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1.
Nat Commun ; 11(1): 4178, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826895

RESUMO

Friedreich's ataxia (FRDA) is an autosomal-recessive neurodegenerative and cardiac disorder which occurs when transcription of the FXN gene is silenced due to an excessive expansion of GAA repeats into its first intron. Herein, we generate dorsal root ganglia organoids (DRG organoids) by in vitro differentiation of human iPSCs. Bulk and single-cell RNA sequencing show that DRG organoids present a transcriptional signature similar to native DRGs and display the main peripheral sensory neuronal and glial cell subtypes. Furthermore, when co-cultured with human intrafusal muscle fibers, DRG organoid sensory neurons contact their peripheral targets and reconstitute the muscle spindle proprioceptive receptors. FRDA DRG organoids model some molecular and cellular deficits of the disease that are rescued when the entire FXN intron 1 is removed, and not with the excision of the expanded GAA tract. These results strongly suggest that removal of the repressed chromatin flanking the GAA tract might contribute to rescue FXN total expression and fully revert the pathological hallmarks of FRDA DRG neurons.


Assuntos
Ataxia de Friedreich/genética , Ataxia de Friedreich/patologia , Gânglios Espinais/metabolismo , Edição de Genes/métodos , Proteínas de Ligação ao Ferro/genética , Organoides/metabolismo , Células Receptoras Sensoriais/metabolismo , Antioxidantes/farmacologia , Sistemas CRISPR-Cas , Diferenciação Celular , Cromatina/metabolismo , Ataxia de Friedreich/tratamento farmacológico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Predisposição Genética para Doença/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Íntrons , Mitocôndrias/metabolismo , Organoides/efeitos dos fármacos , Organoides/patologia , Células Receptoras Sensoriais/patologia , Análise de Sequência de RNA , Transcriptoma
2.
Croat Med J ; 61(3): 230-238, 2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32643339

RESUMO

AIM: To analyze the association of thyroid function and hormone levels with metabolic syndrome (MetS) and its components. METHODS: This cross-sectional population-based study involved 2183 Croatian individuals with no history of thyroid disease, hypertension, diabetes, and hyperlipidemia. MetS was diagnosed according to the National Cholesterol Education Program's Adult Treatment Panel III criteria. RESULTS: We found no association between thyroid function groups and the prevalence of MetS and its components. Clinically hypothyroid participants showed significantly higher triceps skinfold measurements than subclinically hypothyroid and euthyroid participants. Furthermore, clinically hypothyroid participants had higher abdominal skinfold thickness than subclinically hypothyroid participants. Otherwise, suprailiac and abdominal skinfold measurements were higher in the subclinically and clinically hyperthyroid group of participants compared with euthyroid and subclinically hypothyroid participants. A strong positive association of thyroid-stimulating hormone (TSH) and strong negative association of free triiodothyronine (fT3) and free thyroxine (fT4) levels with HOMA-IR and cholesterol levels were found. Furthermore, the fT4 level also showed a strong negative association with HDL and triceps skinfold thickness. CONCLUSIONS: This study supports the standing that TSH, fT3, and fT4 levels are important variables to determine the association of thyroid function with MetS.


Assuntos
Síndrome Metabólica/sangue , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Autoantígenos/imunologia , Colesterol/sangue , Estudos Transversais , Feminino , Humanos , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Medições Luminescentes , Masculino , Pessoa de Meia-Idade , Tireoglobulina/imunologia , Hormônios Tireóideos/sangue , Adulto Jovem
3.
PLoS One ; 15(6): e0233957, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555697

RESUMO

INTRODUCTION: Autoantibodies (autoAbs) against desmoglein-1 (DSG1) and desmoglein-3 (DSG3) have conventionally been studied and well accepted in the pathogenesis of pemphigus vulgaris (PV) and foliaceus (PF). Recent studies have suggested that non-DSG autoAbs may contribute to the pathogenesis of pemphigus, including autoAbs directed at acetylcholine receptors (AChR) and thyroid peroxidase (TPO). The purpose of this study is to retrospectively analyze PV and PF patient sera to better understand the relationship between anti-AChR and -TPO Abs to disease activity and DSG reactivity between patients treated with prednisone and steroid sparing agents (SSA; n = 22) or prednisone and rituximab (n = 21). METHODS: Patients were evaluated at 2 time points, T1 and T2, for disease activity using the Pemphigus Disease Area Index (PDAI), and sera were tested for the presence of TPO, DSG1, DSG3, muscarinic (M3) and nicotinic (n) AChR IgG autoAbs, as well as antibodies against Varicella Zoster Virus (VZV) by ELISA. RESULTS: Disease activity significantly decreased in patients from T1 to T2 (p < .0001). A significant difference was seen in IgG anti-DSG1 (p < .0001) and anti-DSG3 (p = .0049) levels when T1 was compared to T2 in both treatment groups. A significant increase was found between pemphigus patients and normal subjects with nAChR (p < .0001) at T1 but not with m3AChR, TPO or VZV Abs. No significant difference was seen between T1 and T2 values in patients with pemphigus for the non-desmoglein Abs TPO (p = .7559), M3AChR (p = .9003), nAChR (p = .5143) or VZV (p = .2454). These findings demonstrate that although an increase in IgG anti-nAChR autoAbs was found in PV and PF subjects, these Abs did not decrease with treatment. No other non-DSG Abs were increased or significantly changed over time in patients with pemphigus. This suggests that anti -AChR and -TPO Abs may not play a direct role in the pathogenesis of most patients with pemphigus, but does not rule out a role for non-DSG auto antibodies in distinct subsets of pemphigus patient.


