Ping-Jyun Sung

Mesoporous silica nanoparticles for the improved anticancer efficacy of cis-platin

We designed a novel cis-platin (CP) delivery system by modification of mesoporous silica nanoparticle (MSN) surfaces with a carboxylate group through a hydrazone bond. The further immobilization of CP can be achieved through the coordination of the carboxylate-modified MSN surfaces with the hydroxo-substituted CP. This new formulation can efficiently increase efficiency of both the cellular uptake and the drug release under endosomal or lysosomal pHs; therefore, the anti-proliferative effect of this new formulation on the colon cancer cell line (HT-29) was twenty times more than the free CP molecules. In addition, the encapsulation of CP complexes in the confined spaces of MSNs can decrease non-specific release from enzymatic hydrolysis because most hydrolytic enzymes have diameters considerably greater than the pore size of MSNs. The DNA fragmentation and caspase-3 activity assay showed that the apoptosis was induced by DNA damages and then an increase in caspase-3 activity. Thus, the TA-MSN-carboxylate-CP samples were induced cell apoptosis through the caspase-3 dependent pathway. Moreover, the hemolysis assay also indicated that the exposure of the carboxylate-modified MSNs in red blood cells (RBCs) did not observe the release of red hemoglobin from the cell lysis, and the further exposure of the TA-MSN-carboxylate-CP complexes to RBCs also did not observe notably the lysis of RBCs under the effectively therapeutic dosage. Therefore, our design of MSN with controllable release of CP has highly therapeutic effects and is highly biocompatible; however, a low cytotoxicity and site effect were observed.

Survey of briarane-type diterpenoids - Part IV

The structures, names, biological activities, and references of 137 briarane-type diterpenoids are summarized. All briaranes mentioned in this review article were obtained from various octocorals including the specimens belonging to the genus Briareum, Ellisella, Gorgonella, Junceella, Subergorgia, Renilla, and Pachyclavularia.

Antroquinonol inhibits NSCLC proliferation by altering PI3K/mTOR proteins and miRNA expression profiles

Antroquinonol a derivative of Antrodia camphorata has been reported to have antitumor effects against various cancer cells. However, the effect of antroquinonol on cell signalling and survival pathways in non-small cell lung cancer (NSCLC) cells has not been fully demarcated. Here we report that antroquinonol treatment significantly reduced the proliferation of three NSCLC cells. Treatment of A549 cells with antroquinonol increased cell shrinkage, apoptotic vacuoles, pore formation, TUNEL positive cells and increased Sub-G1 cell population with respect to time and dose dependent manner. Antroquinonol treatment not only increased the Sub-G1 accumulation but also reduced the protein levels of cdc2 without altering the expression of cyclin B1, cdc25C, pcdc2, and pcdc25C. Antroquinonol induced apoptosis was associated with disrupted mitochondrial membrane potential and activation of Caspase 3 and PARP cleavage in A549 cells. Moreover, antroquinonol treatment down regulated the expression of Bcl2 proteins, which was correlated with the decreased PI3K and mTOR protein levels without altering pro apoptotic and anti apoptotic proteins. Results from the microarray analysis demonstrated that antroquinonol altered the expression level of miRNAs compared with untreated control in A549 cells. The data collectively suggested the antiproliferative effect of antroquinonol on NSCLC A549 cells, which provides useful information for understanding the anticancer mechanism influenced by antroquinonol and is the first report to suggest that antroquinonol may be a promising chemotherapeutic agent for lung cancer.

Klysimplexins I–T, eunicellin-based diterpenoids from the cultured soft coral Klyxum simplex

New eunicellin-base diterpenoids, klysimplexins I-T (1-12), were isolated from a cultured soft coral Klyxum simplex. Their structures were elucidated by spectroscopic methods, particularly in 1D and 2D NMR experiments. The absolute stereochemistry of 4 was determined by Moshers method. Compounds 9 and 12 have been shown to exhibit cytotoxicity toward a limited panel of cancer cell lines. Compounds 2-6, 10 and 11 were found to display significant in vitro anti-inflammatory activity in LPS-stimulated RAW264.7 macrophage cells by inhibiting the expression of the iNOS protein. Compounds 10 and 11 also could effectively reduce the level of COX-2 protein.

Cladielloides A and B: New Eunicellin-Type Diterpenoids from an Indonesian Octocoral Cladiella sp.

Two new eunicellin-type diterpenoids, cladielloides A (1) and B (2), which were found to possess a 2-hydroxybutyroxy group in their structures, were isolated from an Indonesian octocoral identified as Cladiella sp. The structures of eunicellins 1 and 2 were elucidated by spectroscopic methods. Cladielloide B (2) exhibited moderate cytotoxicity toward CCRF-CEM tumor cells and this compound displayed significant inhibitory effects on superoxide anion generation and elastase release by human neutrophils.

