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1.
Int J Mol Sci ; 24(13)2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37446156

RESUMO

Despite the physiological role of oxidant molecules, oxidative stress (OS) could underlie several human diseases. When the levels of antioxidants are too low or too high, OS occurs, leading to damage at the molecular, tissue and cellular levels. Therefore, antioxidant compounds could represent a way to modulate OS and/or to maintain proper redox balance. This review provides an overview of the methods available to assess total antioxidant capacity (TAC) in biological systems to elucidate the correct terminology and the pathophysiological roles. The clinical context is fundamental to obtain a correct interpretation of TAC. Hence, we discuss metabolic syndrome and infertility, two clinical conditions that involve OS, including the potential prognostic role of TAC evaluation in monitoring antioxidant supplementation. This approach would provide more personalised and precise therapy.


Assuntos
Antioxidantes , Síndrome Metabólica , Humanos , Antioxidantes/metabolismo , Relevância Clínica , Estresse Oxidativo/fisiologia , Oxirredução , Síndrome Metabólica/tratamento farmacológico
2.
Biochim Biophys Acta Mol Basis Dis ; 1865(9): 2257-2266, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075491

RESUMO

Mutations in the gene triosephosphate isomerase (TPI) lead to a severe multisystem condition that is characterized by hemolytic anemia, a weakened immune system, and significant neurologic symptoms such as seizures, distal neuropathy, and intellectual disability. No effective therapy is available. Here we report a compound heterozygous patient with a novel TPI pathogenic variant (NM_000365.5:c.569G>A:p.(Arg189Gln)) in combination with the common (NM_000365.5:c.315G>C:p.(Glu104Asp)) allele. We characterized the novel variant by mutating the homologous Arg in Drosophila using a genomic engineering system, demonstrating that missense mutations at this position cause a strong loss of function. Compound heterozygote animals were generated and exhibit motor behavioural deficits and markedly reduced protein levels. Furthermore, examinations of the TPIArg189Gln/TPIGlu104Asp patient fibroblasts confirmed the reduction of TPI levels, suggesting that Arg189Gln may also affect the stability of the protein. The Arg189 residue participates in two salt bridges on the backside of the TPI enzyme dimer, and we reveal that a mutation at this position alters the coordination of the substrate-binding site and important catalytic residues. Collectively, these data reveal a new human pathogenic variant associated with TPI deficiency, identify the Arg189 salt bridge as critical for organizing the catalytic site of the TPI enzyme, and demonstrates that reduced TPI levels are associated with human TPI deficiency. These findings advance our understanding of the molecular pathogenesis of the disease, and suggest new therapeutic avenues for pre-clinical trials.


Assuntos
Anemia Hemolítica Congênita não Esferocítica/patologia , Erros Inatos do Metabolismo dos Carboidratos/patologia , Triose-Fosfato Isomerase/deficiência , Triose-Fosfato Isomerase/metabolismo , Alelos , Sequência de Aminoácidos , Anemia Hemolítica Congênita não Esferocítica/genética , Animais , Sequência de Bases , Erros Inatos do Metabolismo dos Carboidratos/genética , Domínio Catalítico , Pré-Escolar , Dimerização , Modelos Animais de Doenças , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Mutação de Sentido Incorreto , Linhagem , Estabilidade Proteica , Alinhamento de Sequência , Triose-Fosfato Isomerase/genética
3.
Transfus Apher Sci ; 56(2): 234-237, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28185828

RESUMO

Chronic red blood cell transfusions remain an essential part of supportive treatment in patients with thalassaemia and sickle cell disease (SCD). Red blood cell (RBC) transfusions expose patients to the risk of developing antibodies: RBC alloimmunization occurs when the immune system meets foreign antigens. We created a register of extensively genotyped donors to achieve a better matched transfusion in order to reduce transfusion alloimmunization. Extended RBC antigen typing was determined and confirmed by molecular biology techniques using Human Erythrocyte Antigen (HEA) BeadChip (BioArray Solutions Ltd., Warren, NJ) in periodic blood donors and in patients with thalassaemia and SCD. During 3 years, we typed extensively 1220 periodic blood donors, 898 male and 322 female. We also studied 10 hematologic patients affected by thalassaemia and sickle cell disease referred to our institution as candidate to periodic transfusions. Our patients (8 females and 2 males with a median age of 48 years, range 24-76 years), extensively typed using molecular techniques and screened for RBC alloantibodies, were transfused with a median of 33.5 RBC units. After three years of molecular typing, the "perfect match" transfusion strategy avoided new alloantibodies development in all studied patients.


