A hybrid nanopharmaceutical for specific-amplifying oxidative stress to initiate a cascade of catalytic therapy for pancreatic cancer.

BACKGROUND: Oxidative stress (OS) induced by an imbalance of oxidants and antioxidants is an important aspect in anticancer therapy, however, as an adaptive response, excessive glutathione (GSH) in the tumor microenvironment (TME) acts as an antioxidant against high reactive oxygen species (ROS) levels and prevents OS damage to maintain redox homoeostasis, suppressing the clinical efficacy of OS-induced anticancer therapies. RESULTS: A naturally occurring ROS-activating drug, galangin (GAL), is introduced into a Fenton-like catalyst (SiO2@MnO2) to form a TME stimulus-responsive hybrid nanopharmaceutical (SiO2-GAL@MnO2, denoted SG@M) for enhancing oxidative stress. Once exposed to TME, as MnO2 responds and consumes GSH, the released Mn2+ converts endogenous hydrogen peroxide (H2O2) into hydroxyl radicals (·OH), which together with the subsequent release of GAL from SiO2 increases ROS. The "overwhelming" ROS cause OS-mediated mitochondrial malfunction with a decrease in mitochondrial membrane potential (MMP), which releases cytochrome c from mitochondria, activates the Caspase 9/Caspase 3 apoptotic cascade pathway. Downregulation of JAK2 and STAT3 phosphorylation levels blocks the JAK2/STAT3 cell proliferation pathway, whereas downregulation of Cyclin B1 protein levels arrest the cell cycle in the G2/M phase. During 18 days of in vivo treatment observation, tumor growth inhibition was found to be 62.7%, inhibiting the progression of pancreatic cancer. Additionally, the O2 and Mn2+ released during this cascade catalytic effect improve ultrasound imaging (USI) and magnetic resonance imaging (MRI), respectively. CONCLUSION: This hybrid nanopharmaceutical based on oxidative stress amplification provides a strategy for multifunctional integrated therapy of malignant tumors and image-visualized pharmaceutical delivery.

[Risk factors for hyperuricemia in active and retired employees underwent physical examination].

OBJECTIVE: To observe serum uric acid (UA) level distribution and explore risk factors of hyperuricemia (HUA) in a large cohort of active and retired employees underwent physical examination. METHODS: Physical examination was arranged for 21 700 active and retired employees from May 2010 to September 2011, 16 416 employees were examined and complete examination data were obtained in 14 044 subjects. The distribution characteristics of UA level and correlations of UA level and HUA prevalence rate with gender, age, body mass index (BMI), systolic pressure (SBP), diastolic pressure (DBP), fasting blood-glucose (FPG), serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) were analyzed. RESULTS: HUA prevalence rate was 11.2% in this cohort, which was significantly higher in males (15.8%) than in females (4.1%, P < 0.05). The UA level and the HUA prevalence rate presented a "J" curve relationship with aging and positively correlated with BMI, SBP, DBP, TG, LDL-C, TC and FPG while negatively correlated with HDL-C. Multiple linear regression analysis showed that SBP, BMI, FPG, TG, and LDL-C were independent risk factors while HDL-C and female gender were the protective factors of HUA(all P < 0.01). Aging and high DBP were independent risk factors of HUA for females (all P < 0.05) and LDL-C was risk factor of HUA for males (P < 0.05). CONCLUSIONS: Serum UA level presents a "J" wave relationship with aging. The risk factors of HUA are increased SBP, BMI, FPG, TG, LDL-C while the protective factors of HUA are female gender and high HDL-C.