Assuntos
Autoanticorpos/sangue , Desmogleína 1/imunologia , Desmogleína 3/imunologia , Imunoglobulina G/sangue , Pênfigo/imunologia , Receptor Muscarínico M3/imunologia , Receptores Nicotínicos/imunologia , Adulto , Idoso , Autoantígenos/imunologia , Feminino , Humanos , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Masculino , Pessoa de Meia-Idade , Pênfigo/tratamento farmacológico , Prednisona/uso terapêutico , Estudos Retrospectivos , Rituximab/uso terapêutico , Adulto Jovem
4.
JAMA Netw Open ; 3(3): e201357, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32202644

RESUMO

Importance: Alkaptonuria is an autosomal recessive disorder caused by pathogenic variants in the HGD gene. Deficiency of the HGD enzyme leads to tissue deposition of homogentisic acid (HGA), causing severe osteoarthropathies and cardiac valve degeneration. Although HGD is vital for the catabolism of tyrosine, which provides the basis for thyroid hormone synthesis, the prevalence of thyroid dysfunction in alkaptonuria is unknown. Objective: To assess thyroid structure and function in patients with alkaptonuria. Design, Setting, and Participants: A single-center cohort study was conducted in a tertiary referral center including patients with alkaptonuria followed up for a median of 93 (interquartile range, 48-150) months between February 1, 2000, and December 31, 2018. The alkaptonuria diagnosis was based on clinical presentation and elevated urine HGA levels. A total of 130 patients were considered for participation. Main Outcomes and Measures: Prevalence of thyroid dysfunction in adults with alkaptonuria compared with the general population. Thyrotropin and free thyroxine levels were measured by immunoassay and repeated in each patient a median of 3 (interquartile range, 2-22) times. Neck ultrasonographic scans were analyzed in a subset of participants. Logistic regression was used to test the association of thyroid dysfunction with age, sex, thyroid peroxidase (TPO) antibodies, serum tyrosine levels, and urine HGA levels. Results: Of the 130 patients, 5 were excluded owing to thyroidectomy as the cause of hypothyroidism. The study cohort consisted of 125 patients; the median age was 45 (interquartile range, 35-51) years. Most of the patients were men (72 [57.6%]). The prevalence of primary hyperthyroidism was 0.8% (1 of 125 patients), similar to 0.5% observed in the general population (difference, 0.003; 95% CI, -0.001 to 0.04; P = .88). The prevalence of primary hypothyroidism was 16.0% (20 of 125 patients), which is significantly higher than 3.7% reported in the general population (difference, 0.12; 95% CI, 0.10-0.24; P < .001). Women were more likely to have primary hypothyroidism than men (odds ratio, 10.99; 95% CI, 3.13-38.66; P < .001). Patients with TPO antibodies had a higher likelihood of primary hypothyroidism than those without TPO antibodies (odds ratio, 7.36; 95% CI, 1.89-28.62; P = .004). There was no significant difference in the prevalence of thyroid nodules between patients in this study (29 of 49 [59.2%]) vs the general population (68%) (difference, 0.088; 95% CI, -0.44 to 0.73; P = .20) or of cancer (7% vs 5%; difference, 0.01; 95% CI, -0.01 to 0.17; P = .86). Conclusions and Relevance: The high prevalence of primary hypothyroidism noted in patients with alkaptonuria in this study suggests that serial screening in this population should be considered and prioritized.


Assuntos
Alcaptonúria/metabolismo , Hipotireoidismo/epidemiologia , Adulto , Alcaptonúria/complicações , Alcaptonúria/genética , Autoanticorpos/sangue , Autoantígenos/imunologia , Estudos de Coortes , Feminino , Ácido Homogentísico/urina , Humanos , Hipertireoidismo/epidemiologia , Hipertireoidismo/genética , Hipotireoidismo/genética , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prevalência , Testes de Função Tireóidea , Glândula Tireoide/enzimologia , Tireotropina/sangue , Tiroxina/sangue , Tirosina/sangue
5.
Mymensingh Med J ; 29(1): 156-161, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31915352