Assuntos
Anemia Falciforme , Transfusão de Eritrócitos , Técnicas de Genotipagem/métodos , Talassemia , Reação Transfusional/prevenção & controle , Adolescente , Adulto , Idoso , Anemia Falciforme/genética , Anemia Falciforme/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Talassemia/genética , Talassemia/terapia , Reação Transfusional/genética
4.
Leuk Lymphoma ; 55(2): 270-5, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23647063

RESUMO

Anemia is a frequent sign in patients with diffuse large B-cell lymphoma (DLBCL) at diagnosis. We determined erythropoietin, hepcidin and interleukin-6 (IL-6) in plasma samples of 53 patients with DLBCL. The majority of patients (40/53, 75%) showed defective endogenous erythropoietin production, in particular when anemia was present (p = 0.01). Hepcidin plasma levels were significantly higher in patients compared to controls (p = 0.006), particularly in those with characteristics associated with a more active disease, including elevated lactate dehydrogenase (LDH) (p = 0.0004), B-symptoms (p = 0.07) and an age-adjusted international prognostic index (IPI) score > 1 (p = 0.01). Hepcidin levels correlated strongly to ferritin (r = 0.77, p < 0.0001) and weakly to IL-6 concentrations (r = 0.30, p = 0.03), but not to hemoglobin values. IL-6 inversely correlated to hemoglobin values in both univariate and multivariate analysis (p = 0.04), including hepcidin and erythropoietin as variables. Our findings suggest that elevated hepcidin levels and inadequate erythropoietin response are frequent in DLBCL, but elevated IL-6 plays the major role for the development of anemia.


Assuntos
Anemia/sangue , Eritropoetina/sangue , Hepcidinas/sangue , Interleucina-6/sangue , Linfoma Difuso de Grandes Células B/sangue , Adolescente , Adulto , Anemia/complicações , Feminino , Ferritinas/sangue , Humanos , Técnicas Imunoenzimáticas/métodos , Modelos Logísticos , Linfoma Difuso de Grandes Células B/complicações , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Adulto Jovem
5.
Blood Cells Mol Dis ; 52(2-3): 83-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24055163

RESUMO

OBJECTIVE: Hereditary hemochromatosis (HH) is a common Mendelian disorder of iron metabolism. Eighty percent of northern Europeans descendant HH patients carry the same mutation (p.C282Y) in the HFE gene. Simultaneously, due to a founder effect, its frequency varies considerably between different populations. In Central-Southern Italy the prevalence of p.C282Y mutation is low and in several patients the disease has different causes. Four additional rarer forms have been described. Type 3 HH has been reported in about 50 families and no more than 30 TFR2 pathogenic mutations have been globally identified. The aim of this study is to assess the TFR2 role in non-HFE HH pathogenesis. STUDY DESIGN AND SETTING: TFR2 sequence analysis was performed on 45 Italian patients without HFE mutations. RESULTS: This study revealed TFR2 biallelic pathogenic mutations in 7/45 (15.6%) individuals. Moreover monoallelic TFR2 deleterious defects (18%) or polymorphisms with unclear meaning (36%) were identified. Besides, we recognized 10 novel variants and 9 described changes. CONCLUSION: We believe this to be the largest series of type 3 HH patients described so far. Present findings support the hypothesis of a main role of the TFR2 gene in HH pathogenesis in those regions, such as Central-Southern Italy, where the p.C282Y frequency is low.


Assuntos
Hemocromatose/genética , Receptores da Transferrina/deficiência , Alelos , Sequência de Bases , Análise Mutacional de DNA , Hemocromatose/metabolismo , Hemocromatose/patologia , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/metabolismo , Itália , Mutação , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo
7.
Clin Biochem ; 44(14-15): 1261-3, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21821016

RESUMO

We report a case of a patient affected by compound heterozygosis for two PK-LR gene mutations: p.R486W (c.1456C>T) and p.M403I (c.1209G>A). Our patient suffered from an initial moderate hemolytic anemia which subsequently evolved into a severe form after mitral prosthetic valve replacement for valve regurgitation. Thereafter, the clinical features evolved into a worsening of anemia, heart failure and pulmonary hypertension, in the absence of valve dysfunction. This clinical picture improved only after an intensive transfusion regimen. This case highlights aspects concerning the intricate balance between the risks and benefits of a mechanical prosthetic valve implant in PK-deficient patients.


Assuntos
Implante de Prótese de Valva Cardíaca/efeitos adversos , Valva Mitral/cirurgia , Mutação , Piruvato Quinase/genética , Idoso , Anemia Hemolítica/cirurgia , Heterozigoto , Humanos , Hipertensão Pulmonar/etiologia , Masculino , Piruvato Quinase/deficiência , Reimplante
8.
J Infect ; 63(2): 144-50, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21683094

