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Graves' disease (GD), an autoimmune thyroid disease, is one of the main autoimmune diseases in the general population. It is known that the pathophysiology of this disease may be related to immunological mechanisms dysregulation. These mechanisms can be influenced by GD therapies, such as iodide or antithyroid drugs (ATD). OBJECTIVE: Verify relation between clinical, biochemical and treatment modalities used prior to surgery and histopathological characteristics observed in total thyroidectomy products from patients previously diagnosed with Graves' disease. Furthermore, these data were related to composition of lymphocytic infiltrate in terms of proportions of lymphocytes CD4+, CD8+, CD25+ and CD20+. We aim to contribute to the understanding of the evolution pattern of GD, whose pathophysiology is not yet completely understood. METHODS: Cross-sectional study assessing thyroidectomy products for the presence of lymphocytic infiltrate, as well as the proportion and intensity of CD4+, CD8+, CD25+ and CD20+ markers. We selected 50 patients who underwent total or partial thyroidectomy in a tertiary service between 1996 and 2013 due to GD with histopathological confirmation. The control group (non-autoimmune disease group) consisted of 12 patients with histopathological data compatible with normal perilesional thyroid parenchyma. The intensity of lymphocytic infiltrate and immunohistochemical expression of the markers CD4+ (helper T lymphocytes), CD8+ (cytotoxic T lymphocytes), CD25+ (regulatory T lymphocytes) and CD20+ (B lymphocytes) were retrospectively evaluated and relationship with ultrasound, laboratory and clinical data was assessed. RESULTS: No differences were found in intensity, presence of lymphoid follicles, and expression of CD4+/CD8+/CD25+ in patients with GD who did or did not use ATD or iodide. In the group that did not use ATD, a higher proportion of CD20+ expression was found. The GD group was associated with hyperplastic epithelium and the control group was associated with simple epithelium. There was no difference in ultrasound thyroid volume between the groups. In GD patients with mild lymphocytic infiltrate, higher free thyroxin (FT4) levels were observed than those in patients with no infiltrate or moderate infiltrate. CONCLUSION: We found a lower proportion of intrathyroidal CD20+ B lymphocytes in patients under use of methimazole. However, no difference was observed in intrathyroidal lymphocyte subpopulations related to the short-term use of iodide. The understanding of thyroid autoimmunity, as well as identifying points of pharmacological modulation, are very important for advancement and improvement in treatments for these diseases.
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Antígenos CD20 , Enfermedad de Graves , Metimazol , Glándula Tiroides , Humanos , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/patología , Enfermedad de Graves/inmunología , Metimazol/uso terapéutico , Metimazol/farmacología , Femenino , Masculino , Glándula Tiroides/patología , Glándula Tiroides/metabolismo , Glándula Tiroides/efectos de los fármacos , Adulto , Persona de Mediana Edad , Antígenos CD20/metabolismo , Yoduros/metabolismo , Estudios Transversales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/efectos de los fármacos , Antitiroideos/farmacología , Antitiroideos/uso terapéutico , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/metabolismo , Subgrupos Linfocitarios/inmunología , Tiroidectomía , AncianoRESUMEN
INTRODUCTION: Iodide is an essential micronutrient for the synthesis of thyroid hormones and its imbalance is involved in the origin of different thyroid pathological processes. Selenium (Se) is another essential trace element that contributes to thyroid preservation through the control of the redox homeostasis. Different studies have demonstrated that sodium-iodide-symporter (NIS) is downregulated in the presence of iodide excess and Se supplementation reverses this effect. We also demonstrated that NOX4-derived ROS are involved in NIS repression induced by iodide excess. The aim of this study was to investigate how Se bioavailability is decisive in the sensitivity to iodide excess on a differentiated rat thyroid cell line (FRTL-5). RESULTS: We demonstrated that siRNA-mediated silencing of Nox4 suppressed AKT phosphorylation induced by iodide excess. Iodide increases TGF-ß1 mRNA expression, AKT phosphorylation, ROS levels and decreases GPX1 and TXRND1 mRNAs expression while Se reversed these effects. Furthermore, iodide induced Nrf2 transcriptional activity only in Se-supplemented cultures, suggesting that Se positively influences Nrf2 activation and selenoenzyme response in FRTL-5. Se, also inhibited NF-κB phosphorylation induced by iodide excess. In addition, we found that iodide excess decreased total phosphatase activity and PTP1B and PTEN mRNA expression. Se supply restored only PTEN mRNA expression. Finally, we studied the 2-α-iodohexadecanal (2-IHD) effects since it has been proposed as intermediary of iodide action on thyroid autoregulation. 2-IHD stimulated PI3K/AKT activity and reduced NIS expression by a ROS-independent mechanism. Also, we found that 2-IHD increased TGF-ß1 mRNA and TGF-ß inhibitor (SB431542) reverses the 2-IHD inhibitory effect on NIS mRNA expression, suggesting that TGF-ß1 signaling pathway could be involved. Although Se reduced 2-IHD-induced TGFB1 levels, it could not reverse its inhibitory effect on NIS expression. CONCLUSION: Our study suggests that Se bioavailability may improve the expression of antioxidant genes through the activation of Nrf2, interfere in PI3K/AKT signaling and NIS expression by redox modulation.