RESUMO

Sub clinical hypothyroidism (SCH) is common in clinical practice. Autoimmunity is thought to be the most important cause of SCH. In this cross-sectional study, we investigated 120 SCH patients and 100 healthy controls attending the Endocrinology Outpatient Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from June 2014 to April 2015 for anti-thyroid antibodies (anti-TPO and anti-Tg). Measurement of serum TSH, FT4, anti-TPO, and anti-Tg antibodies were done by using the chemiluminescent sequential immunometric assay. SCH patients had a higher mean age; the frequencies of female subjects, those having family history of thyroid disease or other autoimmune diseases, and goiter were higher in SCH group than in the control group. Forty-five percent (45%) of SCH patients were positive for anti-thyroid antibodies (23.3% for both anti-TPO and anti-Tg, 16.7% for only anti-TPO, and 5% positive for only anti-Tg) in comparison to only 10% anti-thyroid antibody positive controls (none for both antibodies, 8% for only anti-TPO, and 2% positive for only anti-Tg). The SCH subjects in the lower age group, females and with a TSH >10µIU/mL had the higher frequency of thyroid autoimmunity. Female gender, high socioeconomic condition, the presence of other autoimmune diseases, the presence of goiter and TSH >10µIU/mL were associated with higher odds of anti-thyroid antibody positivity in the SCH group, though none were statistically significant. The frequency of anti-thyroid antibody was higher in SCH and was more prevalent among the females, younger patients and those having a goiter, other autoimmune diseases, and TSH >10µIU/mL.


Assuntos
Anticorpos/sangue , Autoanticorpos/sangue , Hipotireoidismo/diagnóstico , Hipotireoidismo/imunologia , Adulto , Autoantígenos , Bangladesh/epidemiologia , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Hipotireoidismo/epidemiologia , Iodeto Peroxidase , Proteínas de Ligação ao Ferro , Prevalência , Tireoglobulina/sangue , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue
6.
Neoplasma ; 67(1): 164-170, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31777257

RESUMO

The differential diagnosis of well-differentiated tumors of follicular cell origin remains the most problematic task in thyroid pathology. Specific morphologic criteria (capsular and/or vascular invasion, nuclear characteristics) are crucial in the diagnosis of these neoplasms. However, the assessment of malignant features is inconclusive in some cases. Moreover, oncocytic thyroid tumors remain controversial in a respect to their pathobiology, behavior and management. Therefore, the useful diagnostic/prognostic thyroid markers are awaited. The aim of our study was to evaluate the expression of galectin-3 and thyroid peroxidase (TPO) in benign and malignant thyroid tumors of follicular cell origin. A total of 186 archival thyroid samples including 38 non-oncocytic follicular adenomas, 53 oncocytic (Hürthle cell) adenomas, 6 non-oncocytic follicular carcinomas, 23 oncocytic (Hürthle cell) carcinomas, 43 non-oncocytic papillary carcinomas, and 23 oncocytic papillary carcinomas were analyzed for galectin-3 and TPO expression by immunohistochemistry. Both types of papillary carcinomas showed significant upregulation of galectin-3 in comparison with the other tumor types, likewise, significant differences in galectin-3 expression were discovered between non-oncocytic and oncocytic variants of studied tumors excluding follicular carcinoma. Significant lowering of TPO was revealed in oncocytic adenomas and papillary carcinomas. In conclusion, the combined use of galectin-3 and TPO markers could help to improve the differential diagnosis of thyroid tumors. Differences in the galectin-3 and TPO expression between some oncocytic and non-oncocytic tumors support their separation in the latest WHO classification of thyroid tumors.


Assuntos
Autoantígenos/genética , Galectina 3/genética , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/genética , Neoplasias da Glândula Tireoide/diagnóstico , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Humanos , Neoplasias da Glândula Tireoide/classificação
7.
Curr Diabetes Rev ; 16(8): 895-899, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31870270

RESUMO

AIMS: Investigation thyroid dysfunction and autoimmunity in pregnant women with gestational diabetes mellitus. BACKGROUND: This article was written to evaluate the thyroid function and anti-thyroid peroxidase (anti- TPO) antibodies in pregnant women with gestational diabetes mellitus (GDM). METHODS: A total of 252 women with GDM and 252 healthy pregnant women were enrolled. Thyroid tests, including TSH, FreeT3, Free T4, and anti-TPO were performed for all women at 24-28 weeks of gestation. Data analysis was then carried out using SPSS ver. 22. RESULTS: There was a significant difference between the experimental group (38.4%) and the control group (14.06%) in terms of the prevalence of subclinical hypothyroidism (p= 0.016). The frequency of anti-TPO was higher in the experimental group than the control group and positive anti-TPO was observed in 18.6% of women with GDM and 10.3% of healthy pregnant women (P= 0.008). CONCLUSION: Thyroid disorders are observed in pregnant women with GDM more frequently than healthy individuals and it may be thus reasonable to perform thyroid tests routinely.


