Cloning and characterization of the

Insomnia is a serious worldwide health threat, affecting nearly one third of the general population. Melatonin has been reported to improve sleep efficiency and it was found that eating melatonin-rich foods could assist sleep. During the last decades, melatonin has been widely identified and qualified in various foods from fungi to animals and plants. Eggs and fish are higher melatonin-containing food groups in animal foods, whereas in plant foods, nuts are with the highest content of melatonin. Some kinds of mushrooms, cereals and germinated legumes or seeds are also good dietary sources of melatonin. It has been proved that the melatonin concentration in human serum could significantly increase after the consumption of melatonin containing food. Furthermore, studies show that melatonin exhibits many bioactivities, such as antioxidant activity, anti-inflammatory characteristics, boosting immunity, anticancer activity, cardiovascular protection, anti-diabetic, anti-obese, neuroprotective and anti-aging activity. This review summaries the dietary sources and bioactivities of melatonin, with special attention paid to the mechanisms of action.

https://www.mdpi.com/2072-6643/9/4/367/pdf

Dietary Sources and Bioactivities of Melatonin.

Oxidative stress caused by lead (Pb) induces iron deficiency in Drosophila melanogaster

Melatonin's therapeutic potential has been highly underestimated because its biological functional roles are diverse and relevant mechanisms are complicated. Among the numerous biological activities of melatonin, its regulatory effects on pluripotent mesenchymal stem cells (MSCs), which are found in bone marrow stem cells (BMSCs) and adipose tissue (AD-MSC), have been recently proposed, which has received increasingly more attention in recent studies. Moreover, receptor-dependent and receptor-independent responses to melatonin are identified to occur in these cells by regulating signaling pathways, which drive the commitment and differentiation of MSCs into osteogenic, chondrogenic, or adipogenic lineages. Therefore, the aim of our current review is to summarize the evidence related to the utility of melatonin as a regulatory agent by focusing on its relationship with the differentiation of MSCs. In particular, we aimed to review its roles in promoting osteogenic and chondrogenic differentiation and the relevant signaling cascades involved. Also, the roles that melatonin and, particularly, its receptors play in these processes are highlighted.

Regulation effects of melatonin on bone marrow mesenchymal stem cell differentiation.

Lead (Pb) toxicity is a public health problem affecting millions worldwide. Advances in 'omic' technology have paved the way to toxico-genomics which is currently revolutionizing the understanding of interindividual variations in susceptibility to Pb toxicity and its functional consequences to exposure. Our objective was to identify, comprehensively analyze, and curate all the potential genetic and epigenetic biomarkers studied to date in relation to Pb toxicity and its association with diseases. We screened a volume of research articles that focused on Pb toxicity and its association with genetic and epigenetic signatures in the perspective of occupational and environmental Pb exposure. Due to wide variations in population size, ethnicity, age-groups, and source of exposure in different studies, researchers continue to be skeptical on the topic of the influence of genetic variations in Pb toxicity. However, surface knowledge of the underlying genetic factors will aid in elucidating the mechanism of action of Pb. Moreover, in recent years, the application of epigenetics in Pb toxicity has become a promising area in toxicology to understand the influence of epigenetic mechanisms such as DNA methylation, chromatin remodeling, and small RNAs for the regulation of genes in response to Pb exposure during early life. Growing evidences of ecogenetic understanding (both genetic and epigenetic processes) in a dose-dependent manner may help uncover the mechanism of action of Pb and in the identification of susceptible groups. Such studies will further help in refining uncertainty factors and in addressing risk assessment of Pb poisoning.

Ecogenetics of lead toxicity and its influence on risk assessment

Melatonin reduces lead levels in blood, brain and bone and increases lead excretion in rats subjected to subacute lead treatment.

