RESUMEN
CONTEXT: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. OBJECTIVE: Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. METHODS: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. RESULTS: From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. CONCLUSIONS: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.
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Discapacidad Intelectual Ligada al Cromosoma X/tratamiento farmacológico , Transportadores de Ácidos Monocarboxílicos/deficiencia , Hipotonía Muscular/tratamiento farmacológico , Atrofia Muscular/tratamiento farmacológico , Simportadores/deficiencia , Triyodotironina/análogos & derivados , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/sangre , Discapacidad Intelectual Ligada al Cromosoma X/genética , Persona de Mediana Edad , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonía Muscular/sangre , Hipotonía Muscular/genética , Atrofia Muscular/sangre , Atrofia Muscular/genética , Mutación , Estudios Retrospectivos , Simportadores/genética , Resultado del Tratamiento , Triyodotironina/administración & dosificación , Triyodotironina/efectos adversos , Triyodotironina/sangre , Adulto JovenRESUMEN
Flavonoids target a variety of pathophysiological mechanisms and are therefore increasingly considered as compounds encompassed with therapeutic potentials in diseases such as cancer, diabetes, arteriosclerosis, and neurodegenerative diseases and mood disorders. Hops (Humulus lupulus L.) is rich in flavonoids such as the flavanone 8-prenylnaringenin, which is the most potent phytoestrogen identified so far, and the prenylchalcone xanthohumol, which has potent tumor-preventive, anti-inflammatory and antiviral activities. In the present study, we questioned whether hops-derived prenylflavonoids and synthetic derivatives thereof act on neuronal precursor cells and neuronal cell lines to induce neuronal differentiation, neurite outgrowth and neuroprotection. Therefore, mouse embryonic forebrain-derived neural precursors and Neuro2a neuroblastoma-derived cells were stimulated with the prenylflavonoids of interest, and their potential to activate the promoter of the neuronal fate-specific doublecortin gene and to stimulate neuronal differentiation and neurite outgrowth was analyzed. In this screening, we identified highly "neuroactive" compounds, which we termed "enhancement of neuronal differentiation factors" (ENDFs). The most potent molecule, ENDF1, was demonstrated to promote neuronal differentiation of neural stem cells and neurite outgrowth of cultured dorsal root ganglion neurons and protected neuronal PC12 cells from cobalt chloride-induced as well as cholinergic neurons of the nucleus basalis of Meynert from deafferentation-induced cell death. The results indicate that hops-derived prenylflavonoids such as ENDFs might be powerful molecules to promote neurogenesis, neuroregeneration and neuroprotection in cases of chronic neurodegenerative diseases, acute brain and spinal cord lesion and age-associated cognitive impairments.
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Diferenciación Celular/efectos de los fármacos , Cromanos/farmacología , Flavonoides/farmacología , Células-Madre Neurales/efectos de los fármacos , Neuritas/fisiología , Neurogénesis , Animales , Muerte Celular/efectos de los fármacos , Línea Celular , Embrión de Pollo , Cobalto/toxicidad , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Flavanonas/farmacología , Ganglios Espinales/citología , Ganglios Espinales/efectos de los fármacos , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Neuropéptidos/metabolismo , Células PC12 , Propiofenonas/farmacología , Ratas , Células Tumorales CultivadasRESUMEN
Olive mill wastewater (OMW) contains a substantial amount of valuable antioxidant phenols that can be recovered for industrial application as food additives and pharmaceuticals. The present study was aimed at extracting different phenolic OMW fractions, and determining their antioxidant potential. Five different OMW fractions were obtained using fractionation techniques, their antioxidant potential determined by DPPH, ORAC and a ß-carotene bleaching test. The total phenol level ranged between 115 and 170 mg/l. The phenolic compounds present in individual fractions were identified using the HPLC-PAD method, where the main compounds were hydroxytyrosol, tyrosol, caffeic acid, vanillic acid, verbascoside, oleuropein, ferulic acid, and p-coumaric acid. The five OMW fractions showed different antioxidant levels depending on the test used. DPPH test showed that the fraction of alkyl aromatic alcohols (AAAs) was the best with EC(50) of 20 mg/l and the pure hydroxytyrosol with 2 mg/l. ORAC test showed that AAA and semi hydrolysed total phenol (s-TP) fractions were significantly better than Trolox when compared to 20 mg/l of Trolox.
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Antioxidantes/análisis , Residuos Industriales/análisis , Olea/química , Fenoles/análisis , Aguas Residuales/análisis , Cromatografía Líquida de Alta PresiónRESUMEN
The multichromophoric dyads 1, 2 and triad 3 have been synthesized by coupling of the appropriately functionalized chlorin derivative with naphthalene diimide dyes through esterification, and subsequent metalation of the chlorin center with zinc acetate. The self-assembly properties of naphthalene diimide (NDI)-zinc chlorin (ZnChl) dyads 1, 2 and triad 3 have been studied in nonpolar, aprotic solvents by UV-vis, CD, and steady-state emission spectroscopy, revealing formation of rod-like structures by noncovalent interactions of zinc chlorin units, while the appended naphthalene diimide dyes do not aggregate at the periphery of the rod antennae. In all these systems, photoexcitation of the enveloping naphthalene diimides at 540 and 620 nm, respectively, leads to highly efficient energy-transfer processes (FRET; phiET > or = 0.99) to the inner zinc chlorin backbone, as explored by time-resolved fluorescence spectroscopy on the picosecond time scale. The efficiencies of zinc chlorin rod aggregates for the harvesting of solar light are markedly increased from 26% for dyad 2 up to 63% for triad 3, compared to the LH capacity of the monochromophoric aggregates of model system ZnChl 6a. Thus, with the self-assembled zinc chlorin rod antenna based on triad 3, a highly efficient artificial LH system has been achieved.