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Selenio , Glándula Tiroides , Ratas , Animales , Glándula Tiroides/metabolismo , Yoduros/metabolismo , Selenio/farmacología , Selenio/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Disponibilidad Biológica , Fosfatidilinositol 3-Quinasas/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Objective: The aim of this study was to investigate how polarized sodium iodide symporter (NIS) expression may regulate iodide metabolism in vivo. Materials and methods: Polarized NIS expression was analyzed in tissues that accumulate iodide by the use of immunohistochemistry and polyclonal antibody against the C-terminal end of human NIS (hNIS). Results: Iodide absorption in the human intestine occurs via NIS expressed in the apical membrane. Iodide is secreted into the lumen of the stomach and salivary glands via NIS expressed in the basolateral membrane and then circulates back from the small intestine to the bloodstream via NIS expressed in the apical membrane. Conclusion: Polarized NIS expression in the human body regulates intestinal-bloodstream recirculation of iodide, perhaps prolonging the availability of iodide in the bloodstream. This leads to more efficient iodide trapping by the thyroid gland. Understanding the regulation and manipulating gastrointestinal iodide recirculation could increase radioiodine availability during theranostic NIS applications.
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Yodo , Simportadores , Humanos , Yoduros/metabolismo , Radioisótopos de Yodo , Cuerpo Humano , Simportadores/metabolismoRESUMEN
Thyroid disruptors are found in food, atmosphere, soil, and water. These contaminants interfere with the thyroid function through the impairment of thyroid hormone synthesis, plasma transport, peripheral metabolism, transport into the target cells, and thyroid hormone action. It is well known that iodide uptake mediated by the sodium-iodide symporter (NIS) is the first limiting step involved in thyroid hormones production. Therefore, it has been described that several thyroid disruptors interfere with the thyroid function through the regulation of NIS expression and/or activity. Perchlorate, nitrate, and thiocyanate competitively inhibit the NIS-mediated iodide uptake. These contaminants are mainly found in food, water and in the smoke of cigarettes. Although the impact of the human exposure to these anions is highly controversial, some studies indicated their deleterious effects in the thyroid function, especially in individuals living in iodine deficient areas. Considering the critical role of thyroid function and the production of thyroid hormones for growth, metabolism, and development, this review summarizes the impact of the exposure to these NIS-inhibitors on thyroid function and their consequences for human health.
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Contaminantes Ambientales , Percloratos , Humanos , Percloratos/toxicidad , Percloratos/metabolismo , Tiocianatos/metabolismo , Tiocianatos/farmacología , Nitratos/metabolismo , Nitratos/farmacología , Glándula Tiroides/metabolismo , Contaminantes Ambientales/metabolismo , Yoduros/metabolismo , Yoduros/farmacología , Hormonas Tiroideas , Agua/metabolismoRESUMEN
In 40-50% of colorectal cancer (CRC) cases, K-Ras gene mutations occur, which induce the expression of the K-Ras4B oncogenic isoform. K-Ras4B is transported by phosphodiesterase-6δ (PDE6δ) to the plasma membrane, where the K-Ras4B-PDE6δ complex dissociates and K-Ras4B, coupled to the plasma membrane, activates signaling pathways that favor cancer aggressiveness. Thus, the inhibition of the K-Ras4B-PDE6δ dissociation using specific small molecules could be a new strategy for the treatment of patients with CRC. This research aimed to perform a preclinical proof-of-concept and a therapeutic potential evaluation of the synthetic I-C19 and 131I-C19 compounds as inhibitors of the K-Ras4B-PDE6δ dissociation. Molecular docking and molecular dynamics simulations were performed to estimate the binding affinity and the anchorage sites of I-C19 in K-Ras4B-PDE6δ. K-Ras4B signaling pathways were assessed in HCT116, LoVo and SW620 colorectal cancer cells after I-C19 treatment. Two murine colorectal cancer models were used to evaluate the I-C19 therapeutic effect. The in vivo biokinetic profiles of I-C19 and 131I-C19 and the tumor radiation dose were also estimated. The K-Ras4B-PDE6δ stabilizer, 131I-C19, was highly selective and demonstrated a cytotoxic effect ten times greater than unlabeled I-C19. I-C19 prevented K-Ras4B activation and decreased its dependent signaling pathways. The in vivo administration of I-C19 (30 mg/kg) greatly reduced tumor growth in colorectal cancer. The biokinetic profile showed renal and hepatobiliary elimination, and the highest radiation absorbed dose was delivered to the tumor (52 Gy/74 MBq). The data support the idea that 131I-C19 is a novel K-Ras4B/PDE6δ stabilizer with two functionalities: as a K-Ras4B signaling inhibitor and as a compound with radiotherapeutic activity against colorectal tumors.
