Tuck-Yun Cheang

MicroRNA-21 Regulates Vascular Smooth Muscle Cell Function via Targeting Tropomyosin 1 in Arteriosclerosis Obliterans of Lower Extremities

Objective —The goal of this study was to determine the expression signature and the potential role of microRNAs in human arteries with arteriosclerosis obliterans (ASO). Methods and Results —The expression profiles of microRNAs in human arteries with ASO and in normal control arteries were determined by quantitative reverse transcription–polymerase chain reaction array. Among the 617 detected microRNAs, multiple microRNAs were aberrantly expressed in arteries with ASO. Some of these dysregulated microRNAs were further verified by quantitative reverse transcription–polymerase chain reaction. Among them, microRNA-21 (miR-21) was mainly located in arterial smooth muscle cells (ASMCs) and was increased by more than 7-fold in ASO that was related to hypoxia inducible factor 1-&agr;. In cultured human ASMCs, cell proliferation and migration were significantly decreased by inhibition of miR-21. 3′-Untranslated region luciferase assay confirmed that tropomyosin 1 was a target of miR-21 that was involved in miR-21-mediated cellular effects, such as cell shape modulation. Conclusion —The results suggest that miR-21 is able to regulate ASMC function by targeting tropomyosin 1. The hypoxia inducible factor-1 &agr;/miR-21/tropomyosin 1 pathway may play a critical role in the pathogenesis of ASO. These findings might provide a new therapeutic target for human ASO.

Calcium carbonate/CaIP6 nanocomposite particles as gene delivery vehicles for human vascular smooth muscle cells

Gene therapy provides great opportunities for treating diseases from genetic disorders to immune system diseases and cancer. Much work has focused on bioactive macromolecules and nanoparticles, which can interact with low-molecular-mass drugs or DNA molecules to form complexes, and have been used for local delivery of therapeutic factors for tissue regeneration or gene therapy. In this study, inorganic amorphous calcium carbonate (ACC) hybrid nanospheres functionalized with a small amount of Ca(II)-IP6 compound (CaIP6) were prepared on a large scale by a facile gas-diffusion method. The results of in vitro transfection experiments show that the obtained functional calcium carbonate/phosphate nanocomposite particles had higher transfection efficiency and lower cytotoxicity level than commercial Lipofectamine 2000. From these results alternative new vectors for gene delivery could be developed. In addition, functionalized inorganic nanocomposite particles are biocompatible and biodegradable, thus the as-prepared hybrid nanospheres are promising for biomedical applications as a safe biomaterial.

The inhibition of human bladder cancer growth by calcium carbonate/CaIP6 nanocomposite particles delivering AIB1 siRNA.

Previously, we reported that inorganic amorphous calcium carbonate (ACC) hybrid nanospheres functionalized with Ca(II)-IP6 compound (CaIP6) is a promising gene vector in vitro. Here, nonviral gene carrier, ACC/CaIP6 nanocomposite particles (NPACC/CaIP6), was evaluated for efficient in vitro and in vivo delivery of small interfering RNA (siRNA) targeting human Amplified in breast cancer 1 (AIB1). The nanoparticle is capable of forming ACC/CaIP6 nanoparticle-siRNA complexes and transferring siRNA into targeted cells with high transfection efficiency. Meanwhile the ACC/CaIP6 nanoparticle-siRNA complexes have no obvious cytotoxicity for human bladder cancer T24 cells. Furthermore, NPACC/CaIP6 effectively protected the encapsulated siRNA from degradation, AIB1 knockdown mediated by ACC/CaIP6/siRNA complexes transfection resulted in cells proliferation inhibition, apoptosis induction and cell cycle arrest in vitro. NPACC/CaIP6 exhibited well tissues penetrability in localized siRNA delivering, intratumoral injection of NPACC/CaIP6/siAIB1 could attenuate tumor growth and downregulation of PI3K/Akt signaling pathway in vivo. We conclude that ACC/CaIP6 nanoparticle is a promising system for effective delivery of siRNA for cancer gene therapy.

Anticancer drug-loaded multifunctional nanoparticles to enhance the chemotherapeutic efficacy in lung cancer metastasis