Human lead (Pb) exposure induces many adverse health effects, including some related to lead accumulation in organs. Although lead bio-distribution in the body has been described, the molecular mechanism underlying distribution and excretion is not well understood. The transport of essential and toxic metals is principally mediated by proteins. How lead affects the expression of metal transporter proteins in the principal metal excretory organs, i.e., the liver and kidney, is unknown. Considering that co-administration of melatonin and lead reduces the toxic effects of lead and lead levels in the blood in vivo, we examined how lead and co-administration of lead and melatonin affect the gene and protein expression of metal transporter proteins (ZIP8, ZIP14, CTR1 and DMT1) in these organs. Rats were exposed intraperitoneally to lead or lead-melatonin. Our results show that Pb exposure induces changes in the protein and gene expression of ZIP8, ZIP14 and CTR1. Alterations in the copper/zinc ratio found in the blood, liver and kidney were likely related to these changes. With DMT1 expression (gene and protein), a positive correlation was found with lead levels in the kidney. Co-administration of melatonin and lead reduced lead-induced DMT1 expression through an unknown mechanism. This effect of melatonin relates to reduced lead levels in the blood and kidney. The metal transport protein function and our results suggest that DMT1 likely contributes to lead accumulation in organs. These data further elucidate the effects of lead on Cu and Zn and the molecular mechanism underlying lead bio-distribution in animals.

Effects of lead and lead–melatonin exposure on protein and gene expression of metal transporters, proteins and the copper/zinc ratio in rats

. Due to increasing drug resistance by Candida species, especially in hospitals, the search for new antifungal agents has intensified. The incorporation of the coumarin scaffold into several nitrogen-containing heterocyclic moieties reportedly increases antimicrobial efficiency. The aim of this study was to design and synthesize a series of simple coumarin-linked triazole derivatives and test their possible antifungal activity against four Candida species. Docking simulations were conducted to explore the binding properties of the test compounds and compare them to reported data on fluconazole, the reference drug. Starting from 3-acetylcoumarins, coumarins 2a-d, 3a-c and 4a-d were obtained in high yields. The concentration of each compound needed to inhibit the Candida species was determined by serial dilution. An inhibition of 62% of C. albicans was produced by 2b (300 µg/ml), 87% of C. tropicalis by 3a (100 µg/ml), 89% of C. parapsilosis by 3a (500 µg/ml), and 87% of C. glabrata by 4a (300 µg/ml). The values ​​of antifungal activity were similar for the coumarin derivatives and fluconazole, the latter of which induced 90% inhibition of the four yeasts at 500 µg/ml. According to the docking simulations, the interactions at the active site of the lanosterol 1,4-demethylase enzyme (CYP51) are similar for the test compounds and fluconazole. The subcellular location of the derivatives was identified as the mitochondrion. These coumarins are characterized by structural simplicity, with the simplest structures showing better antifungal activity than fluconazole. Further research is needed to isolate CYP51 and directly test its inhibition by coumarin derivatives.
                                               
Resumen. Una serie de moleculas de cumarina-triazol se sintetizaron y evaluaron contra diferentes especies de Candida. Las cumarinas 2a-d, 3a-c y 4a-d se obtuvieron utilizando como material de partida las 3-acetilcumarinas en altos rendimientos. La concentracion necesaria de las moleculas para mostrar actividad antifungica contra las cuatro especies de Candida se determino mediante un metodo de diluciones seriadas. Se reporta un 62% de inhibicion de C. albicans usando 2b (300 µg/ml), 87% de inhibicion contra C. parapsilosis por 3a (500 µg/ml), y un 87% de inhibicion a C. glabrata por 4a (300 µg/ml). El efecto de las cumarinas es comparado con el farmaco de referencia fluconazol, que induce un 90% de inhibicion en todas las cepas usando 500 µg/ml. Los resultados del estudio Docking muestran que las interacciones de todas las moleculas en el sitio activo de la enzima CYP51 son similares a las interacciones presentadas por el fluconazol. Finalmente, tomando ventaja de las propiedades fluorescentes de las cumarinas, la localizacion subcelular y penetracion de los compuestos, fue localizada en las mitocondrias. Las cumarinas reportadas, ademas de presentar sencillez estructural, tambien presentan valores de inhibicion de las cepas comparables, y en los casos mencionados, mejores que el farmaco de referencia.

http://www.scielo.org.mx/pdf/jmcs/v63n2/1870-249X-jmcs-63-02-103.pdf

Alberto Flores

Papers

Melatonin reduces lead levels in blood, brain and bone and increases lead excretion in rats subjected to subacute lead treatment.

Effects of lead and lead–melatonin exposure on protein and gene expression of metal transporters, proteins and the copper/zinc ratio in rats

Synthesis, biological evaluation and docking study of possible antifungal compounds with a coumarin-containing triazole side chain