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Antineoplásicos , Neoplasias Colorrectales , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Yoduros , Radioisótopos de Yodo , Ratones , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Thyroid peroxidase (TPO) is a membrane-bound glycoprotein located at the apical side of the thyroid follicular cells that catalyzes both iodination and coupling of iodotyrosine residues within the thyroglobulin molecule, leading to the synthesis of thyroid hormone. Variants in TPO cause congenital hypothyroidism (CH) by iodide organification defect and are commonly inherited in an autosomal recessive fashion. In the present work, we report a detailed population analysis and bioinformatic prediction of the TPO variants indexed in the Genome Aggregation Database (gnomAD) v2.1.1. The proportion of missense cysteine variants and nonsense, frameshift, and splice acceptor/donor variants were analyzed in each ethnic group (European (Non-Finnish), European (Finnish), African/African Americans, Latino/Admixed American, East Asian, South Asian, Ashkenazi Jewish, Other). The results showed a clear predominance of frameshift variants in the East Asian (82%) and European (Finnish) (75%) population, whereas the splice site variants predominate in African/African Americans (99.46%), Other (96%), Latino/Admixed American (94%), South Asian (86%), European (Non-Finnish) (56%) and Ashkenazi Jewish (56%) populations. The analysis of the distribution of the variants indexed in gnomAD v2.1.1 database revealed that most missense variants identified in the An peroxidase domain map in exon 8, followed by exons 11, 7 and 9, and finally in descending order by exons 10, 6, 12 and 5. In total, 183 novel TPO variants were described (13 missense cysteine's variants, 158 missense variants involving the An peroxidase domain and 12 splicing acceptor or donor sites variants) which were not reported in the literature and that would have deleterious effects on prediction programs. In the gnomAD v2.1.1 population, the estimated prevalence of heterozygous carriers of the potentially damaging variants was 1:77. In conclusion, we provide an updated and curated reference source of new TPO variants for application in clinical diagnosis and genetic counseling. Also, this work contributes to elucidating the molecular basis of CH associated with TPO defects.
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Hipotiroidismo Congénito , Tiroglobulina , Humanos , Tiroglobulina/genética , Yoduro Peroxidasa/genética , Monoyodotirosina/genética , Yoduros , Biología Computacional , Cisteína , Hipotiroidismo Congénito/genética , Hormonas Tiroideas , Mutación/genética , Peroxidasas/genética , AlgoritmosRESUMEN
Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding SLC5A5 gene and leading to dyshormonogenic congenital hypothyroidism. Here, we conducted a targeted next-generation sequencing assessment of congenital hypothyroidism-causative genes in a cohort of nine unrelated pediatric patients suspected of having a congenital iodide transport defect based on the absence of 99mTc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic SLC5A5 gene variants, we identified two novel compound heterozygous TG gene variants (p.Q29* and c.177-2A>C), three novel heterozygous TG gene variants (p.F1542Vfs*20, p.Y2563C, and p.S523P), and a novel heterozygous DUOX2 gene variant (p.E1496Dfs*51). Splicing minigene reporter-based in vitro assays revealed that the variant c.177-2A>C affected normal TG pre-mRNA splicing, leading to the frameshift variant p.T59Sfs*17. The frameshift TG variants p.T59Sfs*17 and p.F1542Vfs*20, but not the DUOX2 variant p.E1496Dfs*51, were predicted to undergo nonsense-mediated decay. Moreover, functional in vitro expression assays revealed that the variant p.Y2563C reduced the secretion of the TG protein. Our investigation revealed unexpected findings regarding the genetics of congenital iodide transport defects, supporting the existence of yet to be discovered mechanisms involved in thyroid hormonogenesis.
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Hipotiroidismo Congénito , Tiroglobulina , Niño , Hipotiroidismo Congénito/genética , Oxidasas Duales/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Yoduros/metabolismo , Mutación , Tiroglobulina/genéticaRESUMEN
A simple and efficient one-pot, three-component synthetic method for the preparation of coumarin-3-carboxamides was carried out by the reaction of salicylaldehyde, aliphatic primary/secondary amines, and diethylmalonate. The protocol employs piperidine-iodine as a dual system catalyst and ethanol, a green solvent. The main advantages of this approach are that it is a metal-free and clean reaction, has low catalyst loading, and requires no tedious workup.