BackgroundInhalation of chemotherapeutic drugs directly into the lungs augments the drug exposure to lung cancers. The inhalation of free drugs however results in over exposure and causes severe adverse effect to normal cells. In the present study, epidermal growth factor (EGF)-modified gelatin nanoparticles (EGNP) was developed to administer doxorubicin (DOX) to lung cancers.ResultsThe EGNP released DOX in a sustained manner and effectively internalized in EGFR overexpressing A549 and H226 lung cancer cells via a receptor-mediated endocytosis. In vitro cytotoxicity assay showed that EGNP effectively inhibited the growth of A549 and H226 cells in a dose-dependent manner. In vivo biocompatibility study showed that both GNP and EGNP did not activate the inflammatory response and had a low propensity to cause immune response. Additionally, EGNP maintained a high therapeutic concentration in lungs throughout up to 24 h comparing to that of free drug and GNP, implying the effect of ligand-targeted tumor delivery. Mice treated with EGNP remarkably suppressed the tumor growth (~90% tumor inhibition) with 100% mice survival rate. Furthermore, inhalation of EGNP resulted in elevated levels of cleaved caspase-3 (apoptotic marker), while MMP-9 level significantly reduced comparing to that of control group.ConclusionsOverall, results suggest that EGF surface-modified nanocarriers could be delivered to lungs via inhalation and controlled delivery of drugs in the lungs will greatly improve the therapeutic options in lung cancer therapy. This ligand-targeted nanoparticulate system could be promising for the lung cancer treatment.

Promising plasmid DNA vector based on APTES-modified silica nanoparticles

Nanoparticles have an enormous potential for development in biomedical applications, such as gene or drug delivery. We developed and characterized aminopropyltriethoxysilane-functionalized silicon dioxide nanoparticles (APTES-SiNPs) for gene therapy. Lipofectamine® 2000, a commonly used agent, served as a contrast. We showed that APTES-SiNPs had a gene transfection efficiency almost equal to that of Lipofectamine 2000, but with lower cytotoxicity. Thus, these novel APTES-SiNPs can achieve highly efficient transfection of plasmid DNA, and to some extent reduce cytotoxicity, which might overcome the critical drawbacks in vivo of conventional carriers, such as viral vectors, organic polymers, and liposomes, and seem to be a promising nonviral gene therapy vector.

Bimetallic phosphide hollow nanocubes derived from a prussian-blue-analog used as high-performance catalysts for the oxygen evolution reaction

The development of efficient and stable electrocatalysts for the oxygen evolution reaction (OER) based on earth-abundant materials is of significance to enable water splitting as a feasible source of alternative energy. Metal–organic frameworks (MOFs) have been intensively employed as the templates/precursors to synthesize catalysts with hollow structures for various energy-related applications. In this study, using MOF (Ni–Fe prussian-blue-analog) as a template and precursor, a novel and promising bimetallic phosphide catalyst (Ni0.62Fe0.38)2P was obtained. Benefiting from synergistic effect between the Ni and Fe species, well-defined architecture and high surface area the as-made (Ni0.62Fe0.38)2P hollow nanocubes show a remarkable electrocatalytic performance for the OER in 1 M KOH electrolyte with a low overpotential of only 290 mV at a current density of 10 mA cm−2 and a small Tafel slope of 44 mV per decade, which even surpass the benchmark IrO2 catalyst. Moreover, the (Ni0.62Fe0.38)2P hollow nanocubes exhibit good long-term stability. This facile and novel route to prepare bimetallic phosphide hollow nanocubes as active OER catalysts broadens the scope for designing other noble-metal-free OER efficient catalysts for electrochemical water splitting in the future.

Double-positive expression of high-mobility group box 1 and vascular endothelial growth factor C indicates a poorer prognosis in gastric cancer patients

BackgroundAlthough many studies have indicated that high-mobility group box 1 protein (HMGB1) is associated with oncogenesis and a worse prognosis, the prognostic value of HMGB1 in gastric cancer (GC) remains unclear. In the present work, we aimed to evaluate the role of HMGB1 in GC and examined whether aberrant expression of both HMGB1 and vascular endothelial growth factor C (VEGF-C) increased the malignant potential of GC.MethodsA total of 166 GC patients and 32 normal subjects were enrolled. HMGB1 and VEGF-C expression was detected by tissue microarrays (TMAs) and immunohistochemical staining. The correlation between HMGB1 and VEGF-C expression and their relationships with clinicopathological GC variables were examined. Univariate and multivariate analyses were performed using the Cox proportional hazard model to predict the factors related to the patients‘ overall survival rates.ResultsHMGB1 and VEGF-C expression were observed in 81 (48.80%) and 88 (53.01%) tumors, respectively, significantly higher than the rates among the corresponding controls. In addition, HMGB1 and VEGF-C expression were positively correlated (R2 = 0.972). HMGB1 expression was also closely associated with tumor size, pT stage, nodal status, metastasis status, TNM stage, and poor prognosis. Multivariate survival analysis indicated that patients with HMGB1 and VEGF-C coexpression had the worst prognoses and survival rates (hazard ratio, 2.78; log rank P<0.001).ConclusionsHMGB1 is commonly expressed in GC. Combined evaluation of HMGB1 and VEGF-C may serve as a valuable independent prognostic factor for GC patients.

