Obesity is strongly linked to male infertility. Apoptotic inflammatory response caused by oxidative stress in testicular spermatogenic cells is one of the important causes of obesity-related male infertility. Pituitary adenylate cyclase activating polypeptide (PACAP) as a bioactive peptide secreted by the pituitary gland, has a powerful triple role of anti-oxidation, anti-apoptosis and anti-inflammation, and is involved in male reproduction regulation, but the specific mechanism remains unknown. The purpose of the current study is to explore the role of PACAP in obesity-related male infertility. In cell-level experiments, Mouse spermatocytes (GC-2) were treated with palmitate (PA) to establish an high-fat injury cell model in vitro and then treated with PACAP. In animal-level experiments, C57BL/6 male mice were fed with a high-fat diet (HFD) to induce obesity and then treated with PACAP. The cell mechanism studies showed that PACAP selectively binds to the PAC1 receptor to attenuate palmitic acid-induced mouse spermatogenic cell (GC-2) oxidative damage and apoptotic inflammatory response via the PKA/ERK/Nrf2 signaling axis. However, this mechanism was inhibited in GC-2 cells inhibiting the activity of Nrf2. The animal experiment studies showed that PACAP treatment ameliorated obesity characteristics, including body weight, epididymal adipose weight, testes/body weight, serum lipids levels, and reproductive hormone levels in vivo. Additionally, PACAP was shown to improve the reproductive function of the obese mice, which was characterized by improved testis morphology and sperm parameters via Keap1/Nrf2/ARE pathway. These beneficial effects of PACAP were abolished in obese mice with testis-specific knockdown of Nrf2.
Wailan Shan, Shiyin Lu, Biqian Ou, Jia Feng, Zixian Wang, Huixian Li, Xiaohua Lu, and Ma Yi
Jia-Fwu Shyu, Hwai-Shi Wang, Yi-Ming Shyr, Shin-E Wang, Chia-Hsiang Chen, Joo-Shin Tan, Meng-Feng Lin, Po-Shiuan Hsieh, Huey-Kang Sytwu, and Tien-Hua Chen
Although islet transplantation holds promise for the treatment of diabetes, the scarcity of donor tissue remains a major drawback. The aim of this study is to generate insulin-producing cells from adult human pancreatic cells isolated from surgically resected pancreatic tissue. To isolate pancreatic endocrine precursor cells from 57 surgically resected pancreases, the cells were cultured and propagated in conditioned medium after which they were differentiated in Matrigel. The resultant cells were characterized using morphology, immunofluorescent studies, expression of differentiated pancreatic islet-specific genes using quantitative reverse transcription-PCR, and glucose-induced insulin secretion through analysis of C-peptide secretion. The relationships between propagation of insulin-producing cells and clinical variables of the donor were also analyzed. Finally, insulin-producing cell function was examined in streptozotocin-induced diabetic rats. Pancreatic endocrine precursor cells were successfully cultured; insulin-producing cells cultured from soft pancreas parenchyma had a significantly higher success rate. Morphological examination revealed islet-like cluster formation upon transfer to Matrigel. The presence of the neural stem cell marker nestin, duct cell marker cytokeratin 19, and endocrine cell markers C-peptide and pancreatic and duodenal homeobox 1, was also observed. In addition, glucose-stimulated C-peptide release was significantly increased in the insulin-producing cells. Furthermore, in diabetic rats, transplantation of insulin-producing cells reduced hyperglycemia. Isolated pancreatic endocrine precursor cells from surgically resected pancreatic tissue differentiated into insulin-producing cells and showed characteristics of functional endocrine cells. Thus, surgically resected pancreatic tissue may represent an alternative source of functional insulin-producing cells.