Anti-invasive effects of curcuminoid compounds from Curcuma aromatica Salisb. on murine colon 26-L5 carcinoma cells

ショウガ科に属する Curcuma aromatica Salisb. の根茎のクロロホルム抽出エキスから,化学構造の明らかな4種のクルクミンおよびその関連化合物:curcumin(CA-1),demethoxycurcumin(CA-2),5\u27-methoxycurcumin(CA-3),bisdemethoxycurcumin(CA-4)を分離した。これらの化合物を用いてマウス結腸癌細胞(colon 26-L5)に対する増殖,基底膜への浸潤,細胞運動に及ぼす効果について検討した。クルクミン(CA-1)とその関連化合物(CA-2,3 および4)は,細胞に対して傷害性を示さない10μMの濃度において,マウス結腸癌細胞の基底膜への浸潤を抑制した(それぞれ22.8,28.9,10.3および62.0%の抑制率)。この癌細胞の運動能に対しても同様の抑制効果が観察された。これらのクルクミン関連化合物の中で,CA-4は強い抑制活性を持ち,癌細胞の浸潤および運動能に対して濃度依存的な抑制効果を示した。このように,クルクミン関連化合物の芳香族環のhydroxyl基およびmethoxyl基が癌細胞の浸潤活性の発現と関係している可能性が示唆された。 Bioassay-directed fractionation of the active chloroform extract from the rhizomes of Curcuma aromatica Salisb. (Zingiberaceae) led to the isolation of four main curcuminoid constituents: curcumin (CA-1), demethoxycurcumin (CA-2), 5\u27-methoxycurcumin (CA-3) and bisdemethoxycurcumin (CA-4). This is the first report to describe the isolation of CA-3 from C. aromatica. The chemical structures of these compounds were determined on the basis of spectral analysis and their inhibitory effects on the proliferation, invasion and migration of murine colon 26-L5 adenocarcinoma cells were evaluated in vitro. Curcumin and its analogues (CA-2, 3 and 4), at the non-cytotoxic concentration of 10μM, inhibited the invasive ability of colon 26-L5 cells to the ranges of 22.8, 28.9, 10.3 and 62.0%, respectively. A similar effect of these constituents on the migration of colon 26-L5 cells was also observed. Among these curcuminoids, CA-4 showed the strongest activities, inhibiting both tumor cell invasion and migration in a concentration-dependent manner

“A Good Personal Scientific Relationship”: Philip Morris Scientists and the Chulabhorn Research Institute, Bangkok

Jeff Collin and Ross MacKenzie analyze tobacco industry documents and find that Philip Morris consultants were able to gain access to a Thai research institute that is a WHO Collaborating Centre

Harnessing glycomics technologies: Integrating structure with function for glycan characterization

Glycans, or complex carbohydrates, are a ubiquitous class of biological molecule which impinge on a variety of physiological processes ranging from signal transduction to tissue development and microbial pathogenesis. In comparison to DNA and proteins, glycans present unique challenges to the study of their structure and function owing to their complex and heterogeneous structures and the dominant role played by multivalency in their sequence-specific biological interactions. Arising from these challenges, there is a need to integrate information from multiple complementary methods to decode structure–function relationships. Focusing on acidic glycans, we describe here key glycomics technologies for characterizing their structural attributes, including linkage, modifications, and topology, as well as for elucidating their role in biological processes. Two cases studies, one involving sialylated branched glycans and the other sulfated glycosaminoglycans, are used to highlight how integration of orthogonal information from diverse datasets enables rapid convergence of glycan characterization for development of robust structure–function relationships.National Institutes of Health (U.S.) (GM R37 GM057073-13)Singapore-MIT Alliance for Research and Technolog

The Developmental Neurotoxicity of Arsenic: Cognitive and Behavioral Consequences of Early Life Exposure

Background: More than 200 million people worldwide are chronically exposed to arsenic. Arsenic is a known human carcinogen, and its carcinogenic and systemic toxicity have been extensively studied. By contrast, the developmental neurotoxicity of arsenic has been less well described. The aim of this review was to provide a comprehensive review of the developmental neurotoxicity of arsenic. Methods: We reviewed the published epidemiological and toxicological literature on the developmental neurotoxicity of arsenic. Results: Arsenic is able to gain access to the developing brain and cause neurotoxic effects. Animal models link prenatal and early postnatal exposure to reduction in brain weight, reductions in numbers of glia and neurons, and alterations in neurotransmitter systems. Animal and in vitro studies both suggest that oxidative stress may be a mechanism of arsenic neurotoxicity. Fifteen epidemiological studies indicate that early life exposure is associated with deficits in intelligence and memory. These effects may occur at levels of exposure below current safety guidelines, and some neurocognitive consequences may become manifest only later in life. Sex, concomitant exposures, and timing of exposure appear to modify the developmental neurotoxicity of arsenic. Four epidemiological studies failed to show behavioral outcomes of arsenic exposure. Conclusions: The published literature indicates that arsenic is a human developmental neurotoxicant. Ongoing and future prospective birth cohort studies will allow more precise definition of the developmental consequences of arsenic exposure in early life