RESUMO

OBJECTIVE: Although zidovudine-free regimens are increasingly used in pregnancy, their haematological effects in mothers and newborns are incompletely defined. METHODS: The haematological profiles of 119 HIV-infected women and their neonates with highly active antiretroviral regimens (HAART) in pregnancy including or not zidovudine (ZDV) were investigated. Three groups were compared: 1) women who started ZDV-lamivudine (3TC)-based HAART during pregnancy (ZDVs, n = 60); 2) women on ZDV-3TC-based HAART from conception (ZDVc, n = 18); 3) women on ZDV-free HAART from conception (ZDVf, n = 41). RESULTS: At the beginning of pregnancy, haemoglobin levels were similar in the three groups. By week 36 compared to baseline, haemoglobin levels had a significantly greater decrease in ZDVf women compared to ZDVs women (ZDVf: -2.03 g/dl; ZDVs: -1.36 g/dl, p = 0.036). A similar trend was observed for occurrence of maternal anaemia at 36 weeks. Newborns with no prenatal ZDV exposure had significantly higher haemoglobin levels at birth (ZDVf: 16.1 ± 1.4 g/dl, ZDVs: 14.3 ± 2.0 g/dl; ZDVc: 14.6 ± 2.4 g/dl, p = 0.044 and 0.003, respectively). CONCLUSIONS: Half of ZDV-unexposed mothers had anaemia at the end of pregnancy, but their neonates had normal haemoglobin levels. ZDV initiation was associated with a lower occurrence of maternal anaemia during the third trimester and decreased haemoglobin levels in the newborns. We hypothesize that foetal iron requirements could represent a major determinant of maternal anaemia at the end of pregnancy.


Assuntos
Anemia/diagnóstico , Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Zidovudina/administração & dosagem
9.
Haematologica ; 95(1): 65-70, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19713221

RESUMO

UNLABELLED: Background The MPL(Ser505Asn) mutation has been reported to be a cause of hereditary thrombocythemia. Recently, we detected this mutation in a large proportion of children with familial thrombocythemia, suggesting that in Italy the incidence of MPL(Ser505Asn) mutation could be underestimated. DESIGN AND METHODS: We extended the search for this mutation to all patients with essential thrombocythemia who had a positive family history for thrombocytosis or essential thrombocythemia. We identified eight Italian families positive for the MPL(Ser505Asn) mutation. Clinical and hematologic data were available for members of seven families, including 21 patients with a proven mutation and 20 relatives with thrombocytosis. RESULTS: Fifteen major thrombotic episodes, nine of which were fatal, were recorded among 41 patients. The thrombotic manifestation was stroke in four cases, myocardial infarction in seven cases, fetal loss in two cases, deep vein thrombosis of the leg in one case and Budd Chiari syndrome in one case. Almost all patients over 20 years old had splenomegaly and bone marrow fibrosis, while these were rarely observed in patients under 20 years old, suggesting that these manifestations are associated with aging. Finally, the life expectancy of family members with thrombocytosis was significantly shorter than that of members without thrombocytosis (P=0.003). Conclusions Patients with familial thrombocytosis caused by a MPL(Ser505Asn) mutation have a high risk of thrombosis and, with aging, develop splenomegaly and bone marrow fibrosis, significantly affecting their life expectancy.


Assuntos
Substituição de Aminoácidos/genética , Mielofibrose Primária/genética , Receptores de Trombopoetina/genética , Esplenomegalia/genética , Trombocitose/genética , Trombose/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asparagina/genética , Criança , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Mielofibrose Primária/mortalidade , Fatores de Risco , Serina/genética , Esplenomegalia/mortalidade , Trombocitose/complicações , Trombocitose/mortalidade , Trombopoetina/genética , Trombopoetina/metabolismo , Trombose/mortalidade , Adulto Jovem
11.
Mediterr J Hematol Infect Dis ; 1(1): e2009028, 2009 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-21415996

RESUMO

The clinical approach to thalassemia and hemoglobinopathies, specifically Sickle Cell Disease (SCD), based on transfusions, iron chelation and bone marrow transplantation has ameliorated their prognosis. Nevertheless, infections still may cause serious complications in these patients. The susceptibility to infections in thalassemia and SCD arises both from a large spectrum of immunological abnormalities and from exposure to specific infectious agents. Four fundamental issues will be focused upon as central causes of immune dysfunction: the diseases themselves; iron overload, transfusion therapy and the role of the spleen. Thalassemia and SCD differ in their pathogenesis and clinical course. It will be outlined how these differences affect immune dysfunction, the risk of infections and the types of most frequent infections in each disease. Moreover, since transfusions are a fundamental tool for treating these patients, their safety is paramount in reducing the risks of infections. In recent years, careful surveillance worldwide and improvements in laboratory tests reduced greatly transfusion transmitted infections, but the problem is not completely resolved. Finally, selected topics will be discussed regarding Parvovirus B19 and transfusion transmitted infections as well as the prevention of infectious risk postsplenectomy or in presence of functional asplenia.

12.
Haematologica ; 87(2): 221-2, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11836175

RESUMO

We analyzed the hepcidin gene in 10 Italian patients with hemochromatosis not related to C282Y, H63D or other less frequent HFE mutations, nor to Y250X in TFR2. The sequencing of the whole hepcidin coding region, intron-exon junctions, 5' and partially 3'UTRs, did not reveal any alteration in the studied patients.


Assuntos
Peptídeos Catiônicos Antimicrobianos/genética , Proteínas de Ligação a DNA , Hemocromatose/genética , Proteínas de Membrana , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos HLA/genética , Hemocromatose/epidemiologia , Proteína da Hemocromatose , Hepcidinas , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Reação em Cadeia da Polimerase , Fatores de Transcrição/fisiologia , Fatores Estimuladores Upstream
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