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Yodo , Aminas , Catálisis , Cumarinas , Yoduros , PiperidinasRESUMEN
Iodine(III) reagents have attracted chemical relvance in organic synthesis by their use as safe, non-toxic, green and easy to handle reagents in different transformations. These characteristics make them important alternatives to procedures involving hazardous and harsh reaction conditions. Their versatility as oxidants has been exploited in the functionalization of different aromatic cores, which allow the introduction of several groups. Metal-free arylation using iodine(III) reagents is by far one of the most described topics in the literature; however, other highly relevant non-aromatic groups have been also introduced. Herein, we summarize the most representative developed procedures for the functionalization of aryls and heteroaryls by introducing halogens, using different iodine(III) reagents.
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Yodo , Halogenación , Indicadores y Reactivos , Yoduros , Oxidación-Reducción , Estrés OxidativoRESUMEN
Tributyltin (TBT) is an endocrine disruptor used as a biocide in nautical paints. Even though many TBT effects in marine species are known, data in mammals are scarce, especially regarding the thyroid gland. The present study aimed to evaluate the effect of a subchronic exposure to TBT on thyroid oxidative stress of female Wistar rats. Rats received vehicle (control group), 200 or 1000 ng TBT/kg body weight/day for 40 days. After euthanasia, one part of the thyroids were collected in order to assess iodide uptake; activity and/or mRNA expression of thyroperoxidase (TPO) and dual oxidases (DUOXs); activity and/or mRNA expression of catalase, glutathione peroxidase, superoxide dismutase and NADPH oxidase 4 (CAT, GPx, SOD and NOX4); 4-hydroxynonenal (4-HNE) expression and total thiol groups levels; and mRNA expression of estrogen receptors alpha and beta (ERα and ERß). The remaining part of the thyroid was processed for morphological analysis of estrogen receptor alpha (ERα) and for collagen deposition. Iodide uptake was not changed with treatments. TPO activity and expression were increased in the TBT1000 group (259.81% and 95.17%). The activity, but not mRNA, of CAT (17.36% TBT200; 27.10% TBT1000) and GPx (29.24% TBT200; 28.97% TBT1000) were decreased by TBT. SOD and NADPH oxidase activity, as well as thiol group and 4-HNE levels remained unchanged. Interstitial collagen deposition increased in the TBT200 group (39.54%). The mRNA expression of ERα increased in TBT-treated rats (44.87% TBT200; 36.43% TBT1000), while protein expression was increased but not reaching significance (TBT1000, p = 0.056) by TBT. Therefore, our results show that TBT increases TPO expression and reduces antioxidant enzyme activities in the thyroid gland leading to oxidative stress. Some of these effects could be mediated by the ERα pathway.
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Disruptores Endocrinos , Compuestos de Trialquiltina , Animales , Colágeno/metabolismo , Disruptores Endocrinos/toxicidad , Receptor alfa de Estrógeno/metabolismo , Femenino , Yoduros/metabolismo , Mamíferos/metabolismo , Oxidación-Reducción , Ratas , Ratas Wistar , Compuestos de Sulfhidrilo/metabolismo , Superóxido Dismutasa/metabolismo , Glándula Tiroides/metabolismo , Compuestos de Trialquiltina/toxicidadRESUMEN
Radioiodine therapy (RAI) is a standard and effective therapeutic approach for differentiated thyroid cancers (DTCs) based on the unique capacity for iodide uptake and accumulation of the thyroid gland through the Na+/I- symporter (NIS). However, around 5-15% of DTC patients may become refractory to radioiodine, which is associated with a worse prognosis. The loss of RAI avidity due to thyroid cancers is attributed to cell dedifferentiation, resulting in NIS repression by transcriptional and post-transcriptional mechanisms. Targeting the signaling pathways potentially involved in this process to induce de novo iodide uptake in refractory tumors is the rationale of "redifferentiation strategies". Oxidative stress (OS) results from the imbalance between ROS production and depuration that favors a pro-oxidative environment, resulting from increased ROS production, decreased antioxidant defenses, or both. NIS expression and function are regulated by the cellular redox state in cancer and non-cancer contexts. In addition, OS has been implicated in thyroid tumorigenesis and thyroid cancer cell dedifferentiation. Here, we review the main aspects of redox homeostasis in thyrocytes and discuss potential ROS-dependent mechanisms involved in NIS repression in thyroid cancer.