Assuntos
Autoantígenos/sangue , Doenças Autoimunes/sangue , Diabetes Gestacional/sangue , Hipotireoidismo/sangue , Iodeto Peroxidase/sangue , Proteínas de Ligação ao Ferro/sangue , Adulto , Autoantígenos/imunologia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/imunologia , Feminino , Humanos , Hipotireoidismo/diagnóstico , Hipotireoidismo/imunologia , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Gravidez , Complicações na Gravidez , Testes de Função Tireóidea , Adulto Jovem
8.
Toxicol In Vitro ; 62: 104662, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31629072

RESUMO

Impaired synthesis or action of thyroid hormones (THs) during critically sensitive periods of development can have long term adverse effects on health. Development of rapid assays to identify chemicals that impair THs physiology is an important goal for reducing risks from chemical use. Thyroid peroxidase (TPO) is a key enzyme regulating THs synthesis in thyroid gland and a vulnerable target for chemicals that disrupt THs synthesis. To develop a human-relevant, rapid assay for TPO inhibition, we have engineered two cell lines (CHO and LentiX- 293) to express active human TPO (hTPO) enzyme and applied them in a recently-described assay using a stable fluorescent product (Amplex UltraRed). Assay performance was assessed by comparing activity of 19 reference chemicals with known strong, weak or no TPO inhibitory activity. The assay using hTPO from either cell line consistently identified the relative potency of strong to moderate inhibitors and chemicals known to be inactive. Results were less consistent for chemicals reported to be weak inhibitors of rodent TPO, possibly suggesting some species specificity. Our studies support the use of hTPO from stably transfected cell lines to substitute for animal-derived thyroid microsomes for rapid high throughput screening assays to identify and characterize TPO inhibitors.


Assuntos
Autoantígenos/metabolismo , Bioensaio , Iodeto Peroxidase/metabolismo , Proteínas de Ligação ao Ferro/metabolismo , Animais , Autoantígenos/genética , Linhagem Celular , Cricetulus , Humanos , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/genética , Metimazol/farmacologia , Oxazinas/metabolismo
9.
J Immunol Res ; 2019: 4202145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886301

RESUMO

Background: Chronic spontaneous urticaria (CSU) is a heterogeneous disease with some frequent comorbidities like autoimmune diseases, drug reactions, and inducible urticaria. IgE antibodies against thyroid peroxidase (anti-TPO IgE) could be associated with some of these clinical characteristics. Objective: To explore the clinical characteristics of CSU patients, according to the presence of anti-TPO IgE in serum. Methods: Anti-TPO IgE levels were measured during the clinical control period (Urticaria Activity Score, 0 point) and exacerbation period (≥3 points) in 100 CSU patients. Patients with self-reported exacerbation of skin involvement by foods, nonsteroidal anti-inflammatory drugs (NSAIDs), and physical triggers underwent controlled challenge tests. Results: We identified 2 groups of patients: (1) patients with anti-TPO IgE during the clinical control period or during an exacerbation, who had a higher frequency of atopy, asthma, and positive challenge test results with NSAIDs and (2) patients without anti-TPO IgE during any period, who had a higher frequency of positive challenge test results for inducible urticaria. Among the first group (anti-TPO IgE at any point), we identified 3 subgroups: patients with anti-TPO IgE during the clinical control period (n = 12); patients with anti-TPO IgE during the clinical control period and significantly increased levels during an urticaria exacerbation (n = 18); and patients with anti-TPO IgE only during an exacerbation (n = 13). None of the patients with self-reported food reactions had a positive challenge test result. Conclusion: Anti-TPO IgE is a useful biomarker for differentiating between clinical phenotypes of patients with CSU. Elevation of anti-TPO IgE during exacerbation periods supports an association between this autoantibody and the pathogenesis of urticaria.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Urticária Crônica/diagnóstico , Urticária Crônica/etiologia , Imunoglobulina E/imunologia , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Adolescente , Adulto , Autoanticorpos/sangue , Biomarcadores , Suscetibilidade a Doenças/imunologia , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Tohoku J Exp Med ; 249(3): 231-236, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31776300

RESUMO

Thyroid dysfunction (TD) is caused by thyroid peroxidase (TPO) antibody, as seen in Hashimoto's disease. TD is a common problem of reproductive age and may impair fetal development. Here, we determined the effect of TPO antibody on perinatal outcomes in Japanese women with TD before conception. A retrospective study involving cases of maternal TD with term singleton birth was conducted. The subjects with TD were divided into two groups according to the presence (n = 22) or absence (n = 20) of TPO antibody. The control groups matched for age, parity, and gestational weeks were selected for TPO antibody-positive (n = 44) and -negative TD subjects (n = 40), respectively. Using the standard curve of Japanese placental weight, the frequency of placental weight less than the 50th percentile (small placenta) was examined. Placental weight was lower among TPO antibody-positive TD subjects, compared with TPO antibody-negative TD subjects (p < 0.01). However, other outcomes were similar between the groups. Importantly, compared with control mothers, placental weight was significantly lower (p < 0.01), birth weight tended to be lower (p = 0.07), and the incidence of gestational diabetes mellitus was higher (p = 0.02) among TPO antibody-positive subjects. There was no significant difference in placental weight between TPO antibody-negative subjects and controls. The frequency of small placenta was significantly higher in TPO antibody-positive subjects (odds ratio: 16.7) even when considering diabetes and pregnancy induced hypertension. Thus, the presence of TPO antibody is associated with lower placental weight among Japanese women having TD.


