Phyllanthus spp. Induces Selective Growth Inhibition of PC-3 and MeWo Human Cancer Cells through Modulation of Cell Cycle and Induction of Apoptosis

BACKGROUND: Phyllanthus is a traditional medicinal plant that has been used in the treatment of many diseases including hepatitis and diabetes. The main aim of the present work was to investigate the potential cytotoxic effects of aqueous and methanolic extracts of four Phyllanthus species (P.amarus, P.niruri, P.urinaria and P.watsonii) against skin melanoma and prostate cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: Phyllanthus plant appears to possess cytotoxic properties with half-maximal inhibitory concentration (IC(50)) values of 150-300 µg/ml for aqueous extract and 50-150 µg/ml for methanolic extract that were determined using the MTS reduction assay. In comparison, the plant extracts did not show any significant cytotoxicity on normal human skin (CCD-1127Sk) and prostate (RWPE-1) cells. The extracts appeared to act by causing the formation of a clear "ladder" fragmentation of apoptotic DNA on agarose gel, displayed TUNEL-positive cells with an elevation of caspase-3 and -7 activities. The Lactate Dehydrogenase (LDH) level was lower than 15% in Phyllanthus treated-cancer cells. These indicate that Phyllanthus extracts have the ability to induce apoptosis with minimal necrotic effects. Furthermore, cell cycle analysis revealed that Phyllanthus induced a Go/G1-phase arrest on PC-3 cells and a S-phase arrest on MeWo cells and these were accompanied by accumulation of cells in the Sub-G1 (apoptosis) phase. The cytotoxic properties may be due to the presence of polyphenol compounds such as ellagitannins, gallotannins, flavonoids and phenolic acids found both in the water and methanol extract of the plants. CONCLUSIONS/SIGNIFICANCE: Phyllanthus plant exerts its growth inhibition effect in a selective manner towards cancer cells through the modulation of cell cycle and induction of apoptosis via caspases activation in melanoma and prostate cancer cells. Hence, Phyllanthus may be sourced for the development of a potent apoptosis-inducing anticancer agent

Allele-Specific Knockdown of ALS-Associated Mutant TDP-43 in Neural Stem Cells Derived from Induced Pluripotent Stem Cells

TDP-43 is found in cytoplasmic inclusions in 95% of amyotrophic lateral sclerosis (ALS) and 60% of frontotemporal lobar degeneration (FTLD). Approximately 4% of familial ALS is caused by mutations in TDP-43. The majority of these mutations are found in the glycine-rich domain, including the variant M337V, which is one of the most common mutations in TDP-43. In order to investigate the use of allele-specific RNA interference (RNAi) as a potential therapeutic tool, we designed and screened a set of siRNAs that specifically target TDP-43(M337V) mutation. Two siRNA specifically silenced the M337V mutation in HEK293T cells transfected with GFP-TDP-43(wt) or GFP-TDP-43(M337V) or TDP-43 C-terminal fragments counterparts. C-terminal TDP-43 transfected cells show an increase of cytosolic inclusions, which are decreased after allele-specific siRNA in M337V cells. We then investigated the effects of one of these allele-specific siRNAs in induced pluripotent stem cells (iPSCs) derived from an ALS patient carrying the M337V mutation. These lines showed a two-fold increase in cytosolic TDP-43 compared to the control. Following transfection with the allele-specific siRNA, cytosolic TDP-43 was reduced by 30% compared to cells transfected with a scrambled siRNA. We conclude that RNA interference can be used to selectively target the TDP-43(M337V) allele in mammalian and patient cells, thus demonstrating the potential for using RNA interference as a therapeutic tool for ALS

Structures and solvatochromic phosphorescence of dicationic terpyridyl-platinum(II) complexes with foldable oligo(ortho-phenyleneethynylene) bridging ligands

