No abstract

Endometriosis is a benign gynecological disease characterized by abnormal growth of endometrial-like cells outside the uterus. Melatonin, a hormone secreted by the pineal gland, has been shown to have therapeutic effects in various diseases, including endometriosis. However, the underlying molecular mechanisms are yet to be elucidated. The results of this study demonstrated that melatonin and dienogest administration effectively reduced surgically induced endometriotic lesions in a mouse model. Melatonin suppressed proliferation, induced apoptosis, and dysregulated calcium homeostasis in endometriotic cells and primary endometriotic stromal cells. Melatonin also caused mitochondrial dysfunction by permeating through the mitochondrial membrane to disrupt redox homeostasis in the endometriotic epithelial and stromal cells. Furthermore, melatonin affected oxidative phosphorylation systems to decrease ATP production in End1/E6E7 and VK2/E6E7 cells. This was achieved through messenger RNA-mediated downregulation of respiratory complex subunits. Melatonin inhibited the PI3K/AKT and ERK1/2 pathways and the mitochondria-associated membrane axis and further suppressed the migration of endometriotic epithelial and stromal cells.Furthermore, we demonstrated that tiRNA GluCTC and tiRNA AspGTC were associated with the proliferation of endometriosis and that melatonin suppressed the expression of these tiRNAs in primary endometriotic stromal cells and lesions in a mouse model. Thus, melatonin can be used as a novel therapeutic agent to manage endometriosis.

No abstract

Canine osteosarcoma is an aggressive primary bone tumor that shows metastasis to distal regions and is associated with a high mortality rate. However, the pathophysiological mechanisms of canine osteosarcoma are not well characterized. In addition, development of prognostic factors and novel therapeutic agents is necessary to efficiently treat osteosarcoma. Therefore, we studied the effects of myricetin, an antioxidant found in berries, nuts, teas, wine, and vegetables, on apoptosis and signal transduction in the canine osteosarcoma cell lines, D-17 and DSN. Results of the present study demonstrated that treatment with myricetin decreased cell proliferation and DNA replication, while it increased apoptotic DNA fragmentation in D-17 and DSN cells. In addition, it increased generation of ROS, lipid peroxidation, and depolarization of MMP in both D-17 and DSN cells. Myricetin treatment activated phosphorylation of AKT, p70S6K, ERK1/2, JNK, and p90RSK in canine osteosarcoma cells. Moreover, inhibition of PI3K and MAPK using LY294002, U0126, or SP600125, in addition to myricetin treatment, effectively suppressed cell proliferation compared to treatment with myricetin or each inhibitor alone. Therefore, we concluded that myricetin may be a potentially effective and less toxic therapeutic agent to prevent and control progression of canine osteosarcoma.

Ochratoxin A (OTA) is a mycotoxin originating from Penicillium and Aspergillus. In addition to toxic effects in various tissues and cells, including neurons, immune cells, hepatocytes, and nephrons, it also causes carcinogenesis and teratogenesis. Although the negative effects of OTA with respect to the pathogenesis of diseases and the malfunction of various organs have been studied widely, the biological signaling mechanisms in testicular cells are less well known. Therefore, we determined the hazardous effect of OTA in two types of testicular cells: TM3 (mouse Leydig cells) and TM4 (mouse Sertoli cells). Treatment with OTA led to a significant decrease in the proliferation of both cell lines, as revealed by an increased proportion of cells in the sub-G1 phase. In addition, the phosphorylation of signaling molecules belonging to the PI3K (Akt, P70S6K, and S6) and MAPK (ERK1/2 and JNK) pathways was regulated by OTA in a dose-dependent manner in TM3 and TM4 cells. Furthermore, the combination treatment of OTA and signaling inhibitors (LY294002, U0126, or SP600125) exerted synergistic antiproliferative effects in TM3 and TM4 cells. OTA also reduced the concentration of calcium ions in the cytosol and mitochondria, which disrupted the calcium homeostasis necessary for maintaining the normal physiological functions of testicular cells. In conclusion, the results of the present study demonstrate the mechanism underlying the antiproliferative effects of OTA in mouse testicular cells. Exposure to OTA may result in abnormal sperm maturation and the failure of spermatogenesis, which leads to male infertility.