Bioactive 4-hydroxycinnamide and bioactivities of Polyalthia cerasoides

Constituents from Polyalthia cerasoides, stem bark methanol extract, were previously documented. This study reports the first isolation of bioactive N-(4-hydroxy-β-phenethyl)-4-hydroxycinnamide (1) from ethyl acetate extract of the plant species including stigmasterol and a mixture of triterpenes from hexane and dichloromethane extracts. Trace essential elements were found in the hexane extract in ppm level. The plant extracts were evaluated for their antimicrobial and antioxidative activities. The dichloromethane extract displayed the highest activity against Corynebacterium diphtheriae NCTC 10356 with MIC of 32 μg/mL, as well as, the highest SOD activity with an IC50 of 4.51 μg/mL

Aromatase inhibitory activity of 1,4-naphthoquinone derivatives and QSAR study

A series of 2-amino(chloro)-3-chloro-1,4-naphthoquinone derivatives (1-11) were investigated for their aromatase inhibitory activities. 1,4-Naphthoquinones 1 and 4 were found to be the most potent compounds affording IC50 values 5.2 times lower than the reference drug, ketoconazole. A quantitative structure-activity relationship (QSAR) model provided good predictive performance (R2 CV = 0.9783 and RMSECV = 0.0748) and indicated mass (Mor04m and H8m), electronegativity (Mor08e), van der Waals volume (G1v) and structural information content index (SIC2) descriptors as key descriptors governing the activity. To investigate the effects of structural modifications on aromatase inhibitory activity, the model was employed to predict the activities of an additional set of 39 structurally modified compounds constructed in silico. The prediction suggested that the 2,3-disubstitution of 1,4-naphthoquinone ring with halogen atoms (i.e., Br, I and F) is the most effective modification for potent activity (1a, 1b and 1c). Importantly, compound 1b was predicted to be more potent than its parent compound 1 (11.90-fold) and the reference drug, letrozole (1.03-fold). The study suggests the 1,4-naphthoquinone derivatives as promising compounds to be further developed as a novel class of aromatase inhibitors

CometChip: A High-throughput 96-Well Platform for Measuring DNA Damage in Microarrayed Human Cells

DNA damaging agents can promote aging, disease and cancer and they are ubiquitous in the environment and produced within human cells as normal cellular metabolites. Ironically, at high doses DNA damaging agents are also used to treat cancer. The ability to quantify DNA damage responses is thus critical in the public health, pharmaceutical and clinical domains. Here, we describe a novel platform that exploits microfabrication techniques to pattern cells in a fixed microarray The ‘CometChip’ is based upon the well-established single cell gel electrophoresis assay (a.k.a. the comet assay), which estimates the level of DNA damage by evaluating the extent of DNA migration through a matrix in an electrical field. The type of damage measured by this assay includes abasic sites, crosslinks, and strand breaks. Instead of being randomly dispersed in agarose in the traditional assay, cells are captured into an agarose microwell array by gravity. The platform also expands from the size of a standard microscope slide to a 96-well format, enabling parallel processing. Here we describe the protocols of using the chip to evaluate DNA damage caused by known genotoxic agents and the cellular repair response followed after exposure. Through the integration of biological and engineering principles, this method potentiates robust and sensitive measurements of DNA damage in human cells and provides the necessary throughput for genotoxicity testing, drug development, epidemiological studies and clinical assays.National Institute of Environmental Health Sciences (Training Grant in Environmental Toxicology T32-ES007020)Massachusetts Institute of Technology. Center for Environmental Health Sciences (P30-ES002109)National Institute of Environmental Health Sciences (5-UO1-ES016045)National Institute of Environmental Health Sciences (1-R21-ES019498)National Institute of Environmental Health Sciences (R44-ES021116

Elucidating the Structure-Activity Relationships of the Vasorelaxation and Antioxidation Properties of Thionicotinic Acid Derivatives

Nicotinic acid, known as vitamin B3, is an effective lipid lowering drug and intense cutaneous vasodilator. This study reports the effect of 2-(1-adamantylthio)nicotinic acid (6) and its amide 7 and nitrile analog 8 on phenylephrine-induced contraction of rat thoracic aorta as well as antioxidative activity. It was found that the tested thionicotinic acid analogs 6-8 exerted maximal vasorelaxation in a dose-dependent manner, but their effects were less than acetylcholine (ACh)-induced nitric oxide (NO) vasorelaxation. The vasorelaxations were reduced, apparently, in both NG-nitro-L-arginine methyl ester (L-NAME) and indomethacin (INDO). Synergistic effects were observed in the presence of L-NAME plus INDO, leading to loss of vasorelaxation of both the ACh and the tested nicotinic acids. Complete loss of the vasorelaxation was noted under removal of endothelial cells. This infers that the vasorelaxations are mediated partially by endothelium-induced NO and prostacyclin. The thionicotinic acid analogs all exhibited antioxidant properties in both 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide dismutase (SOD) assays. Significantly, the thionicotinic acid 6 is the most potent vasorelaxant with ED50 of 21.3 nM and is the most potent antioxidant (as discerned from DPPH assay). Molecular modeling was also used to provide mechanistic insights into the vasorelaxant and antioxidative activities. The findings reveal that the thionicotinic acid analogs are a novel class of vasorelaxant and antioxidant compounds which have potential to be further developed as promising therapeutics