The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.

Cancer initiating cells (CICs) are responsible for the unrestrained cell growth and chemoresistance of malignant tumors. Histone demethylation has been shown to be crucial for self-renewal/differentiation of stem cells, but it remains elusive whether lysine-specific demethylase 1 (LSD1) regulates the stemness properties of CICs. Here we report that the abundant expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is associated with the progression of hepatocellular carcinoma (HCC). Lgr5(+) HCC cells behave similarly to CICs and are highly tumorigenic and resistant to chemotherapeutic agents. Importantly, Lgr5(+) cells express higher levels of LSD1, which in turn regulates Lgr5 expression and promotes the self-renewal and drug resistance of Lgr5(+) CICs. Mechanistically, LSD1 promotes β-catenin activation by inhibiting the expression of several suppressors of β-catenin signaling, especially Prickle1 and APC in Lgr5(+) CICs, by directly regulating the levels of mono- and di-methylation of histone H3 lysine-4 at the promoters of these genes. Furthermore, LSD1-associated activation of the β-catenin signaling is essential for maintaining the activity of Lgr5(+) CICs. Together, our findings unravel the LSD1/Prickle1/APC/β-catenin signaling axis as a novel molecular circuit regulating the stemness and chemoresistance of hepatic Lgr5(+) CICs and provide potential targets to improve chemotherapeutic efficacies against HCC.

Liver X receptor a (LXRa) and sterol regulatory element binding protein-1c (SREBP-1c) were studied in rats with nonalcoholic steatohepatitis (NASH) induced by a high-fat diet. Forty 5-week-old rats were fed either a high-fat diet (n = 30) or a normal diet (n = 10) for 9, 13 or 17 weeks. The mRNA and protein levels for LXRa and SREBP-1c were measured at each time point, as was fatty acid synthase (FAS) activity and the serum levels of free fatty acid (FFA) and triglyceride (TG). The mRNA and protein levels for LXRa and SREBP-1c, FAS activity and serum levels of FFA and TG all significantly increased from week 9 in the high-fat diet rats versus controls. In conclusion, a high-fat diet upregulates LXRa which, in turn, upregulates SREBP1c, increasing the activity of FAS and FFA and accumulation of TG in hepatocytes. Thus, LXRa and SREBP-1c contribute to the development of NASH.

Objective Adverse environmental exposure inuteropredisposes to adult disease, including hypertension. Exposure to lipopolysaccharide (LPS) results in increased blood pressure in offspring, but the exact mechanisms are not clear. Our previous study shows dysfunction of renal D1receptor (D1R) isascribed to the pathogenesis of hypertension, which is associated with reactive oxidativestress (ROS). In this study, we test whether dysfunction of renal D1R is involved in fetal programmed hypertension, and whether oxidative stress contribute to this process. Methods Pregnant Sprague–Dawley (SD) rats were intraperitoneally injected with LPS (0.79 mg/kg) or saline (0.5 ml) at gestation day 8, 10 and 12. After birth, the blood pressure is measured, and treated with or without antioxidant tempol in tap water for 3 weeks at postnatal 12 week. Results As compared with control rats, the LPS-treated offspring rats showed higher blood pressure, decreased renal sodium excretion with increased plasma ROS activity. After treatment with tempol for 3 week, the increased blood pressure, decreased sodium excretion were reversed to normal levels in LPS rats. Our further study found LPS rats had lower renal D1R expression, higher D1R phosphorylation, and D1R-mediated natriuresis and diuresis were lost. As an important kinase of D1R phosphorylation, G coupled receptor protein kinase 4 (GRK4) expression was increased in LPS rats. Tempol treatment reversed the decreased D1R expression, increased D1R phosphorylation and GRK4 expression. Moreover, the impaired D1R-mediated natriuresis and diuresis were restored to the control levels in LPS rats after tempol treatment. Conclusion Pprenatal LPS exposure, via impairment of ROS on renal D1R function, leads to hypertension in offspring. Reversion of renal D1R function by alleviation of ROS might be a target for therapy of fetal programming hypertension.

Objective Oxidative stress plays an important role in the pathogenesis of hypertension, particularly associated with obesity-related hypertension. Increased oxidative stress leads to an imbalance of the natriuretic and antinatriuretic factors of the renal renin angiotensin system (RAS). We hypothesise that superoxide-lowering therapy using tempol reverses this imbalance resulting to natriuresis and diuresis, thus lowering the blood pressure of obese Zucker rats. Methods Lean and obese Zucker rats received regular or antioxidant enzyme superoxide dismutase (SOD) mimetic tempol (1.0 mmol/l) in the drinking water for 4 weeks. Results Results showed that, compared with lean rats, obese rats exhibited higher blood pressures, higher levels of renal oxidative stress, accompanied by increased natriuretic responses to AT1R antagonist (candesartan) and AT2R agonist (CGP-42112A) and reduced natriuretic response to MasR agonist (ang-[1–7]). Moreover, obese rats had higher levels of ACE, AT1R and AT2R, lower levels of ACE2 and Mas receptors in the kidney. All of the above-mentioned abnormalities were reversed to some degree by tempol treatment. Conclusion Our study indicates that superoxide-lowering therapy with tempol reverses the imbalance of renal RAS components in obesity-related hypertension, which would be helpful to restore the renal function and lower blood pressure.