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Simportadores , Neoplasias de la Tiroides , Homeostasis , Humanos , Yoduros/metabolismo , Radioisótopos de Yodo/uso terapéutico , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo , Simportadores/genética , Simportadores/metabolismo , Neoplasias de la Tiroides/patologíaRESUMEN
Background: Congenital iodide transport defect (ITD) is an uncommon cause of dyshormonogenic congenital hypothyroidism characterized by the absence of active iodide accumulation in the thyroid gland. ITD is an autosomal recessive disorder caused by loss-of-function variants in the sodium/iodide symporter (NIS)-coding SLC5A5 gene. Objective: We aimed to identify, and if so to functionally characterize, novel ITD-causing SLC5A5 gene variants in a cohort of five unrelated pediatric patients diagnosed with dyshormonogenic congenital hypothyroidism with minimal to absent 99mTc-pertechnetate accumulation in the thyroid gland. Methods: The coding region of the SLC5A5 gene was sequenced using Sanger sequencing. In silico analysis and functional in vitro characterization of a novel synonymous variant were performed. Results: Sanger sequencing revealed a novel homozygous synonymous SLC5A5 gene variant (c.1326A>C in exon 11). In silico analysis revealed that the c.1326A>C variant is potentially deleterious for NIS pre-mRNA splicing. The c.1326A>C variant was predicted to lie within a putative exonic splicing enhancer reducing the binding of splicing regulatory trans-acting protein SRSF5. Splicing minigene reporter assay revealed that c.1326A>C causes exon 11 or exon 11 and 12 skipping during NIS pre-mRNA splicing leading to the NIS pathogenic variants p.G415_P443del and p.G415Lfs*32, respectively. Significantly, the frameshift variant p.G415Lfs*32 is predicted to be subjected to degradation by nonsense-mediated decay. Conclusions: We identified the first exonic synonymous SLC5A5 gene variant causing aberrant NIS pre-mRNA splicing, thus expanding the mutational landscape of the SLC5A5 gene leading to dyshormonogenic congenital hypothyroidism.
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Hipotiroidismo Congénito , Simportadores , Niño , Hipotiroidismo Congénito/genética , Exones , Humanos , Yoduros/metabolismo , Precursores del ARN , Simportadores/genéticaRESUMEN
Organoselenyl iodide promoted the intramolecular nucleophilic cyclization of N-alkynyl ethylcarbamates in the synthesis of 4-(organoselenyl) oxazolones. The reaction was regioselective, giving the five-membered oxazolone products as the unique regioisomer via an initial activation of the carbon-carbon triple bond through a seleniranium intermediate, followed by an intramolecular 5-endo-dig cyclization mode. The generality of the methodology has been proven by applying the optimized reaction conditions to different organoselenyl iodides and N-alkynyl ethylcarbamates having different substituents directly bonded to the nitrogen atom and in the terminal position of the alkyne.
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Yoduros , Oxazolona , Carbono , Catálisis , Ciclización , Estructura Molecular , Oxazolona/químicaRESUMEN
The Amazon rainforest is a heterogeneous ecosystem and its soils exhibit geographically variable concentrations of trace elements. In this region, anthropic activities - e.g., agriculture and mining - are numerous and varied, and even natural areas are at risk of contamination by trace elements, either of geogenic or anthropogenic origin. A reliable dataset of benchmark values for selenium (Se), barium (Ba), and iodine (I) concentrations in soils is needed for use as a reference in research and public policies in the region. In this study, 9 selected sites in the Brazilian Amazon rainforest within areas represented by Oxisols and Ultisols were assessed for relevant soil physicochemical characteristics, along with the concentrations of total Se (SeTot), total Ba (BaTot), and sequentially-extracted soluble Se (SeSol) and adsorbed Se (SeAd) in 3 different soil layers (0-20, 20-40, and 40-60 cm). In addition, organically bound-Se (SeOrg) and total I (ITot) concentrations in the surface layer (0-20 cm) were measured. Soil Se concentrations (SeTot) were considered safe and are likely a result of contributions of sedimentary deposits from the Andes. Available Se (SeSol + SeAd) accounted for 4.5% of SeTot, on average, while SeOrg in the topsoil accounted for more than 50% of SeTot. Barium in the western Amazon (state of Acre) and central Amazon (Anori, state of Amazonas) exceeded national prevention levels (PVs). Furthermore, the average ITot in the studied topsoils (5.4 mg kg-1) surpassed the worldwide mean. Notwithstanding, the close relationship found between the total content of the elements (Se, Ba, and I) and soil texture (clay, silt, and sand) suggests their geogenic source. Finally, our data regarding SeTot, BaTot, and ITot can be used to derive regional quality reference values for Amazon soils and also for updating prevention (PV) and investigation (IV) values established for selected elements by the Brazilian legislation.