Assuntos
Anticorpos/sangue , Autoantígenos/imunologia , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Placenta/patologia , Glândula Tireoide/fisiopatologia , Adulto , Feminino , Humanos , Tamanho do Órgão , Gravidez , Resultado da Gravidez
11.
Presse Med ; 48(11 Pt 1): e307-e315, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31727487

RESUMO

INTRODUCTION: Fertility disorders in autoimmune diseases are well described. However, little is known about the presence of a humoral serum autoimmunity in case of infertility (antinuclear antibodies, ACAN or antiphospholipid, APL) without criteria of autoimmune disease. METHODS: We studied the prevalence, associated factors, and efficacy of immunomodulatory therapy in patients with unexplained infertility. Two groups were created retrospectively among patients followed in medically assisted procreation (PMA) for infertility: a group with serum autoimmunity (AI+) (ACAN, APL or anti-thyroperoxidase antibodies) and a group without serum autoimmunity (HAVE-). Clinical, biological, and therapeutic data were collected. RESULTS: The prevalence of autoimmunity was 33% among consultant patients. One hundred patients were seen in internal medicine consultation, 70 were included in the AI+ group and 30 in the AI- group. In the AI+ group, 76% had ACANs, 29% had anti-TPOs and 23% had APLs. There was a significant correlation between ACAN level and the presence of endometriosis (P=0.048). Immunomodulatory therapy was introduced for 68 of the 70 women in the AI+ group; pregnancy occurred in 28 patients (40%) during the treatment period, compared with 7 in the "AI-" group (23%), with a tendency to significance (P=0.09). In conclusion, there is an increased prevalence of serum autoimmunity in patients with fertility disorders, possibly with the efficacy of an immunomodulatory treatment to confront prospective therapeutic studies.


Assuntos
Autoanticorpos/sangue , Autoimunidade , Infertilidade Feminina/imunologia , Anticorpos Antinucleares/sangue , Anticorpos Antifosfolipídeos/sangue , Autoantígenos/imunologia , Implantação do Embrião , Endometriose/imunologia , Feminino , França , Humanos , Imunomodulação , Infertilidade Feminina/sangue , Infertilidade Feminina/terapia , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Gravidez , Estudos Retrospectivos
12.
Kathmandu Univ Med J (KUMJ) ; 17(65): 57-60, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31734680

RESUMO

Background Pregnancy is an important event in reproductive years of women life. It has a reversible effect on the thyroid gland and its functions. The role of thyroid gland function and conception has been known for a long time. The most common thyroid gland dysfunction in pregnancy is hypothyroidism. It is estimated that the prevalence is 1.5-4.4% of pregnant women. It is known to cause complications during pregnancy leading to adverse pregnancy outcomes. Objective To observe the pregnancy outcomes in patients with hypothyroidism. Method This is a retrospective study conducted from January 2015 to December 2018. Two hundred and thirty nine patients with hypothyroidism were included. They were investigated for thyroid stimulating hormone (TSH), free tri iodothyronin (FT ), free thyroxine (FT ) levels and for auto-antibodies against thyroperoxidase (anti TPO). All these patients after the detection of hypothyroidism were under thyroxine hormone replacement. Result Amongst 239 ladies with hypothyroidism 97.5% came from hilly region. Seventy seven (32%)of them had history of abortions. Twenty three (9.8%) of them had antepartum hemorrhage. Eleven (4.6%) had preeclampsia during this pregnancy. Seven (2.9%) had fetuses with intrauterine growth restriction (IUGR). Seven (2.9%) had fetuses with preterm delivery. Twenty seven (11.3%) of fetuses had APGAR Score of < 6. Conclusion Of 239 women with hypothyroidism, many had history of recurrent abortions and also complications during antenatal period like preeclampsia, abruption placenta, IUGR and preterm delivery. After thyroxine replacement, risk is much lowered and it has a positive outcome.


Assuntos
Hipotireoidismo/fisiopatologia , Resultado da Gravidez , Aborto Espontâneo , Adulto , Autoanticorpos/sangue , Autoantígenos/imunologia , Feminino , Terapia de Reposição Hormonal/métodos , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/epidemiologia , Recém-Nascido , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Gravidez , Complicações na Gravidez/epidemiologia , Estudos Retrospectivos , Tiroxina/uso terapêutico , Adulto Jovem
13.
Nat Commun ; 10(1): 5080, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31704944

RESUMO

Hyperaccumulators typically refer to plants that absorb and tolerate elevated amounts of heavy metals. Due to their unique metal trafficking abilities, hyperaccumulators are promising candidates for bioremediation applications. However, compared to bacteria-based bioremediation systems, plant life cycle is long and growing conditions are difficult to maintain hindering their adoption. Herein, we combine the robust growth and engineerability of bacteria with the unique waste management mechanisms of plants by using a more tractable platform-the common baker's yeast-to create plant-like hyperaccumulators. Through overexpression of metal transporters and engineering metal trafficking pathways, engineered yeast strains are able to sequester metals at concentrations 10-100 times more than established hyperaccumulator thresholds for chromium, arsenic, and cadmium. Strains are further engineered to be selective for either cadmium or strontium removal, specifically for radioactive Sr90. Overall, this work presents a systematic approach for transforming yeast into metal hyperaccumulators that are as effective as their plant counterparts.


