Prostate cancer (PCa) is a leading cause of mortality and morbidity globally, but its specific geographic patterns and temporal trends are under-researched. To test the hypotheses that PCa incidence is higher and PCa mortality is lower in countries with higher socioeconomic development, and that temporal trends for PCa incidence have increased while mortality has decreased over time. Data on age-standardized incidence and mortality rates in 2012 were retrieved from the GLOBOCAN database. Temporal patterns were assessed for 36 countries using data obtained from Cancer incidence in five continents volumes I-X and the World Health Organization mortality database. Correlations between incidence or mortality rates and socioeconomic indicators (human development index [HDI] and gross domestic product [GDP]) were evaluated. The average annual percent change in PCa incidence and mortality in the most recent 10 yr according to join-point regression. Reported PCa incidence rates varied more than 25-fold worldwide in 2012, with the highest incidence rates observed in Micronesia/Polynesia, the USA, and European countries. Mortality rates paralleled the incidence rates except for Africa, where PCa mortality rates were the highest. Countries with higher HDI (r=0.58) and per capita GDP (r=0.62) reported greater incidence rates. According to the most recent 10-yr temporal data available, most countries experienced increases in incidence, with sharp rises in incidence rates in Asia and Northern and Western Europe. A substantial reduction in mortality rates was reported in most countries, except in some Asian countries and Eastern Europe, where mortality increased. Data in regional registries could be underestimated. PCa incidence has increased while PCa mortality has decreased in most countries. The reported incidence was higher in countries with higher socioeconomic development. The incidence of prostate cancer has shown high variations geographically and over time, with smaller variations in mortality.

We tested the hypotheses that the global incidence of bladder cancer was increasing but its mortality was reducing and its incidence was positively correlated with country-specific socioeconomic development. We retrieved data on age-standardized incidence and mortality rates/100,000 from the GLOBOCAN database in 2012. Temporal patterns were examined for 39 countries from the Cancer Incidence in Five Continents volumes I-X and other national registries. We evaluated the correlation between the incidence/mortality rates and Human Development Index (HDI)/ logarithmic values of Gross Domestic Product per capita (GDP). The average annual percent change of the incidence and mortality rates in the most recent 10 years was examined by joinpoint regression analysis. The highest incidence rates were observed in Southern Europe, Western Europe and North America. The mortality rates were the highest in Western Asia and Northern Africa. The incidence was positively correlated with HDI (r = 0.66 [men]; r = 0.50 [women]) and to a lesser extent logarithmic values of GDP per capita (r = 0.60 [men]; r = 0.50 [women], all p < 0.01). Many European countries experienced incidence rise. A substantial mortality reduction was observed in most countries, yet increases in mortality rates were observed in the Philippines and Iceland. These findings identified countries where more preventive actions are required.

G-protein-coupled receptor-30 (GPR30) shows estrogen-binding affinity and mediates non-genomic signaling of estrogen to regulate cell growth. We here showed for the first time, in contrast to the reported promoting action of GPR30 on the growth of breast and ovarian cancer cells, that activation of GPR30 by the receptor-specific, non-estrogenic ligand G-1 inhibited the growth of androgen-dependent and androgen-independent prostate cancer (PCa) cells in vitro and PC-3 xenografts in vivo. However, G-1 elicited no growth or histological changes in the prostates of intact mice and did not inhibit growth in quiescent BPH-1, an immortalized benign prostatic epithelial cell line. Treatment of PC-3 cells with G-1 induced cell-cycle arrest at the G₂ phase and reduced the expression of G₂-checkpoint regulators (cyclin-A2, cyclin-B1, cdc25c, and cdc2) and phosphorylation of their common transcriptional regulator NF-YA in PC-3 cells. With extensive use of siRNA-knockdown experiments and the MEK inhibitor PD98059 in this study, we dissected the mechanism underlying G-1-induced inhibition of PC-3 cell growth, which was mediated through GPR30, followed by sustained activation of Erk1/2 and a c-jun/c-fos-dependent upregulation of p21, resulting in the arrest of PC-3 growth at the G₂ phase. The discovery of this signaling pathway lays the foundation for future development of GPR30-based therapies for PCa.

Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor, inhibits the inactivation and degradation of glucagon like peptide 1 (GLP-1), which is used for the treatment of type 2 diabetes mellitus. However, little is known about the role of GLP-1 in hypertension. This study investigated whether the activation of GLP-1 signaling protects endothelial function in hypertension. Two-week sitagliptin treatment (10 mg/kg per day, oral gavage) improved endothelium-dependent relaxation in renal arteries, restored renal blood flow, and reduced systolic blood pressure in spontaneously hypertensive rats. In vivo sitagliptin treatment elevated GLP-1 and GLP-1 receptor expressions, increased cAMP level, and subsequently activated protein kinase A, liver kinase B1, AMP-activated protein kinase-α and endothelial NO synthase in spontaneously hypertensive rat renal arteries. Inhibition of GLP-1 receptor, adenylyl cyclase, protein kinase A, AMP-activated protein kinase-α, or NO synthase reversed the protective effects of sitagliptin. We also demonstrate that GLP-1 receptor agonist exendin 4 in vitro treatment had similar vasoprotective effects in spontaneously hypertensive rat renal arteries and increased NO production in spontaneously hypertensive rat aortic endothelial cells. Studies using transient expressions of wild-type and dominant-negative AMP-activated protein kinase-α2 support the critical role of AMP-activated protein kinase-α in mediating the effect of GLP-1 in endothelial cells. Ex vivo exendin 4 treatment also improved endothelial function of renal arteries from hypertensive patients. Our results elucidate that upregulation of GLP-1 and related agents improve endothelial function in hypertension by restoring NO bioavailability, suggesting that GLP-1 signaling could be a therapeutic target in hypertension-related vascular events.

The present study investigated whether or not calcitriol, an active form of vitamin D, protects against renovascular dysfunction in hypertension and, if so, whether or not such protection alters the expression of key proteins involved in that dysfunction. Changes in isometric tension showed that the impaired endothelium-dependent relaxations in renal arteries of hypertensive patients were enhanced by 12 h in vitro treatment with calcitriol. Dihydroethidium fluorescence revealed an elevated level of reactive oxygen species (ROS) in these arteries which was reduced by calcitriol. Immunofluorescence showed that calcitriol treatment reduced the expression of AT₁R, NOX-2, NOX-4, and p67^phox and increased that of superoxide dismutase (SOD)-1. Twelve-hour exposure to calcitriol prevented angiotensin (Ang) II-induced increases in ROS and the over-expression of NOX-2, NOX-4, and p67^phox in renal arteries from normotensive patients. A specific antagonist of the human vitamin D receptor (VDR), TEI-9647, abolished these effects of calcitriol. Both in vitro exposure to and chronic in vivo administration of calcitriol enhanced relaxations to acetylcholine and abolished exaggerated endothelium-dependent contractions in renal arteries of normotensive rats pre-exposed to Ang II or harvested from spontaneously hypertensive rats (SHR). Reactive oxygen species levels and expressions of AT₁R, NAD(P)H oxidase subunits, SOD-1, and SOD-2 in SHR arteries were normalized by the chronic treatment with calcitriol. In vivo and in vitro activation of VDR with calcitriol improves endothelial function by normalizing the expressions of AT₁R and radical generating and scavenging enzymes and thus preventing ROS over-production. The present findings suggest that calcitriol is effective in preserving endothelial function in hypertension.