Melatonin rescues zebrafish embryos from the parkinsonian phenotype restoring the parkin/PINK1/DJ-1/MUL1 network.

Multiple studies reporting mitochondrial impairment in Parkinson's disease (PD) involve knockout or knockdown models to inhibit the expression of mitochondrial-related genes, including parkin, PINK1, and DJ-1 ones. Melatonin has significant neuroprotective properties, which have been related to its ability to boost mitochondrial bioenergetics. The meaning and molecular targets of melatonin in PD are yet unclear. Zebrafish are an outstanding model of PD because they are vertebrates, their dopaminergic system is comparable to the nigrostriatal system of humans, and their brains express the same genes as mammals. The exposure of 24 hpf zebrafish embryos to MPTP leads to a significant inhibition of the mitochondrial complex I and the induction of sncga gene, responsible for enhancing γ-synuclein accumulation, which is related to mitochondrial dysfunction. Moreover, MPTP inhibited the parkin/PINK1/DJ-1 expression, impeding the normal function of the parkin/PINK1/DJ-1/MUL1 network to remove the damaged mitochondria. This situation remains over time, and removing MPTP from the treatment did not stop the neurodegenerative process. On the contrary, mitochondria become worse during the next 2 days without MPTP, and the embryos developed a severe motor impairment that cannot be rescued because the mitochondrial-related gene expression remained inhibited. Melatonin, added together with MPTP or added once MPTP was removed, prevented and recovered, respectively, the parkinsonian phenotype once it was established, restoring gene expression and normal function of the parkin/PINK1/DJ-1/MUL1 loop and also the normal motor activity of the embryos. The results show, for the first time, that melatonin restores brain function in zebrafish suffering with Parkinson-like disease.

Treatment of Plantar Warts with a Nitric-Zinc Complex Solution: A Review of 72 Cases.

BACKGROUND: There are multiple conservative treatment options for plantar warts, but none have proven to be universally effective. Nitric acid is often used empirically by podiatrists in the treatment of plantar warts. A novel medical device or topical solution of nitric-zinc complex solution (NZCS) could potentially offer an effective and safe alternative for the targeted treatment of plantar warts. OBJECTIVE: To observe the rate of complete healing of NZCS in a series of plantar wart cases and to establish the minimum number of product applications and time needed for healing. This will help standardize and protocolize its use. METHODS: A descriptive study was conducted involving 72 patients who exhibited symptoms of plantar warts. These patients underwent chemical treatment using a nitric-zinc complex. RESULTS: The cure rate with NZCS was 59.2%. The average number of NZCS applications was 5.9 ± 3.0 and the mean duration of treatment was 9.4 ± 7.1 weeks. A recurrence rate of 6.7% was observed. CONCLUSIONS: The topical solution of the nitric-zinc complex is an effective treatment for plantar warts, which can be considered a first-line treatment option in the general population.

Environment-Sensitive Probes for Illuminating Amyloid Aggregation In Vitro and in Zebrafish.

The aberrant aggregation of certain peptides and proteins, forming extracellular plaques of fibrillar material, is one of the hallmarks of amyloid diseases, such as Alzheimer's and Parkinson's. Herein, we have designed a new family of solvatochromic dyes based on the 9-amino-quinolimide moiety capable of reporting during the early stages of amyloid fibrillization. We have rationally improved the photophysical properties of quinolimides by placing diverse amino groups at the 9-position of the quinolimide core, leading to higher solvatochromic and fluorogenic character and higher lifetime dependence on the hydrophobicity of the environment, which represent excellent properties for the sensitive detection of prefibrillar aggregates. Among the different probes prepared, the 9-azetidinyl-quinolimide derivative showed striking performance in the following ß-amyloid peptide (Aß) aggregation in solution in real time and identifying the formation of different types of early oligomers of Aß, the most important species linked to cytotoxicity, using novel, multidimensional fluorescence microscopy, with one- or two-photon excitation. Interestingly, the new dye allowed the visualization of proteinaceous inclusion bodies in a zebrafish model with neuronal damage induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Our results support the potential of the novel fluorophores as powerful tools to follow amyloid aggregation using fluorescence microscopy in vivo, revealing heterogeneous populations of different types of aggregates and, more broadly, to study protein interactions.

In Vivo Determination of Mitochondrial Respiration in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Zebrafish Reveals the Efficacy of Melatonin in Restoring Mitochondrial Normalcy.