Assuntos
Proteínas de Transporte/genética , Engenharia Metabólica/métodos , Metais Pesados/metabolismo , Saccharomyces cerevisiae/genética , Antiporters/genética , Antiporters/metabolismo , Arsênico/metabolismo , Biodegradação Ambiental , Cádmio/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Cromo/metabolismo , Proteínas de Transporte de Cobre/genética , Proteínas de Transporte de Cobre/metabolismo , Transportador de Cobre 1/genética , Transportador de Cobre 1/metabolismo , Proteínas de Ligação ao Ferro/genética , Proteínas de Ligação ao Ferro/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Proteínas SLC31/genética , Proteínas SLC31/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Estrôncio/metabolismo , Radioisótopos de Estrôncio/metabolismo
14.
Int J Mol Sci ; 20(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640150

RESUMO

NRF2 (Nuclear factor Erythroid 2-related Factor 2) signaling is impaired in Friedreich's Ataxia (FRDA), an autosomal recessive disease characterized by progressive nervous system damage and degeneration of nerve fibers in the spinal cord and peripheral nerves. The loss of frataxin in patients results in iron sulfur cluster deficiency and iron accumulation in the mitochondria, making FRDA a fatal and debilitating condition. There are no currently approved therapies for the treatment of FRDA and molecules able to activate NRF2 have the potential to induce clinical benefits in patients. In this study, we compared the efficacy of six redox-active drugs, some already adopted in clinical trials, targeting NRF2 activation and frataxin expression in fibroblasts obtained from skin biopsies of FRDA patients. All of these drugs consistently increased NRF2 expression, but differential profiles of NRF2 downstream genes were activated. The Sulforaphane and N-acetylcysteine were particularly effective on genes involved in preventing inflammation and maintaining glutathione homeostasis, the dimethyl fumarate, omaxevolone, and EPI-743 in counteracting toxic products accumulation, the idebenone in mitochondrial protection. This study may contribute to develop synergic therapies, based on a combination of treatment molecules.


Assuntos
Acetilcisteína/farmacologia , Ataxia de Friedreich/patologia , Proteínas de Ligação ao Ferro/metabolismo , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Biópsia , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ataxia de Friedreich/tratamento farmacológico , Ataxia de Friedreich/metabolismo , Humanos , Terapia de Alvo Molecular , Oxirredução , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Ativação Transcricional/efeitos dos fármacos
15.
Nat Commun ; 10(1): 4853, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649262

RESUMO

Few secreted proteins involved in plant infection common to necrotrophic bacteria, fungi and oomycetes have been identified except for plant cell wall-degrading enzymes. Here we study a family of iron-binding proteins that is present in Gram-negative and Gram-positive bacteria, fungi, oomycetes and some animals. Homolog proteins in the phytopathogenic bacterium Dickeya dadantii (IbpS) and the fungal necrotroph Botrytis cinerea (BcIbp) are involved in plant infection. IbpS is secreted, can bind iron and copper, and protects the bacteria against H2O2-induced death. Its 1.7 Å crystal structure reveals a classical Venus Fly trap fold that forms dimers in solution and in the crystal. We propose that secreted Ibp proteins binds exogenous metals and thus limit intracellular metal accumulation and ROS formation in the microorganisms.


Assuntos
Arabidopsis/metabolismo , Cobre/metabolismo , Proteínas de Ligação ao Ferro/metabolismo , Ferro/metabolismo , Doenças das Plantas/microbiologia , Espécies Reativas de Oxigênio/metabolismo , Anti-Infecciosos Locais/farmacologia , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Botrytis/genética , Botrytis/metabolismo , Proteínas de Transporte/metabolismo , Defensinas/genética , Dimerização , Gammaproteobacteria/efeitos dos fármacos , Gammaproteobacteria/genética , Gammaproteobacteria/metabolismo , Peróxido de Hidrogênio/farmacologia , Proteínas de Ligação ao Ferro/genética , Doenças das Plantas/genética , Sideróforos/genética , Sideróforos/metabolismo
16.
Nucleic Acids Res ; 47(20): 10728-10743, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31584077

RESUMO

Friedreich's ataxia (FRDA) is an untreatable disorder with neuro- and cardio-degenerative progression. This monogenic disease is caused by the hyper-expansion of naturally occurring GAA repeats in the first intron of the FXN gene, encoding for frataxin, a protein implicated in the biogenesis of iron-sulfur clusters. As the genetic defect interferes with FXN transcription, FRDA patients express a normal frataxin protein but at insufficient levels. Thus, current therapeutic strategies are mostly aimed to restore physiological FXN expression. We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. Here, by in vitro screening, we have identified a number of SINEUPs targeting human FXN mRNA and capable to up-regulate frataxin protein to physiological amounts acting at the post-transcriptional level. Furthermore, FXN-specific SINEUPs promote the recovery of disease-associated mitochondrial aconitase defects in FRDA-derived cells. In summary, we provide evidence that SINEUPs may be the first gene-specific therapeutic approach to activate FXN translation in FRDA and, more broadly, a novel scalable platform to develop new RNA-based therapies for haploinsufficient diseases.


