Small heterodimer partner (SHP) is an epigenetically regulated nuclear transcriptional repressor that suppresses the development of liver cancer by inhibiting cellular growth. Here we report a novel cytoplasmic function of SHP through its regulation of mitochondrial activity. SHP is a pivotal cell death receptor that targets mitochondria, where it binds with Bcl-2, disrupts Bcl-2/Bid interaction, and induces cytochrome c release. The apoptosis inducer AHPN {retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid} acts by regulating SHP gene expression and promotes the translocation of SHP from the nucleus to the mitochondria. Induction of apoptosis by SHP activation inhibits peritoneal pancreatic tumor growth. Our findings provide for the first time a mechanism by which SHP regulates cell survival, namely, by controlling mitochondrial function via modulating the activity of Bcl-2 through AHPN-mediated or AHPN-independent action. Thus, SHP regulates a mechanism by which apoptotic signals can mediate local control of mitochondrial function and apoptosis, which in turn may limit tumorigenesis.

The small heterodimer partner (SHP; NROB2), a member of the nuclear receptor superfamily, contributes to the biological regulation of several major functions of the liver. However, the role of SHP in cellular proliferation and tumorigenesis has not been investigated before. Here we report that SHP negatively regulates tumorigenesis both in vivo and in vitro. SHP−/− mice aged 12 to 15 months old developed spontaneous hepatocellular carcinoma, which was found to be strongly associated with enhanced hepatocyte proliferation and increased cyclin D1 expression. In contrast, overexpressing SHP in hepatocytes of SHP-transgenic mice reversed this effect. Embryonic fibroblasts lacking SHP showed enhanced proliferation and produced increased cyclin D1 messenger RNA and protein, and SHP was shown to be a direct negative regulator of cyclin D1 gene transcription. The immortal SHP−/− fibroblasts displayed characteristics of malignant transformed cells and formed tumors in nude mice. Conclusion These results provide first evidence that SHP plays tumor suppressor function by negatively regulating cellular growth.

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Layer-by-Layer (LbL) self-assembly has been investigated for several decades. However, the conventional LbL method has performance problems on the chair-side caused by its cumbersome and time-consuming process. Thus, we investigate a new LbL self-assembly technique for the fast and high efficient preparation process based on the brush. The multilayer films fabricated by simple sequential brushing of polyelectrolyte solutions are compared to the classical dipping method. We characterize the multilayer films by characteristics such as their morphology and thickness, and compare them against those of the classic method by profilometry, atomic force microscopy. We prepare multilayer films with biocompatible polyelectrolytes, chitosan, and alginate incorporated with a hydrophobic drug carrier. For the drug carrier, a poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) block copolymer is introduced to construct micelles containing dexamethasone, which is a well-known osteogenesis-inducing drug. The hydrogen bonding behavior between adjacent layers and micelles is investigated by Fourier transform infrared spectroscopy. Additionally, we analyze the release profiles, degradation profiles and toxicity of the multilayer films for biomedical applications. From these results, we can identify the brushing LbL method as a reliable and more efficient multilayer film-construction process compared to conventional dipping LbL, especially for practical applications in dental and clinical situations.

To utilize potentials of nitric oxide (NO) gas in anti-bacterial, anticancer, wound healing applications, numerous studies have been conducted to develop a NO delivery system in the past few decades. Even though a coating method and film types are essential to apply in biomedical device coating from previous NO delivery systems, release control from the coating system is still challenging. In this study, we introduced a multilayered polymeric coating system to overcome the uncontrollable NO release kinetics of film systems. We used biocompatible gelatin and tannic acid to construct a rough, porous structured film based on the layer-by-layer self-assembly method. The multilayered polymeric structure facilitated the controlled amount of NO release from (Gel/TA) n film and showed burst release in early period owing to their large surface area from the rough, porous structure. We synthesized the proton-responsive NO donor, N- diazeniumdiolate (NONOates), into the (Gel/TA) n film through a chemical reaction under high pressure NO gas. NO release profile was analyzed by a real-time NO analysis machine (NOA 280i). Then, the NO-releasing (Gel/TA) n film was tested its toxicity against human dermal fibroblast cells and bactericidal effects against Staphylococcus aureus .

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Because nitric oxide (NO) gas is an endogenously produced signaling molecule related to numerous physiological functions, manystudies have been conducted to develop NO delivery systems for potential biomedical applications. However, NO is a reactive radical gas molecule that has a very short life-time and readily transforms into nitrogen oxide species via reaction with oxygen species. Therefore, it is necessary to develop an NO delivery carrier that allows local release of the NO gas at the site of application. In this study, Laponite (LP) nanoclay was used to fabricate an NO delivery carrier through the formation of Laponite− polyamine (LP−PAn) composites. The Laponite clay and pentaethylenehexamine (PEHA) formed a macromolecular structure by electrostatic interaction and the nitric oxide donor, N-diazeniumdiolate (NONOates), was synthesized into the LP−PAn composite. We investigated the conformation of the LP−PAn composite structure and the NO donor formation by ζ potential, X-ray diffraction, and UV−vis and Fourier transform infrared (FT-IR) spectroscopies and also by analyzing the NO release profile. Additionally, we confirmed the applicability in biomedical applications via a cell viability and in vitro endothelial cell tube formation assay.

Incidence ofglaucoma, a severe disease leading to irreversible loss of vision, is increasing with global aging populations. Lowering intraocular pressure (IOP) is the only proven treatment method for glaucoma. Nitric oxide (NO) is an emerging material targeting the conventional outflow pathway by relaxing the trabecular meshwork (TM). However, there is little understanding on the NO level effective in IOP lowering without toxicity. Here, we report a novel long-term NO-releasing polydiazeniumdiolate (NOP) that enables lowering IOP via the conventional outflow pathway. NOP is composed of carbon-bound polydiazeniumdiolate, a stable NO donor moiety. NO release was monitored with accurate parameters by real-time detection of gas and analysis of the accumulated release profile. Based on the NO release information, the selected safe level of NOP exhibited effective TM relaxation and a potential IOP lowering effect in vivo without side effects. This work provides new insights into nitric oxide release behavior that should be considered for glaucoma treatment.