A series of binuclear organoplatinum(II) complexes, [(tBu 3tpy)Pt-(C≡C-1,2-C 6H 4) n-C≡C-Pt(tBu 3tpy)]-[ClO 4] 2 (1-7, n = 1, 2, 3, 4, 5, 6, 8; tBu 3tpy = 4,4′,4″-tri- tert-butyl-2,2′:6′,2″-terpyridine) with foldable oligo(orthophenyleneethynylene) linkers were prepared and characterized by spectroscopic methods and/or X-ray crystallographic analyses. In the crystal structures of 3·2.5 CH 3OH, 5·CH 3CN, and 6·4CH 3CN, each of the bridging orthophenyleneethynylene ligands has a partially folded conformation. In aerated water/acetonitrile mixtures with water percentages larger than 40%, the emission of complexes 3-7 are red-shifted and enhanced when compared to those recorded in acetonitrile. The red-shift in emission energy and enhanced emission intensity can be attributed to the inter- and/or intramolecular interactions induced by the addition of water to solutions of the platinum(II) complexes in acetonitrile. Data from dynamic light scattering and transmission electron microscopy studies revealed that these binuclear platinum(II) complexes aggregated into nanosized particles in acetonitrile/water mixtures. Hydrophobic folding of the ortho-phenyleneethynylene linkers in acetonitrile/water mixtures is postulated. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.link_to_subscribed_fulltex

First synthesis of naturally occurring (±)-epi-conocarpan

(±)-epi-Conocarpan 1 was synthesized via the key intermediate 5-bromo-cis-2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzofuran 6 which was synthesized by a ruthenium(II) porphyrin-catalyzed intramolecular C-H insertion reaction using aryl tosylhydrazone salt 5 as the carbene source, starting from the commercially available 5-bromo-2-hydroxyacetophenone. © 2003 Elsevier Science Ltd. All rights reserved.link_to_subscribed_fulltex

Electronic structures and spectroscopic properties of [Pt(CNMe)2(CN)2]n (n = 1-4): A theoretical exploration of promising phosphorescent materials

The structures of [Pt(CNMe)2(CN)2]n (n = 1-4) in the ground states (S0) and lowest-energy triplet excited states (T1) were calculated by using the second-order Møller-Plesset perturbation (MP2) and density functional theory (DFT) methods, respectively. The MP2 results show that the formation of the dimer causes a significant red shift in emission energy, and the frequency calculations reveal that a weak metal-metal interaction exists in the S 0 state, which is greatly enhanced in the 3[d σ·pσ] excited state. The aggregation of [Pt(CNMe)2-(CN)2]n (n = 1-4) was explored by using the slate-type VWN functional in the DFT method. The 3B u→1Ag transition in the dimer at 509 nm corresponds to the experimental higher-energy emission at 530 nm in CH 3CN solution, while the 3A′→ 1A′ transitions in the trimer and tetramer at 557 and 650 nm, respectively, are responsible for the low-energy emission at 584 nm observed experimentally. The analyses of the Wiberg bond indices for the Pt-Pt bond indicate that the dimer may be the most stable form in solution and that the oligomer species (n = 3 and 4) can be treated as a special dimer in which the excess z electron ligand is bonded to the Pt atoms of the central dimer. © Wiley-VCH Verlag GmbH & Co. KGaA, 2007.link_to_subscribed_fulltex

Organo- and hydrogelators based on luminescent monocationic terpyridyl platinum(II) complexes with biphenylacetylide ligands

A series of phosphorescent terpyridyl platinum(II) complexes with ancillary biphenylacetylide ligands, namely, [(R 3tpy)PtC≡C(biphenyl)]X (R=tBu, H, or Et 2N; tpy=2,2'6',2'-terpyridyl; X is an anion) were synthesized and structurally characterized by various spectroscopic techniques and X-ray diffraction methods. Despite a lack of long alkyl chain(s) or hydrogen-bonding motif(s), complexes [(tpy)PtC≡C(biphenyl)]Cl and [(tBu 3tpy)PtC≡C(biphenyl)]X (X=Cl, ClO 4, PF 6, or BF 4) were found to gelate water and organic solvents, respectively. The self-aggregation of these complexes in solutions and the resulting gels were investigated with variable-temperature (VT) 1H NMR spectroscopy, polarized optical microscopy, and absorption/emission spectroscopy. SEM micrographs on dry gels revealed entangled nanofibers with diameters of 20-40 nm and lengths of tens of micrometers. Powder X-ray diffraction (PXRD) study revealed various degrees of crystallinity of these fibrillar nanostructures. The substituents on both the terpyridyl and acetylide ligands and counterion of these complexes play a profound but concerted role in tuning the intermolecular metal⋯metal and/or π-π interactions, and hence the gelation properties. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.link_to_subscribed_fulltex