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Yodo , Selenio , Contaminantes del Suelo , Oligoelementos , Bario , Brasil , Ecosistema , Monitoreo del Ambiente , Yoduros , Bosque Lluvioso , Selenio/análisis , Suelo/química , Contaminantes del Suelo/análisisRESUMEN
The Rose Bengal-photocatalyzed perfluorohexylation of olefins, alkynes, and electron-rich aromatic compounds in water was achieved employing perfluorohexyl iodide as fluoroalkyl source and TMEDA as sacrificial donor under green LED irradiation. Alkenes and alkynes rendered products derived from the atom transfer radical addition (ATRA) pathway, and in the case of alkynes, exclusively as E-stereoisomers. These are the first examples of photocatalyzed ATRA reactions carried out excursively in water alone. The reactions of aromatic compounds under the current protocol in water present the advantage of employing a perfluoroalkyl iodide (C6F13-I) as source of perfluorohexyl radicals. Examples of photocatalytic late-stage incorporations of fluoroalkyl moieties into two commercial drugs of widespread use are reported.
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Rosa Bengala , Agua , Alquenos/química , Alquinos/química , Yoduros , Estructura MolecularRESUMEN
CONTEXT: Iodide transport defect (ITD) (Online Mendelian Inheritance in Man No. 274400) is an uncommon cause of dyshormonogenic congenital hypothyroidism due to loss-of-function variants in the SLC5A5 gene, which encodes the sodium/iodide symporter (NIS), causing deficient iodide accumulation in thyroid follicular cells. OBJECTIVE: This work aims to determine the molecular basis of a patient's ITD clinical phenotype. METHODS: The propositus was diagnosed with dyshormonogenic congenital hypothyroidism with minimal 99mTc-pertechnetate accumulation in a eutopic thyroid gland. The propositus SLC5A5 gene was sequenced. Functional in vitro characterization of the novel NIS variant was performed. RESULTS: Sanger sequencing revealed a novel homozygous missense p.G561E NIS variant. Mechanistically, the G561E substitution reduces iodide uptake, because targeting of G561E NIS to the plasma membrane is reduced. Biochemical analyses revealed that G561E impairs the recognition of an adjacent tryptophan-acidic motif by the kinesin-1 subunit kinesin light chain 2 (KLC2), interfering with NIS maturation beyond the endoplasmic reticulum, and reducing iodide accumulation. Structural bioinformatic analysis suggests that G561E shifts the equilibrium of the unstructured tryptophan-acidic motif toward a more structured conformation unrecognizable to KLC2. Consistently, knockdown of Klc2 causes defective NIS maturation and consequently decreases iodide accumulation in rat thyroid cells. Morpholino knockdown of klc2 reduces thyroid hormone synthesis in zebrafish larvae leading to a hypothyroid state as revealed by expression profiling of key genes related to the hypothalamic-pituitary-thyroid axis. CONCLUSION: We report a novel NIS pathogenic variant associated with dyshormonogenic congenital hypothyroidism. Detailed molecular characterization of G561E NIS uncovered the significance of KLC2 in thyroid physiology.
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Hipotiroidismo Congénito/genética , Errores Innatos del Metabolismo/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Simportadores/genética , Hormonas Tiroideas/metabolismo , Animales , Humanos , Recién Nacido , Yoduros/metabolismo , Cinesinas , Masculino , Mutación Missense , Fenotipo , Ratas , Glándula Tiroides/metabolismoRESUMEN
The spreading of different infections can occur through direct contact with glass surfaces in commonly used areas. Incorporating the use of alternative therapies in these materials seems essential to reduce and also avoid bacterial resistance. In this work, the capability to kill microbes of glass surfaces coated with two electroactive metalated phthalocyanines (ZnPc-EDOT and CuPc-EDOT) is assessed. The results show that both of these materials are capable of producing reactive oxygen species; however, the polymer with Zn(II) (ZnPc-PEDOT) has a singlet oxygen quantum yield 8-fold higher than that of the Cu(II) containing analogue. This was reflected in the in vitro experiments where the effectiveness of the surfaces was tested in bacterial suspensions, monitoring single microbe inactivation upon attachment to the polymers, and eliminating mature biofilms. Furthermore, we evaluated the use of an inorganic salt (KI) to potentiate the photodynamic inactivation mediated by an electropolymerized surface. The addition of the salt improved the efficiency of phototherapy at least two times for both polymers; nevertheless, the material coated with ZnPc-PEDOT was the only one capable of eliminating >99.98% of the initial microbes loading under different circumstances.