Briaexcavatolides A–J, new diterpenes from the gorgonian briareum excavatum

Abstract Ten new briarane-type diterpenes have been isolated from the gorgonian octocoral Briareum excavatum . The structures of these secondary metabolites, named briaexcavatolides A–J ( 1 – 10 ), were established by spectroscopic and chemical methods. The structure, including the relative configuration of briaexcavatolide B ( 2 ), was further confirmed by a single-crystal X-ray structure analysis. Cytotoxicity of these compounds toward various cancer cell lines also is described.

Layered double hydroxide nanoparticles to enhance organ-specific targeting and the anti-proliferative effect of cisplatin

To evaluate the role of charge in the nanoparticle distribution we modified the external surface of layered double hydroxide nanoparticles with various organic groups bearing different charges and further a near-infrared (NIR) fluorescent dye (Cy5.5) is conjugated in the layered structure to assess the biodistribution. The functionalized nanocomposites performed as highly efficient contrast agents since Cy5.5 molecule stabilization inside the layered structure can safeguard them from metabolization in the physiological environments. The cell viability, lactate dehydrogenase and hemolytic assays showed no cytotoxicity with an exceptionally low release of both lactate dehydrogenase and hemoglobin from the treated cells. The in vivo biodistribution results disclosed a high accumulation of positive amino-layered double hydroxides (LDHs) in the lungs. In contrast, there is a rapid clearance of negatively charged carboxylate-LDHs from blood flow by liver uptake. Interestingly neutral LDH-PEG5000 showed enhanced blood circulation time, without high fluorescent accumulation in the major organs. In vitro cellular uptake studies from flow cytometry are relevant to the interactions between the nanoparticle surfaces and various cell types and the data are relevant to effects observed for in vivo biodistribution. To further demonstrate that surface functionalization on LDH nanoparticles can promote targeted drug release, we further immobilized hydroxo-substituted cisplatin (CP) on carboxylate-modified LDHs by coordination bonding. Due to the ideal cleaving property of the carboxylate group the coordinated CP can be efficiently released by the increase of acidic proton and Cl- concentration in the endosomal environment. Functionalized LDHs can be successfully employed as targeted drug delivery systems. When the LDH-CP complex accumulate primarily in the targeted organ, the high positive charge on the framework of LDHs cause susceptibility to rapid endocytosis, which facilitates sustained drug release with minimal systemic toxicity providing the apt treatment in the targeted organ.

Excavatoids E and F: discovery of two new briaranes from the cultured octocoral Briareum excavatum.

Two new briarane-related diterpenoids, designated as excavatoids E (1) and F (2), were isolated from the cultured octocoral Briareum excavatum. The structures of compounds 1 and 2 were established on the basis of extensive spectral data analysis. Briaranes 1 and 2 were found to exhibit moderate inhibitory effects on elastase release by human neutrophils.

Resveratrol inhibits glucose-induced migration of vascular smooth muscle cells mediated by focal adhesion kinase.

SCOPE Diabetes is a critical factor for atherosclerosis, as hyperglycemia induces vascular smooth muscle cell (VSMC) proliferation and migration and subsequently contributes to the formation of atherosclerotic lesions. This study investigates whether resveratrol plays a regulatory role in the proliferation and migration of VSMCs under high glucose induction to imitate a hyperglycemic condition. METHODS AND RESULTS Resveratrol inhibited the migration of VSMCs in the wound-healing assay and the formation of lamellipodia and filopodia as assessed by atomic force microscopy scanning. Resveratrol suppressed the mRNA expression of c-Src, Rac1, cdc42, IRS-1, MEKK1, MEKK4, and mitogen-activated protein kinase along with the protein levels of c-Src, p-Src, and cdc42 in VSMCs. Resveratrol decreased the level of p-FAK protein under normal glucose conditions. Resveratrol could inhibit the activities of matrix metalloproteinase (MMP) 2 and MMP 9 as shown by zymography. Moreover, resveratrol also regulated the mitogen-activated protein kinase pathway and MMP activities of VSMC migration under the high glucose condition. CONCLUSION The antimigratory effects of resveratrol by reduced MMP expression through the inhibition of Rac1, p-FAK, and lamellipodia formation and the activation of p-AKT and p-ERK1/2 suggest that resveratrol is a potential compound for the treatment of vascular diseases via the regulation of VSMC migration.

Discovery of New Eunicellins from an Indonesian Octocoral Cladiella sp.

Two new 11-hydroxyeunicellin diterpenoids, cladieunicellin F (1) and (–)-solenopodin C (2), were isolated from an Indonesian octocoral Cladiella sp. The structures of eunicellins 1 and 2 were established by spectroscopic methods, and eunicellin 2 was found to be an enantiomer of the known eunicellin solenopodin C (3). Eunicellin 2 displayed inhibitory effects on the generation of superoxide anion and the release of elastase by human neutrophils. The previously reported structures of two eunicellin-based compounds, cladielloides A and B, are corrected in this study.