ; 99(5): 925-935, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32157419

RESUMO

Sickle cell disease (SCD) is an autosomal recessive blood disorder which occurs due to point mutation in the ß-globin chain of hemoglobin. Since the past decades, various therapies have been put forth, which are based on obstructing pathophysiological mechanisms of SCD including inhibition of Gardos channel and cation fluxes which in turn prevents sickle erythrocyte destruction and dehydration. The pharmacological approaches are based on the mechanism of reactivating γ-globin expression by utilizing fetal hemoglobin (HbF)-inducing drugs such as hydroxyurea. In SCD, gene therapy could be considered as a promising tool which involves modifying mutation at the gene-specific target by either promoting insertion or deletion of globins. Although there are various therapies emerged so far in the treatment of SCD, many of them have faced a major setback in most of developing countries in terms of cost, unavailability of expertise, and suitable donor. Therefore, in addition to pathophysiological aspects, this review will discuss new advancements and approaches made in the therapeutic domain of SCD including a viewpoint of modulating hemoglobin in SCD by the intervention of probiotics.


Assuntos
Anemia Falciforme , Eritrócitos Anormais , Hemoglobina Fetal , Hidroxiureia/uso terapêutico , Canais de Potássio Ativados por Cálcio de Condutância Intermediária , Probióticos/uso terapêutico , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Anemia Falciforme/fisiopatologia , Eritrócitos Anormais/metabolismo , Eritrócitos Anormais/patologia , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo
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