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Antiinfecciosos , Yodo , Yoduros , Fármacos Fotosensibilizantes/farmacología , Polímeros/farmacología , Oxígeno SingleteRESUMEN
BACKGROUND: Esophageal cancer is the eighth most common cancer. The prognosis is bleak in patients with advanced stages. Patients with early disease have a better prognosis than those with advanced stage. There are several techniques for the screening of premalignant and superficial lesions including chromoendoscopy. OBJECTIVE: This article aimed to determine the effectiveness of chromoendoscopy with toluidine blue combined with Lugol's solution for diagnosis of esophageal premalignant and superficial neoplastic lesions in high risk patients. METHODS: Routine white light upper endoscopy was performed. Toluidine blue was sprayed from the gastroesophageal junction to 20 cm of the dental arch. Then the uptake dye areas were characterized. Later Lugol's solution was sprayed. Areas with less-intense staining were characterized. Biopsy of the toluidine blue capturing areas and areas with less-intense staining of Lugol's solution were taken. In the cases where lesions were not evidenced after application of dyes, biopsies four quadrants of the esophageal mucosa were taken. The samples were evaluated by a digestive pathologist. RESULTS: Barrett's esophagus was the most common premalignant lesion and the early neoplastic lesion was adenocarcinoma with a sensitivity of 100%, specificity 85.7%, positive predictive value 30%, negative predictive value 100%, positive likelihood ratio 7 negative likelihood ratio 0. CONCLUSION: Chromoendoscopy with toluidine blue combined with Lugol's solution is a useful tool in the screening of esophageal premalignant lesions and superficial neoplasms.
Asunto(s)
Detección Precoz del Cáncer/métodos , Neoplasias Esofágicas/diagnóstico por imagen , Esofagoscopía/métodos , Lesiones Precancerosas/diagnóstico por imagen , Adulto , Esófago de Barrett/diagnóstico por imagen , Esófago de Barrett/patología , Colorantes/administración & dosificación , Estudios Transversales , Mucosa Esofágica/diagnóstico por imagen , Mucosa Esofágica/patología , Esofagitis Péptica/diagnóstico por imagen , Femenino , Humanos , Yoduros/administración & dosificación , Masculino , Persona de Mediana Edad , Lesiones Precancerosas/patología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Sensibilidad y Especificidad , Cloruro de Tolonio/administración & dosificaciónRESUMEN
INTRODUCTION: Direct visual inspection for cervical cancer screening remains controversial, whereas colposcopy-biopsy is considered the gold standard for diagnosis of preneoplastic cervical lesions. OBJECTIVES: To determine the rates of cervical intraepithelial neoplasia grade 2 or more and of false positives for colposcopy and direct visual inspection. MATERIALS AND METHODS: Women aged 25-59 underwent direct visual inspection with acetic acid (VIA), Lugol's iodine (VIA-VILI), and colposcopy. Punch biopsies were obtained for all positive tests. Using histology as the gold standard, detection and false positive rates were compared for VIA, VIA-VILI, and colposcopy (two thresholds). Sensitivity and false positive ratios with the corresponding 95% confidence intervals were estimated. RESULTS: We included 5,011 women in the analysis and we obtained 602 biopsies. Positivity rates for colposcopy high-grade and low-grade diagnosis were 1.6% and 10.8%. Positivity rates for VIA and VIA-VILI were 7.4% and 9.9%. VIA showed a significantly lower detection rate than colposcopy with low-grade diagnosis as the threshold (SR=0.72; 95% CI 0.57-0.91), and significantly lower false positive rate (FPR=0.70; 95% CI 0.65-0.76). No differences between VIA-VILI and colposcopy low-grade threshold were observed. VIA and VIA-VILI showed significantly higher detection and false positive rates than colposcopy high-grade threshold. Sensitivity rates for visual inspection decreased with age and false positive rates increased. For all age groups, false positive rates for VIA and VIA-VILI were significantly higher than colposcopy. CONCLUSIONS: Detection rates for VIA-VILI similar to colposcopy low-grade threshold represent a chance to reduce cervical cancer mortality through see-and-treat approaches among women with limited access to health care. Lower detection rates suggest reviewing high-grade colposcopy findings as the threshold for biopsy in certain settings.
