RESUMO
The integration of different sources of biological information about what defines a behavioral phenotype is difficult to unify in an entity that reflects the arithmetic sum of its individual parts. In this sense, the challenge of Systems Biology for understanding the "psychiatric phenotype" is to provide an improved vision of the shape of the phenotype as it is visualized by "Gestalt" psychology, whose fundamental axiom is that the observed phenotype (behavior or mental disorder) will be the result of the integrative composition of every part. Therefore, we propose the term "Gestaltomics" as a term from Systems Biology to integrate data coming from different sources of information (such as the genome, transcriptome, proteome, epigenome, metabolome, phenome, and microbiome). In addition to this biological complexity, the mind is integrated through multiple brain functions that receive and process complex information through channels and perception networks (i.e., sight, ear, smell, memory, and attention) that in turn are programmed by genes and influenced by environmental processes (epigenetic). Today, the approach of medical research in human diseases is to isolate one disease for study; however, the presence of an additional disease (co-morbidity) or more than one disease (multimorbidity) adds complexity to the study of these conditions. This review will present the challenge of integrating psychiatric disorders at different levels of information (Gestaltomics). The implications of increasing the level of complexity, for example, studying the co-morbidity with another disease such as cancer, will also be discussed.
RESUMO
9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b]quinolone (D3ClP) is a bioisostere of N-(4-(acridin-9-ylamino)-3-methoxyphenyl)methanesulfonamide (m-AMSA) a DNA topoisomerase II inhibitor with proven cytotoxic activity and known to induce DNA damage and apoptotic cell death in K562 cells. However, recent evidence is not consistent with DNA topoisomerase II (DNA TOP2) as the primary target of D3ClP, in contrast to m-AMSA. We provide evidence of histone γH2AX phosphorylation at Ser135 in HeLa cells treated with D3ClP, a marker of DNA double strand repair through Mre11-Rad50-Nbs1 (MRN) pathway. Using two-dimensional gel electrophoresis and mass spectrometry, the upregulation of the protein GRP78, the cleavage of Cytokeratin 18, and the downregulation of prothymosine, calumenin, and the α chain of the nascent polypeptide associated complex were observed in HeLa cells treated with D3ClP. An increase in GRP78 has been related with the onset and progression of the unfolded protein response (UPR), a process aimed to reduce endoplasmic reticulum (ER) stress and protein misfolding. The IRE1-α dependent splicing of mRNA encoding X-box binding protein 1 was detected. Microtubule-associated Proteins 1A/1B, Light Chain 3-II (LC3b-II) accumulation was observed, and suggest some involvement of autophagy. The production of the pro-apoptotic protein DNA-damage-inducible protein 153 (GADD-153) was also detected. These results, are consistent with the induction of the UPR and the DNA-Damage Response in D3ClP-treated HeLa cells, and are also consistent with a concurrent apoptotic cell death. J. Cell. Biochem. 118: 1164-1173, 2017. © 2016 Wiley Periodicals, Inc.