Assuntos
Ataxia de Friedreich/genética , Regulação da Expressão Gênica , Proteínas de Ligação ao Ferro/genética , Modelos Biológicos , RNA não Traduzido/metabolismo , Aconitato Hidratase/metabolismo , Linhagem Celular , Fibroblastos/metabolismo , Humanos , Linfócitos/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA não Traduzido/genética
17.
PLoS One ; 14(10): e0223209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31665133

RESUMO

Friedreich's ataxia (FA) is a neurodegenerative disease with no approved therapy that is the result of frataxin deficiency. The identification of human FA blood biomarkers related to disease severity and neuro-pathomechanism could support clinical trials of drug efficacy. To try to identify human biomarkers of neuro-pathomechanistic relevance, we compared the overlapping gene expression changes of primary blood and skin cells of FA patients with changes in the Dorsal Root Ganglion (DRG) of the KIKO FA mouse model. As DRG is the primary site of neurodegeneration in FA, our goal was to identify which changes in blood and skin of FA patients provide a 'window' into the FA neuropathomechanism inside the nervous system. In addition, gene expression in frataxin-deficient neuroglial cells and FA mouse hearts were compared for a total of 5 data sets. The overlap of these changes strongly supports mitochondrial changes, apoptosis and alterations of selenium metabolism. Consistent biomarkers were observed, including three genes of mitochondrial stress (MTIF2, ENO2), apoptosis (DDIT3/CHOP), oxidative stress (PREX1), and selenometabolism (SEPW1). These results prompted our investigation of the GPX1 activity as a marker of selenium and oxidative stress, in which we observed a significant change in FA patients. We believe these lead biomarkers that could be assayed in FA patient blood as indicators of disease severity and progression, and also support the involvement of mitochondria, apoptosis and selenium in the neurodegenerative process.


Assuntos
Biomarcadores/sangue , Ataxia de Friedreich/sangue , Gânglios Espinais/metabolismo , Estresse Oxidativo/genética , Animais , Antioxidantes/metabolismo , Apoptose/genética , Modelos Animais de Doenças , Fatores de Iniciação em Eucariotos/sangue , Ataxia de Friedreich/genética , Ataxia de Friedreich/patologia , Gânglios Espinais/patologia , Regulação da Expressão Gênica/genética , Fatores de Troca do Nucleotídeo Guanina/sangue , Humanos , Proteínas de Ligação ao Ferro/genética , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/sangue , Miocárdio/metabolismo , Selênio/metabolismo , Fator de Transcrição CHOP/sangue
18.
Environ Int ; 132: 105124, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31479957

RESUMO

BACKGROUND: Animal studies suggest that organophosphate (OP) pesticides exposure affects thyroid function, but evidence in humans remains sparse and inconclusive. Gestational exposure is of particular interest, since thyroid hormone is essential for fetal brain development. OP pesticides are able to cross the placental and blood-brain barrier and may interfere with fetal development processes regulated by thyroid hormone. OBJECTIVE: To investigate the association of gestational OP pesticides exposure during pregnancy with maternal and cord blood thyroid hormone concentrations. METHODS: This study was embedded within Generation R (Rotterdam, the Netherlands), a prospective population-based birth cohort. Mother-child pairs with OP pesticides assessment and maternal (N = 715) or cord blood (N = 482) thyroid hormone measurements were included. OP pesticides exposure was assessed at <18, 18-25, and >25 weeks gestation by measuring six urinary dialkylphosphate (DAP) metabolites. Thyroid stimulating hormone (TSH) and free thyroxine (FT4) were measured in maternal and cord blood. Maternal measures also included total thyroxine (TT4) and TPO antibodies (TPOAbs). To study the association of creatinine-adjusted DAP metabolite concentrations with thyroid function and TPO antibodies, multivariable linear regression models including relevant confounders were used. RESULTS: There was no association of DAP metabolites with maternal TSH, FT4, TT4 or TPOAb concentrations during pregnancy. Similarly, there was no association of DAP metabolites with cord blood TSH or FT4. Results did not change when DAP concentrations were analyzed at individual time points or as mean gestational exposure. CONCLUSION: Gestational OP pesticides exposure, as assessed by repeatedly measured urinary DAP metabolite concentrations in an urban population, was not associated with maternal or cord blood thyroid hormone concentrations. These findings do not support a mediating role for serum thyroid hormone availability in the relation of early life exposure to low levels of OP pesticides with child neurodevelopment. However, disruption of the thyroid system at tissue level cannot be excluded. In addition, this is one of the first studies on this subject and measurement error in DAP metabolites might have resulted in imprecise estimates. Future studies should use more urine samples to increase precision and should investigate specific OP pesticide metabolites.