Introducción. La inspección visual directa para la tamización del cáncer cervical sigue siendo controversial, mientras que la colposcopia y la biopsia siguen considerándose como métodos de referencia para diagnosticar lesiones cervicales precancerosas. Objetivo. Determinar las tasas de detección de neoplasia intraepitelial cervical de grado 2 y de los falsos positivos en la colposcopia y la inspección visual directa. Materiales y métodos. Se seleccionaron mujeres de 25 a 59 años sometidas a citología convencional, inspección visual directa con ácido acético y disolución de Lugol y colposcopia. Se practicó biopsia en todas las pruebas positivas. Utilizando la histología como el medio de verificación de referencia, se compararon las tasas de detección y de falsos positivos de cada prueba. Se estimaron las razones de sensibilidad y de falsos positivos con los correspondientes intervalos de confianza. Resultados. Se incluyeron 5.011 mujeres. Las colposcopias positivas de alto y bajo grado correspondieron a 1,6 y 10,8 %, respectivamente. La inspección visual directa con ácido acético y solución yodada de Lugol fue positiva en 7,4 y 9,9 %, respectivamente. La inspección visual directa con ácido acético tuvo tasas de detección y falsos positivos significativamente menores que la coloscopia con umbral de bajo grado (razón de sensibilidad: 0,72; IC95% 0,57-0,91; razón de falsos positivos: 0,70; CI95% 0,65-0,76); no hubo diferencias entre la inspección visual directa con solución yodada de Lugol y la colposcopia con dicho umbral. Las tasas de detección y de falsos positivos de los dos tipos de inspección visual fueron significativamente más altas que las de la colposcopia con el umbral de alto grado. Las tasas de detección de la inspección visual disminuyeron con la edad y las de falsos positivos aumentaron. Conclusiones: Las tasas de detección similares para la inspección visual directa con ácido acético o con solución yodada de Lugol y la colposcopia con umbral de bajo grado representan una oportunidad para reducir la mortalidad por cáncer de cuello uterino cuando el acceso a los servicios de salud es limitado. Las tasas de detección más bajas para la colposcopia con umbral de alto grado sugieren la necesidad de revisar dicho umbral en ciertos entornos.
Asunto(s)
Detección Precoz del Cáncer/métodos , Displasia del Cuello del Útero/patología , Neoplasias del Cuello Uterino/patología , Ácido Acético , Adulto , Biopsia , Colombia , Colposcopía , Reacciones Falso Positivas , Femenino , Humanos , Yoduros , Persona de Mediana EdadRESUMEN
ABSTRACT BACKGROUND: Esophageal cancer is the eighth most common cancer. The prognosis is bleak in patients with advanced stages. Patients with early disease have a better prognosis than those with advanced stage. There are several techniques for the screening of premalignant and superficial lesions including chromoendoscopy. OBJECTIVE: This article aimed to determine the effectiveness of chromoendoscopy with toluidine blue combined with Lugol's solution for diagnosis of esophageal premalignant and superficial neoplastic lesions in high risk patients. METHODS: Routine white light upper endoscopy was performed. Toluidine blue was sprayed from the gastroesophageal junction to 20 cm of the dental arch. Then the uptake dye areas were characterized. Later Lugol's solution was sprayed. Areas with less-intense staining were characterized. Biopsy of the toluidine blue capturing areas and areas with less-intense staining of Lugol's solution were taken. In the cases where lesions were not evidenced after application of dyes, biopsies four quadrants of the esophageal mucosa were taken. The samples were evaluated by a digestive pathologist. RESULTS: Barrett's esophagus was the most common premalignant lesion and the early neoplastic lesion was adenocarcinoma with a sensitivity of 100%, specificity 85.7%, positive predictive value 30%, negative predictive value 100%, positive likelihood ratio 7 negative likelihood ratio 0. CONCLUSION: Chromoendoscopy with toluidine blue combined with Lugol's solution is a useful tool in the screening of esophageal premalignant lesions and superficial neoplasms.
RESUMO CONTEXTO: O câncer de esôfago é o oitavo câncer mais comum. O prognóstico é sombrio em pacientes com estágios avançados. Pacientes com doença precoce têm um melhor prognóstico do que aqueles com estágio avançado. Existem várias técnicas para a triagem de lesões pré-malignas e superficiais, incluindo cromoendoscopia. OBJETIVO: Este artigo objetivou determinar a efetividade da cromoendoscopia com azul de toluidina combinada com a solução de Lugol para o diagnóstico de lesões neoplásicas pré-malignas e superficiais esofágicas em pacientes de alto risco. MÉTODOS - A endoscopia de luz branca de rotina foi realizada de forma rotineira. O azul do toluidina foi pulverizado desde a junção gastroesofágica até 20 cm da arcada dentária. As áreas impregnadas pela tintura da tomada foram então caracterizadas. Mais adiante a solução de Lugol foi pulverizada. Áreas com coloração menos intensa foram caracterizadas. Foram realizadas biópsias das áreas de captura de azul de toluidina e áreas com coloração menos intensa da solução de Lugol. Nos casos onde as lesões não foram evidenciadas após a aplicação das tinturas, foram feitas biópsias em quatro quadrantes da mucosa esofágica. As amostras foram avaliadas por um patologista especializado. RESULTADOS: O esôfago de Barrett foi a lesão pré-maligna mais frequente e a lesão neoplásica precoce foi adenocarcinoma com sensibilidade de 100%, especificidade de 85,7%, valor preditivo positivo de 30%, valor preditivo negativo 100%, razão de verossimilhança positiva 7 e razão de verossimilhança negativa 0. CONCLUSÃO: A cromoendoscopia com azul de toluidina combinada com a solução de Lugol é uma ferramenta útil na triagem de lesões pré-malignas esofágicas e neoplasias superficiais.