Discovery of novel tranylcypromine-based derivatives as LSD1 inhibitors for gastric cancer treatment.

As an important epigenetic regulator, histone lysine specific demethylase 1 (LSD1) has become an attractive target for the discovery of anticancer agents. In this work, a series of tranylcypromine-based derivatives were designed and synthesized. Among them, compound 12u exhibited the most potent inhibitory potency on LSD1 (IC50 = 25.3 nM), and also displayed good antiproliferative effects on MGC-803, KYSE450 and HCT-116 cells with IC50 values of 14.3, 22.8 and 16.3 µM, respectively. Further studies revealed that compound 12u could directly act on LSD1 and inhibit LSD1 in MGC-803 cells, thereby significantly increasing the expression levels of mono-/bi-methylation of H3K4 and H3K9. In addition, compound 12u could induce apoptosis and differentiation, inhibit migration and cell stemness in MGC-803 cells. All these findings suggested that compound 12u was an active tranylcypromine-based derivative as a LSD1 inhibitor that inhibited gastric cancer.

Discovery of the theobromine derivative MQS-14 that induces death of MGC-803 cells mainly through ROS-mediated mechanisms.

Reactive oxygen species (ROS) play crucial roles in maintaining redox balance and regulating physiological processes, ROS levels in cancer cells are relatively higher than those in normal cells. Therefore, elevating cellular ROS levels may be a viable strategy for selective killing of cancer cells. In this work, we synthesized a series of new theobromine derivatives and evaluated their cytotoxicity against gastric cancer cells MGC-803, SGC-7901 and HGC-27. Particularly, MQS-14 potently inhibited cell growth of MGC-803, SGC-7901 and HGC-27 cells at low micromolar levels. Mechanistic studies showed that compound MQS-14 decreased cell viability of MGC-803 cells and inhibited cell division revealed by the CFDA and EdU staining assays. MQS-14 increased cellular ROS levels and activated the MAPK pathway accompanied by the decreased p-ERK and increased p-JNK expression. MQS-14 also induced DNA damage and apoptosis in MGC-803 cells. To conclude, MQS-14 induced cell death of MGC-803 cells partly through elevating cellular ROS levels.

Ligand-based design, synthesis and biological evaluation of xanthine derivatives as LSD1/KDM1A inhibitors.

Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for disease treatment. To date, a large number of LSD1 inhibitors have been developed, some of which are currently being evaluated in clinical trials for the treatment of cancers, virus infection, and neurodegenerative diseases. In this paper, we for the first time reported the ligand-based design of fragment-like xanthine derivatives as LSD1 inhibitors, of which compound 4 possessed acceptable pharmacological inhibition against LSD1 (IC50 = 6.45 µM) and favorable fragment-like nature, and therefore could be used as a promising template to design new LSD1 inhibitors. Interestingly, compounds 6c and 6i strongly suppressed growth of MGC-803 cells partly dependent on their LSD1 inhibition, and were also found to be able to inhibit BRD4 and IDO1. The docking studies were performed to rationalize the biochemical potency against LSD1 and to explain the observed activity discrepancy. The proof-of-concept work may provide an example for other natural ligand-based drug design.

Role of Arcuate Nucleus in the Regulation of Feeding Behavior in the Process of Altitude Acclimatization in Rats.

Liu, Xiang-Wen, Jie Yin, Qi-Sheng Ma, Chu-Chu Qi, Ji-Ying Mu, Lang Zhang, Li-Ping Gao, and Yu-Hong Jing. Role of arcuate nucleus in the regulation of feeding behavior in the process of altitude acclimatization in rats. High Alt Med Biol. 18:234-241, 2017.-Highly efficient energy utilization and metabolic homeostasis maintenance rely on neuromodulation. Altitude exposure is known to stimulate neuroendocrine systems to respond to acute hypoxia and adaptive acclimatization. However, limited data on how the adaptive regulation of the arcuate nucleus performs in the process of altitude acclimatization are available. In the present study, male Sprague Dawley rats were transported to Huashixia, Qinghai (with an altitude of 4400 m) from Xian (with an altitude of 300 m) by air; rats were consistently raised in Xian as control. Food uptake and body weight were measured consecutively after being subjected to high-altitude condition. Contents of plasma leptin and ghrelin were analyzed by the Enzyme Linked Immunosorbent Assay (ELISA) Kits. Brain coronal sections were obtained, and neuropeptide Y (NPY), proopiomelanocotin (POMC), and c-fos immunoreactivity in arcuate nucleus were observed. Arcuate nucleus was isolated from the hypothalamus, and the mRNA of NPY and POMC were measured by quantitative real-time polymerase chain reaction. Our results showed both food consumption and body weight decreased in the high plateau compared with rats raised in the low-altitude condition. Plasma leptin increased at the early stage, and ghrelin decreased at a later stage after reaching the high plateau. The peak of c-fos immunoreactivity in the arcuate nucleus was at day 3 after reaching the high plateau. The expression level of NPY increased, and POMC decreased in the arcuate nucleus at day 7 after reaching the high plateau compared with the plain control group. These results indicate that the arcuate nucleus of hypothalamus performs an important function in regulating feeding behavior during altitude acclimatization. Our study suggested that altitude acclimation is regulated by the hypothalamus that received leptin and ghrelin signals to response by its microcircuit, including NPY- and POMC-neurons in the arcuate nucleus.