CaCO3/CaIP6 composite nanoparticles effectively deliver AKT1 small interfering RNA to inhibit human breast cancer growth

Background Small interfering RNA (siRNA)-mediated gene therapy is a promising strategy to temporarily inhibit the expression of genes involved in development of breast cancer. The lack of a safe and efficient gene delivery system has become a major hurdle for siRNA-mediated gene therapy in breast cancer. Our previous studies have demonstrated that inorganic amorphous calcium carbonate (ACC) hybrid nanospheres functionalized with CaIP6 (ACC/CaIP6) nanoparticles are an efficient nucleic acid delivery tool. The present study aimed to evaluate the safety and efficiency of ACC/CaIP6 in delivering siRNA targeting AKT1 (siAKT1) for the treatment of breast cancer. Methods The cytotoxicity of the ACC/CaIP6 nanoparticles was evaluated using a tetrazolium assay. The transfection efficiency and intracellular distribution of ACC/siAKT1 were analyzed by flow cytometry and confocal laser scanning microscopy, respectively. A series of in vitro and in vivo assays was performed to evaluate the effects of ACC/CaIP6/siAKT1 on growth of breast cancer cells. Results ACC/CaIP6 nanoparticles effectively transfected cells with little or no toxicity. AKT1 knockdown by ACC/CaIP6/siAKT1 inhibited cell cycle progression and promoted apoptosis of MCF-7 cells. Intratumoral injection of ACC/CaIP6/siAKT1 significantly suppressed the growth of breast cancer in mice. Conclusion ACC/CaIP6 nanoparticles are a safe and efficient method of delivering siRNA for gene therapy in breast cancer.

Marine fungal metabolite 1386A alters the microRNA profile in MCF-7 breast cancer cells

Marine fungal metabolite 1386A is a newly identified small molecular compound extracted from the mangrove fungus 1386A in the South China Sea. Preliminary experiments have demonstrated its amazing cytotoxity to cancer cells, while the mechanism remains poorly understood. microRNAs (miRNAs) are a newly identified class of small regulatory RNAs which play an important role in gene regulation at the post-transcriptional level. They usually function as oncogenes or tumor suppressors and are related to drug sensitivity and resistance. We aimed to test the hypothesis that the potential antineoplastic compound, 1386A, alters the miRNA profile in MCF-7 and whether its unknown mechanism may be predicted by analysis of the altered miRNA profile. Cell proliferation was analyzed by MTT assay. The alteration of the miRNA expression profile of MCF-7 cells was investigated using advanced microarray technology. Silico analysis using TargetScan was used to predict the putative targeted transcripts encoding the dysregulated miRNAs. 1386A inhibited MCF-7 cell proliferation in a time- and dose-dependent manner (the IC50 value at 48 h was 17.1 µmol/l). 1386A (17.1 µmol/l) significantly altered the global miRNA expression profile of the MCF-7 cells at 48 h. Forty-five miRNAs were differentially expressed in MCF-7 cells. Target prediction suggested that these miRNAs potentially target many oncogenes and tumor-suppressor genes associated with cancer development, progression and metastasis. The promising antineoplastic compound marine fungal metabolite 1386A alters the miRNA profiles of MCF-7 breast cancer cells. Analyzing the alteration of the miRNA profile caused by this potential antineoplastic compound may help to predict the unknown mechanism of 1386A.

In situ redox deposition of palladium nanoparticles on oxygen-deficient tungsten oxide as efficient hydrogenation catalysts

Noble metal/metal oxide support hybrid materials have attracted tremendous interest due to their wide applications in catalysis. Herein, we have developed a novel and surfactant-free method to prepare Pd/WO3−x composite materials with clean surfaces. Oxygen-vacancy-rich WO3−x nanowires (NWs) provide free electrons to reduce Pd2+, and surface-clean Pd nanoparticles (NPs) directly grow on WO3−x surfaces through an in situ redox reaction between reductive WO3−x and metal salt precursor (Na2PdCl4) in aqueous solution. The as-obtained Pd/WO3−x nanocomposites show excellent catalytic activities for the hydrogenation of 4-nitrophenol (4-NP) and styrene. The apparent rate constant for 4-NP reduction is 0.045 s−1, over the Pd/WO3−x catalyst. The turnover frequency (TOF) value for styrene hydrogenation is 1074.5 h−1, thus, exhibiting high catalytic performance. Moreover, the obtained Pd/WO3−x catalyst exhibits good stability. Oxygen vacancies in WO3−x NWs can accelerate electron transport and promote hydrogen adsorption and dissociation on the surface of the catalyst. The strong interaction between Pd NPs and WO3−x support contributes to the excellent performance. Our work provides a novel and simple strategy to directly fabricate other-noble metal NP loaded oxygen-deficient metal oxides as highly efficient catalysts for chemical transformation.