Although mitochondria dysfunction is related to multiple diseases, no in vivo studies are available on mitochondrial respiration in animal parkinsonian models. Our aim is to analyze in vivo mitochondrial respiration, which reflects changes in mitochondrial bioenergetics more precisely than in vitro mitochondrial preparations. These experiments can be carried out in zebrafish embryos, which were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) from 24 to 72 hours postfertilization (hpf). A reduction in electron transfer system capacity, ATP turnover, and increased proton leak were observed at 72 hpf in MPTP-treated embryos. These changes were followed by a significant oxidative stress due to inhibition in antioxidative defense and autophagy impairment. After removing MPTP from the treatment at 72 hpf, these bioenergetic deficiencies persisted up to 120 hpf. The administration of melatonin to zebrafish embryos at 72 hpf, when mitochondrial dysfunction is already present, restored the respiratory capacity and ATP production, reduced oxidative stress, and normalized autophagy after 48 h. Melatonin also counteracted mortality and embryonic malformations due to MPTP. Our results confirm for the first time the efficacy of melatonin in restoring parkinsonian phenotypes in animals.

Mitochondrial impairment and melatonin protection in parkinsonian mice do not depend of inducible or neuronal nitric oxide synthases.

MPTP-mouse model constitutes a well-known model of neuroinflammation and mitochondrial failure occurring in Parkinson's disease (PD). Although it has been extensively reported that nitric oxide (NO●) plays a key role in the pathogenesis of PD, the relative roles of nitric oxide synthase isoforms iNOS and nNOS in the nigrostriatal pathway remains, however, unclear. Here, the participation of iNOS/nNOS isoforms in the mitochondrial dysfunction was analyzed in iNOS and nNOS deficient mice. Our results showed that MPTP increased iNOS activity in substantia nigra and striatum, whereas it sharply reduced complex I activity and mitochondrial bioenergetics in all strains. In the presence of MPTP, mice lacking iNOS showed similar restricted mitochondrial function than wild type or mice lacking nNOS. These results suggest that iNOS-dependent elevated nitric oxide, a major pathological hallmark of neuroinflammation in PD, does not contribute to mitochondrial impairment. Therefore, neuroinflammation and mitochondrial dysregulation seem to act in parallel in the MPTP model of PD. Melatonin administration, with well-reported neuroprotective properties, counteracted these effects, preventing from the drastic changes in mitochondrial oxygen consumption, increased NOS activity and prevented reduced locomotor activity induced by MPTP. The protective effects of melatonin on mitochondria are also independent of its anti-inflammatory properties, but both effects are required for an effective anti-parkinsonian activity of the indoleamine as reported in this study.

Parámetros de estética facial y gradiente sociogenético en niños chilenos / Facial esthetics and sociogenetic gradient parameters in chilean children

Objetivo: determinar valores antropométricos de estética facial de niños de 5 y 8 años de edad, concaracterísticas físicas y oclusales normales, pertenecientes a diferentes grupos sociogenéticos deSantiago de Chile, debido a que es un país con marcada mezcla indígena, y compararlos entre sísegún sexo y estrato para cada grupo etáreo y con los valores norteamericanos utilizados internacionalmentepublicados por Farkas. Metodos: se realizó un análisis facial basado en Arnett y Farkas,utilizando fotografía digital apoyada por examen clínico, en cuatro muestras, clasificadas según denticióny estrato. Resultados: no existen diferencias entre sexo ni estrato en Chile, ni tampoco cuando estasson comparadas con las medidas norteamericanas. Conclusiones: las mediciones antropométricasfaciales determinadas para los distintos grupos sociogenéticos en Santiago Chile no difieren entre sini con las publicadas por Farkas, por lo que estas pueden ser utilizadas en la clínica en Santiago conpoblaciones étnicamente mixtas.

Purpose: to compare anthropometric measurements of facial esthetics in 5 and 8 years old children,with normal physical and occlusal characteristics, belonging to different sociogenetic groups fromSantiago de Chile (mixed ethnic population); and with north American Caucasian parameters publishedby Farkas. Methods: a facial analysis based on Arnett and Farkas was carried out, using digitalphotography supported by a clinical examination, in four samples, according to the dentition andsociogenetic stratum. Results: the results show no differences in Chile according to sex and stratum,neither with Caucasian measurements. Conclusion: the anthropometric measurements of facialaesthetics in sociogenetic groups from Santiago are not different with Farkas Caucasian measurementsand can be used for clinical purposes in mixed ethnically Chilean populations.