No abstract

Prostaglandin reductase 2 (PTGR2) is the enzyme that catalyzes 15-keto-PGE2, an endogenous PPARγ ligand, into 13,14-dihydro-15-keto-PGE2. Previously, we have reported a novel oncogenic role of PTGR2 in gastric cancer, where PTGR2 was discovered to modulate ROS-mediated cell death and tumor transformation. In the present study, we demonstrated the oncogenic potency of PTGR2 in pancreatic cancer. First, we observed that the majority of the human pancreatic ductal adenocarcinoma tissues was stained positive for PTGR2 expression but not in the adjacent normal parts. In vitro analyses showed that silencing of PTGR2 expression enhanced ROS production, suppressed pancreatic cell proliferation, and promoted cell death through increasing 15-keto-PGE2. Mechanistically, silencing of PTGR2 or addition of 15-keto-PGE2 suppressed the expressions of solute carrier family 7 member 11 (xCT) and cystathionine gamma-lyase (CTH), two important providers of intracellular cysteine for the generation of glutathione (GSH), which is widely accepted as the first-line antioxidative defense. The oxidative stress-mediated cell death after silencing of PTGR2 or addition of 15-keto-PGE2 was further abolished after restoring intracellular GSH concentrations and cysteine supply by N-acetyl-L-cysteine and 2-Mercaptomethanol. Our data highlight the therapeutic potential of targeting PTGR2/15-keto-PGE2 for pancreatic cancer.

Aims/Introduction: Vascular adhesion protein-1 (VAP-1) is a membrane-bound amine oxidase highly expressed in mature adipocytes and released into the circulation. VAP-1 has been strongly implicated in several pathological processes, including diabetes, inflammation, hypertension, hepatic steatosis and renal diseases, and is an important disease marker and therapeutic target. Here, we aimed to identify the genetic loci for circulating VAP-1 levels. Materials and Methods: We carried out a genomic-wide linkage scan for the quantitative trait locus of circulating VAP-1 levels in 1,100 Han Chinese individuals from 398 families in the Stanford Asian Pacific Program for Hypertension and Insulin Resistance study. Regional association fine mapping was carried out using additional single-nucleotide polymorphisms. Results: The estimated heritability of circulating VAP-1 levels is high (h 2 = 69%). The most significant quantitative trait locus for circulating VAP-1 was located at 38 cM on chromosome 20, with a maximum empirical logarithm of odds score of 4.11 (P = 6.86 9 10 -6 ) in females. Regional single-nucleotide polymorphism fine mapping within a 1-unit support region showed the strongest association signals in the MACRO domain containing 2 (MACROD2) gene in females (P = 5.38 9 10 -6

The type 2 diabetes pandemic in recent decades is a huge global health threat. This pandemic is primarily attributed to the surplus of nutrients and the increased prevalence of obesity worldwide. In contrast, calorie restriction and weight reduction can drastically prevent type 2 diabetes, indicating a central role of nutrient excess in the development of diabetes. Recently, the molecular links between excessive nutrients, organelle stress, and development of metabolic disease have been extensively studied. Specifically, excessive nutrients trigger endoplasmic reticulum stress and increase the production of mitochondrial reactive oxygen species, leading to activation of stress signaling pathway, inflammatory response, lipogenesis, and pancreatic beta-cell death. Autophagy is required for clearance of hepatic lipid clearance, alleviation of pancreatic beta-cell stress, and white adipocyte differentiation. ROS scavengers, chemical chaperones, and autophagy activators have demonstrated promising effects for the treatment of insulin resistance and diabetes in preclinical models. Further results from clinical trials are eagerly awaited.

Adiponectin is an important adipose-specific protein, which possesses insulin (INS)-sensitizing, antiinflammatory, and antiatherosclerotic functions. However, its regulation remains largely unknown. In this study, we identified that ryanodine receptor (RyR)3 plays an important role in the regulation of adiponectin expression. RyR3 was expressed in 3T3-L1 preadipocytes, and its level was decreased upon adipogenesis. Silencing of RyR3 expression in 3T3-L1 preadipocytes resulted in up-regulated adiponectin promoter activity, enhanced adiponectin mRNA expression, and more adiponectin protein secreted into the medium. An inverse relation between RyR3 and adiponectin mRNA levels was also observed in adipose tissues of db/db mice. In addition, knockdown of RyR3 with small interfering RNA (siRNA) in db/db mice and high-fat diet-fed obese mice increased serum adiponectin level, improved INS sensitivity, and lowered fasting glucose levels. These effects were in parallel with decreased mitochondrial Ca(2+), increased mitochondrial mass, and reduced activating transcription factor 3 (atf3) expression. Overexpression of atf3 in 3T3-L1 preadipocytes blocked the effect of RyR3 silencing on adiponectin expression, indicating that an atf3-dependent pathway mediates the effect downstream of RyR3 silencing. Our data suggest that RyR3 may be a new therapeutic target for improving INS sensitivity and related metabolic disorders.