Assuntos
Sangue Fetal/química , Compostos Organofosforados/urina , Praguicidas/urina , Tireotropina/sangue , Tiroxina/sangue , Adulto , Autoantígenos/sangue , Monitoramento Biológico , Feminino , Humanos , Iodeto Peroxidase/sangue , Proteínas de Ligação ao Ferro/sangue , Países Baixos , Gravidez , Gestantes , Adulto Jovem
19.
Proc Natl Acad Sci U S A ; 116(39): 19421-19430, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31511419

RESUMO

The function of frataxin (FXN) has garnered great scientific interest since its depletion was linked to the incurable neurodegenerative disease Friedreich's ataxia (FRDA). FXN has been shown to be necessary for iron-sulfur (Fe-S) cluster biosynthesis and proper mitochondrial function. The structural and functional core of the Fe-S cluster assembly complex is a low-activity pyridoxal 5'-phosphate (PLP)-dependent cysteine desulfurase enzyme that consists of catalytic (NFS1), LYRM protein (ISD11), and acyl carrier protein (ACP) subunits. Although previous studies show that FXN stimulates the activity of this assembly complex, the mechanism of FXN activation is poorly understood. Here, we develop a radiolabeling assay and use stopped-flow kinetics to establish that FXN is functionally linked to the mobile S-transfer loop cysteine of NFS1. Our results support key roles for this essential cysteine residue in substrate binding, as a general acid to advance the Cys-quinonoid PLP intermediate, as a nucleophile to form an NFS1 persulfide, and as a sulfur delivery agent to generate a persulfide species on the Fe-S scaffold protein ISCU2. FXN specifically accelerates each of these individual steps in the mechanism. Our resulting architectural switch model explains why the human Fe-S assembly system has low inherent activity and requires activation, the connection between the functional mobile S-transfer loop cysteine and FXN binding, and why the prokaryotic system does not require a similar FXN-based activation. Together, these results provide mechanistic insights into the allosteric-activator role of FXN and suggest new strategies to replace FXN function in the treatment of FRDA.


Assuntos
Liases de Carbono-Enxofre/metabolismo , Proteínas de Ligação ao Ferro/metabolismo , Proteínas com Ferro-Enxofre/metabolismo , Enxofre/metabolismo , Regulação Alostérica , Liases de Carbono-Enxofre/química , Liases de Carbono-Enxofre/genética , Domínio Catalítico , Cisteína/metabolismo , Humanos , Cinética , Complexos Multiproteicos/metabolismo , Mutação , Ligação Proteica , Fosfato de Piridoxal/metabolismo , Sulfetos/metabolismo
20.
J Pediatr Endocrinol Metab ; 32(11): 1265-1273, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31430255

RESUMO

Background Permanent primary congenital hypothyroidism (CH) can be caused by thyroid dysgenesis or dyshormonogenesis. A molecular genetic study is recommended in dyshormonogenesis, in syndromic hypothyroidism and when there is a family history of CH. The aim of this study was to identify a monogenic etiology for CH in selected individuals from a cohort of primary permanent CH. Methods From an initial cohort of 79 patients with permanent CH (3-19 years), 11 patients were selected for molecular analyses. Nine patients with dyshormonogenesis (normal in-situ gland or goiter) were screened for causative variants, by next-generation sequencing (NGS), in 28 genes known to be responsible for CH. One patient with a family history of CH was screened for the paired-box gene 8 (PAX8) gene and another patient with a syndromic CH was screened for the NKX2-1 gene. Results We found a monogenic basis of disease in eight patients, involving the thyroid peroxidase (TPO) gene (four patients), the thyroglobulin (TG) gene (two patients), and the PAX8 and NKX2-1 genes (one patient each). Two patients were heterozygotes, one harboring a variant in the TG gene and the other in the SLC5A5 gene. In one patient, we found no potential causative variants in any of the 28 genes screened. We described five novel variants: three in the TG gene, one in the NKX2-1 and one in the SLC5A5 gene, all of them classified as pathogenic. Conclusions In eight of the 11 screened patients, a monogenic disease was found. These results highlight the advantage of using an NGS panel and provide further data regarding the molecular basis of CH.


Assuntos
Autoantígenos/genética , Hipotireoidismo Congênito/genética , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/genética , Mutação , Fator de Transcrição PAX8/genética , Simportadores/genética , Tireoglobulina/genética , Fator Nuclear 1 de Tireoide/genética , Adolescente , Adulto , Biomarcadores/análise , Criança , Pré-Escolar , Estudos de Coortes , Hipotireoidismo Congênito/epidemiologia , Feminino , Seguimentos , Testes Genéticos , Humanos , Masculino , Prognóstico , Adulto Jovem
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