Correlation between circadian rhythm related genes, type 2 diabetes, and cancer: Insights from metanalysis of transcriptomics data.

Clock genes work as an auto-regulated transcription-translational loop of circadian genes that drives the circadian rhythms in each cell and they are essential to physiological requests. Since metabolism is a dynamic process, it involves several physiological variables that circadian cycling. The clock genes alterations can affect multiple systems concomitantly, because they constitute the promoter factors for relevant metabolic pathways. Considering the intertwined structure of signaling, regulatory, and metabolic processes within a cell, we employed a genome-scale biomolecular network. Accordingly, a meta-analysis of diabetic-associated transcriptomic datasets was performed, and the core information on differentially expressed genes (DEGs) was obtained by statistical analyses. In the current study, meta-analysis was performed on type 2 diabetes, circadian rhythm-related genes, and breast, bladder, liver, pancreas, colon and rectum cancer-associated transcriptome data using the integration of gene expression profiles with genome-scale biomolecular networks in diabetes samples. First, we detected downregulated and upregulated DEGs in mouse cortex and hypothalamus samples of mice with sleep deprivation. In summary, upregulated genes active genes associated with oxidative phosphorylation, cancer and diabetes, mainly in hypothalamus specimens. In cortex, we observed mainly downregulation of immune system. DEGs were combined with 214 circadian rhythm related genes to type 2 DM and cancer samples. We observed that several common genes deregulated in both diseases. Klf10, Ntkr3, Igf1, Usp2, Ezh2 were both downregulated in type 2 DM and cancer samples, while Arntl2 and Agrp were upregulated. It seems that the changes in mRNA are contributing to the phenotypic changes in type 2 DM, resulting in phenotypic changes associated with the malignant transformation. Taking those genes to perform a survival analysis, we found only Igf1, Usp2 and Arntl2 genes associated with patient outcomes. While Igf1 and Usp2 downregulation had a negative impact, Arntl2 upregulation was associated with poor survival both in BLCA and BRCA cancer samples. Our data stimulate efforts in news studies to achieve the experimental and clinical validation about these biomolecules.

Semicarbazone derivatives as promising therapeutic alternatives in leishmaniasis.

In the present study, we investigated the in vitro and in vivo leishmanicidal activity of synthetic compounds, containing a semicarbazone scaffold as a peptide mimetic framework. The leishmanicidal effect against amastigotes of Leishmania amazonensis was also evaluated at concentration of 100 µM-0.01 nM. The derivatives 2e, 2f, 2g and 1g, beyond the standards miltefosine and pentamidine, significantly diminished the number of L. amazonensis amastigotes in macrophages. These derivatives were also active against amastigotes of L. braziliensis. As 2g presented potent leishmanicidal activity against the amastigotes of L. amazonensis in macrophages, we also investigated the in vivo leishmanicidal activity of this compound against L. amazonensis. Approximately 105L. amazonensis promastigotes were subcutaneously inoculated into the dermis of the right ear of BALB/c mice, which were subsequently treated with 2g (p.o. or i.p.), miltefosine (p.o.) or glucantime (i.p.) at 30 µmol/kg/day x 28 days. Thus, a similar reduction in the lesion size was observed after the administration of 2g through oral (63.7 ±â€¯10.1%) and intraperitoneal (61.8 ±â€¯3.7%) routes. A larger effect was observed after treatment with miltefosine (97.7 ±â€¯0.4%), and glucantime did not exhibit activity at the dose administered. With respect to the ear parasite load, 2g diminished the number of parasites by p.o. (30.5 ±â€¯5.1%) and i.p. (33.3 ±â€¯4.3%) administration. In addition, 2g induced in vitro apoptosis, autophagy and cell cycle alterations on L. amazonensis promastigotes. In summary, the derivative 2g might represent a lead candidate for antileishmanial drugs, as this compound displayed pronounced leishmanicidal activity.

New oxidovanadium(IV) N-acylhydrazone complexes: promising antileishmanial and antitrypanosomal agents.

Searching for new promising metal-based hits against Trypanosoma cruzi and Leishmania parasites, two related oxidovanadium(IV) N-acylhydrazone complexes, [V(IV)O(LASSBio1064-2H)(H2O)], 1, and [V(IV)O(LASSBio1064-2H)(phen)]·(H2O), 2, where LASSBio1064=(E)-N'-(2-hydroxybenzylidene-4-chlorobenzohydrazide and phen = 1,10-phenanthroline, were synthesized and characterized in the solid state and in solution by elemental analysis, conductimetric measurements and ESI-MS, FTIR, EPR and (51)V NMR spectroscopies and were evaluated on T. cruzi and Leishmania major. In addition, their unspecific cytotoxicity was tested against murine macrophages. Furthermore, to provide insight into the possible mechanism of its antiparasitic action, [VO(LASSbio1064-2H)(phen)].(H2O) was tested for its DNA interaction ability on plasmid DNA by atomic force microscopy (AFM) and on CT DNA by using DNA viscosity measurements and fluorescence spectroscopy. Both complexes were active in vitro against the epimastigote form of T. cruzi (Tulahuen 2 strain) showing IC50 values of the same order or significantly lower than that of the reference trypanosomicidal drug Nifurtimox. However, only the mixed-ligand oxidovanadium(IV) complex 2, which includes phen in its coordination sphere, showed activity on L. major promastigotes with a IC50 value of 22.1 ± 0.6 µM. The compounds show low toxicity on mammalian cells (IC50 > 100 µM). DNA interaction studies showed that the mixed-ligand complex is able to interact with this biomolecule probably through an intercalative mode, pointing out at DNA as a potential target in the parasite. The results suggest that [V(IV)O(LASSBio1064-2H)(phen)]·(H2O) may be a promising compound for further drug development stages.