Cancer is a major cause of morbidity and mortality worldwide, with a disease burden estimated to increase over the coming decades. Disease heterogeneity and limited information on cancer biology and disease mechanisms are aspects that 2D cell cultures fail to address. Here, we review the current ‘state-of-the-art’ in 3D tissue-engineering (TE) models developed for, and used in, cancer research. We assess the potential for scaffold-based TE models and microfluidics to fill the gap between 2D models and clinical application. We also discuss recent advances in combining the principles of 3D TE models and microfluidics, with a special focus on biomaterials and the most promising chip-based 3D models.
Recent findings indicate that different Endocrine Disrupting Chemicals (EDCs) interfere with lipid metabolic pathways in mammals and promote fat accumulation, a previously unknown site of action for these compounds. The antifoulant and environmental pollutant tributyltin (TBT), which causes imposex in gastropod snails, induces an “obesogenic” phenotype in mammals, through the activation of the nuclear receptors retinoid X receptor (RXR) and peroxisome proliferator-activated receptor gamma (PPARγ). In teleosts, the effects of TBT on the lipid metabolism are poorly understood, particularly following exposure to low, environmental concentrations. In this context, the present work shows that exposure of zebrafish to 10 and 50 ng/L of TBT (as Sn) from pre-hatch to 9 months of age alters the body weight, condition factor, hepatosomatic index and hepatic triglycerides in a gender and dose related manner. Furthermore, TBT modulated the transcription of key lipid regulating factors and enzymes involved in adipogenesis, lipogenesis, glucocorticoid metabolism, growth and development in the brain and liver of exposed fish, revealing sexual dimorphic effects in the latter. Overall, the present study shows that the model mammalian obesogen TBT interferes with triglyceride accumulation and the transcriptional regulation of lipid metabolism in zebrafish and indentifies the brain lipogenic transcription profile of fish as a new target of this compound.
Nuclear receptors are transcription factors that regulate networks of target genes in response to small molecules. There is a strong bias in our knowledge of these receptors because they were mainly characterized in classical model organisms, mostly vertebrates. Therefore, the evolutionary origins of specific ligand-receptor couples still remain elusive. Here we present the identification and characterization of a retinoic acid receptor (RAR) from the mollusk Nucella lapillus (NlRAR). We show that this receptor specifically binds to DNA response elements organized in direct repeats as a heterodimer with retinoid X receptor. Surprisingly, we also find that NlRAR does not bind all-trans retinoic acid or any other retinoid we tested. Furthermore, NlRAR is unable to activate the transcription of reporter genes in response to stimulation by retinoids and to recruit coactivators in the presence of these compounds. Three-dimensional modeling of the ligand-binding domain of NlRAR reveals an overall structure that is similar to vertebrate RARs. However, in the ligand-binding pocket (LBP) of the mollusk receptor, the alteration of several residues interacting with the ligand has apparently led to an overall decrease in the strength of the interaction with the ligand. Accordingly, mutations of NlRAR at key positions within the LBP generate receptors that are responsive to retinoids. Altogether our data suggest that, in mollusks, RAR has lost its affinity for all-trans retinoic acid, highlighting the evolutionary plasticity of its LBP. When put in an evolutionary context, our results reveal new structural and functional features of nuclear receptors validated by millions of years of evolution that were impossible to reveal in model organisms.
Drug toxicity frequently goes concealed until clinical trials stage, which is the most challenging, dangerous and expensive stage of drug development. Both the cultures of cancer cells in traditional 2D assays and animal studies have limitations that cannot ever be unraveled by improvements in drug-testing protocols. A new generation of bioengineered tumors is now emerging in response to these limitations, with potential to transform drug screening by providing predictive models of tumors within their tissue context, for studies of drug safety and efficacy. Considering the NCI60, a panel of 60 cancer cell lines representative of 9 different cancer types: leukemia, lung, colorectal, central nervous system (CNS), melanoma, ovarian, renal, prostate and breast, we propose to review current "state of art" on the 9 cancer types specifically addressing the 3D tissue models that have been developed and used in drug discovery processes as an alternative to complement their study.
Hyperargininemia is a metabolic disorder biochemically characterized by tissue accumulating of arginine and other guanidino compounds. Convulsions, lethargy and psychomotor delay or cognitive deterioration are predominant clinical features of this disease. Although neurologic symptoms predominate in this disorder, their pathophysiology is still unknown. In the present study we initially investigated the in vitro effect of arginine, homoarginine, N-acetylarginine and argininic acid on acetylcholinesterase and butyrylcholinesterase in hippocampus and serum of 15-, 30- and 60-day-old rats. Results showed that arginine in vitro significantly decreased acetylcholinesterase activity in hippocampus of 15-day-old rats and increased this enzyme activity in hippocampus of 60-day-old rats, homoarginine and N-acetylarginine significantly increased acetylcholinesterase activity both in hippocampus of 15- and 30-day-old rats. On the other hand, butyrylcholinesterase was inhibited by homoarginine in serum of 15-day-old rats. The influence of the antioxidants trolox and ascorbic acid on the effects elicited by arginine, homoarginine and N-acetylarginine was also studied. Results showed that these antioxidants were able to prevent the alteration on acetylcholinesterase and butyrylcholinesterase activities caused by guanidine compounds studied, suggesting that alterations on these cholinesterases were probably mediated by free radicals. It is presumed that these results might be associated, at least in part, with the neuronal dysfunction of patients affected by hyperargininemia.
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