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OBJECTIVE: The aim of the study was to improve the bioavailability of Cinacalcet hydrochloride (CLC) and enhance its efficacy by the nanoemulsion drug delivery system. MATERIALS AND METHODS: First, cinacalcet hydrochloride-nanoemulsion (CLC-NE) was prepared and optimized through the pseudo ternary phase diagram and central composite design response surface methodology (CCD). The release of CLC-NE in vitro was investigated with four different dissolution media, and the bioavailability of CLC-NE in vivo was studied through beagle dogs. Finally, the pharmacodynamics of CLC-NE was evaluated by the rat model of uremia. RESULTS: Oleic acid, op-10, and PEG-200 were selected as oil phase, emulsifier, and co-emulsifier, respectively. The optimum ratio of oleic acid, op-10, PEG-200, and water was 9.87%, 38.33%, 12.78%, and 39.02%. CLC-NE has similar dissolution rates in different pH media, and the relative bioavailability of CLC-NE was 166.5%. The uremia model showed that CLC-NE could enhance renal function and reduce the excessive phosphorus (P), serum creatinine (Scr), and urea nitrogen (Urea) of model rats, as well as the inhibited increase of fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH). CONCLUSIONS: The solubility, bioavailability, and pharmacodynamics of CLC can be significantly improved through the nanoemulsion drug delivery system. [ABSTRACT FROM AUTHOR]

Background: Mutations in HBx gene are frequently found in HBV-associated hepatocellular carcinoma (HCC). Activation of hypoxia-inducible factor-1α (HIF-1α) contributes to HCC development and progression. Wild-type HBx has been demonstrated to activate HIF-1α, but the effect of HBx mutations on HIF-1α has not been elucidated.Methods: HBx mutations were identified by gene sequencing in 101 HCC tissues. Representative HBx mutants were cloned and transfected into HCC cells. Expression and activation of HIF-1α were analysed by western blot and luciferase assays, respectively. The relationship between HBx mutants and HIF-1α expression in HCC tissues was also evaluated.Results: The dual mutations K130M/V131I enhanced the functionality of HBx as they upregulated the expression and transcriptional activity of HIF-1α. The C-terminal truncations and deletion mutations, however, weakened the ability of HBx to upregulate HIF-1α. Meanwhile, the C-terminus was further found to be essential for the stability and transactivation of HBx. In the HCC tissues, there was a positive association between the HBx mutants and HIF-1α expression.Conclusion: Different mutations of HBx exert differentiated effects on the functionality of HIF-1α, however, the overall activity of HBx mutants appears to increase the expression and transcriptional activity of HIF-1α. [ABSTRACT FROM AUTHOR]

The role of thromboxane A2 (TxA2) in smoking-associated lung cancer is poorly understood. This study was conducted to study the role of TxA2 in smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-promoted cell survival and growth in human lung cancer cells. We found that NNK increased TxA2 synthase (TxAS) expression and thromboxane B2 (TxB2) generation in cultured lung cancer cells, the result of which was supported by the increased level of TxAS in lung cancer tissues of smokers. Both TxAS-specific inhibitor furegrelate and TxA2 receptor antagonist SQ29548 completely blocked NNK-mediated cell survival and growth via inducting apoptosis. TxA2 receptor agonist U46619 reconstituted a near-full survival and growth response to NNK when TxAS was inhibited, affirming the role of TxA2 receptor in NNK-mediated cell survival and growth. Suppression of cyclic adenosine monophosphate response element binding protein (CREB) activity by its small interference RNA blocked the effect of NNK. Phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) also had a positive role. Altogether, our results have revealed that NNK stimulates TxA2 synthesis and activates its receptor in lung cancer cells. The increased TxA2 may then activate CREB through PI3K/Akt and extracellular ERK pathways, thereby contributing to the NNK-promoted survival and growth of lung cancer cells. [ABSTRACT FROM AUTHOR]

In this article, we primarily focus on the treatment approaches currently marketed and in advanced stages of development for Alzheimer's disease (AD). Amyloid plaques and neurofibrillary tangles remain the pathologic hallmarks of AD, and much progress has been made in unraveling the molecular biology of these changes. In addition, there is also intense research into inflammatory and oxidative mechanisms as well as vascular and neurochemical alterations in AD. Therapies targeted at these mechanisms are discussed. [ABSTRACT FROM AUTHOR]