Angiogenesis is an important mediator of tumor progression. As tumors expand, diffusion distances from the existing vascular supply increases, resulting in hypoxia in the cancer cells. Sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and nutrients. The key regulator of hypoxia-induced angiogenesis is the transcription factor known as hypoxia-inducible factor (HIF)-1. HIF-1alpha is stabilized by hypoxia-induced reactive oxygen species (ROS) and enhances the expression of several types of hypoxic genes, including that of the angiogenic activator known as vascular endothelial cell growth factor (VEGF). In this study, we found that melatonin, a small lipophilic molecule secreted primarily by the pineal gland, destabilizes hypoxia-induced HIF-1alpha protein levels in the HCT116 human colon cancer cell line. This destabilization of HIF-1alpha resulted from the antioxidant activity of melatonin against ROS induced by hypoxia. Moreover, under hypoxia, melatonin suppressed HIF-1 transcriptional activity, leading to a decrease in VEGF expression. Melatonin also blocked in vitro tube formation and invasion and migration of human umbilical vein endothelial cells induced by hypoxia-stimulated conditioned media of HCT116 cells. These findings suggest that melatonin could play a pivotal role in tumor suppression via inhibition of HIF-1-mediated angiogenesis.

Mitochondrial dysfunction has been found to be associated with various pathological conditions, particularly cancer. However, the mechanisms underlying tumor malignancy induced by mitochondrial dysfunction are not fully understood. In the present study, the effects of mitochondrial dysfunction on epithelial-mesenchymal transition (EMT), were investigated using mitochondrial-depleted ρ(0) cells derived from the Hep3B hepatocarcinoma cell line. The Hep3B/ρ(0) cells displayed the EMT phenotype with more aggressive migration and higher invasiveness compared to their parental cells. The Hep3B/ρ(0) cells also showed typical expression pattern of EMT markers such as vimentin and E-cadherin. These phenotypes in Hep3B/ρ(0) cells were mediated by increased transforming growth factor-β (TGF-β) through the canonical Smad-dependent signaling pathway. Additionally, TGF-β signaling was activated via induction of c-Jun/AP-1 expression and activity. Therefore, mitochondrial dysfunction induces EMT through TGF-β/Smad/Snail signaling via c-Jun/AP-1 activation. These results indicate that mitochondrial dysfunction plays an important role in the EMT process and could be a novel therapeutic target for malignant cancer therapy.

Persistent neurochemical disturbances by repeating drug reward and withdrawal lead to addiction. Particularly, drug withdrawal, usually starting within hours of the last dose, is considered as a critical step in the transition to addiction and a treatment clue. The aim of this study was to uncover metabolic effects associated with methamphetamine (MA) short-term abstinence using both non-targeted and targeted metabolomics. Metabolic alterations were investigated in rat plasma collected immediately after 16 days of MA self-administration and after 12 and 24 h of abstinence. Principal component analysis revealed that the highest level of separation occurred between the 24 h and saline (control) groups based on the significantly changed ion features, 257/320/333 and 331/409/388, in the SA/12 h/24 h groups in positive and negative modes of UPLC-QTOF-ESI-MS, respectively. Targeted metabolomics revealed dynamic changes in the biosynthesis/metabolism of amino acids, including the phenylalanine, tyrosine, and tryptophan biosynthesis and the valine, leucine, and isoleucine biosynthesis. Integrating non-targeted and targeted metabolomics data uncovered rapid and distinct changes in the metabolic pathways involved in energy metabolism, the nervous system, and membrane lipid metabolism. These findings provide essential knowledge of the dynamic metabolic effects associated with short-term MA abstinence and may help identify early warning signs of MA dependence.

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Metabolomics is a powerful tool used to understand comprehensive changes in the metabolic response and to study the phenotype of an organism by instrumental analysis. It most commonly involves mass spectrometry followed by data mining and metabolite assignment. For the last few decades, hair has been used as a valuable analytical sample to investigate retrospective xenobiotic exposure as it provides a wider window of detection than other biological samples such as saliva, plasma, and urine. Hair contains functional metabolomes such as amino acids and lipids. Moreover, segmental analysis of hair based on its growth rate can provide information on metabolic changes over time. Therefore, it has great potential as a metabolomics sample to monitor chronic diseases, including drug addiction or abnormal conditions. In the current review, the latest applications of hair metabolomics in animal studies and clinical settings are highlighted. For this purpose, we review and discuss the characteristics of hair as a metabolomics sample, the analytical techniques employed in hair metabolomics and the consequence of hair metabolome alterations in recent studies. Through this, the value of hair as an alternative biological sample in metabolomics is highlighted.