Acteoside from Conandron ramondioides Reduces Microcystin-LR Cytotoxicity by Inhibiting Intracellular Uptake Mediated by OATP1B3.

The hepatotoxin microcystin-LR is a strong inhibitor of serine/threonine protein phosphatase (PP) 1 and PP2A. The onset of its cytotoxicity depends on its selective uptake via the hepatocyte uptake transporters, organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Understanding and preventing the cytotoxicity of microcystin-LR is crucial to maintain human health.

Atractylodin Produces Antinociceptive Effect through a Long-Lasting TRPA1 Channel Activation.

Atractylodin (ATR) is a bioactive component found in dried rhizomes of (AL) De Candolle. Although AL has accumulated empirical evidence for the treatment of pain, the molecular mechanism underlying the anti-pain effect of ATR remains unclear. In this study, we found that ATR increases transient receptor potential ankyrin-1 (TRPA1) single-channel activity in hTRPA1 expressing HEK293 cells.

Development of a Ligand Screening Tool Using Full-Length Human Peroxisome Proliferator-Activated Receptor-Expressing Cell Lines to Ameliorate Metabolic Syndrome.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily and include three subtypes (PPARα, PPARδ, and PPARγ). They regulate gene expression in a ligand-dependent manner. PPARα plays an important role in lipid metabolism.

In Vitro Inhibition of Cholera Toxin Production in Vibrio cholerae by Methanol Extract of Sweet Fennel Seeds and Its Components.

A newly emerged Vibrio cholerae O1 El Tor variant strain with multidrug resistance is considered a threat to public health. Recent strategies to suppress virulence factors production instead of bacterial growth may lead to less selective pressure for the emergence of resistant strains. The use of spices and their active constituents as the inhibitory agents against cholera toxin (CT) production in V.

Evodiamine suppresses capsaicin-induced thermal hyperalgesia through activation and subsequent desensitization of the transient receptor potential V1 channels.

Evodiae fructus (EF), a fruit of Evodia rutaecarpa Bentham, has long been used as an analgesic drug in traditional Chinese and Japanese medicine. However, the underlying molecular mechanism of its pharmacological action is unclear. Here, using calcium imaging, whole-cell patch-clamp recording, and behavioral analysis, we investigated the pharmacological action of EF and its principal compound, evodiamine, on the transient receptor potential (TRP) V1 channels.

Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs.

A series of 1-aryl-3,4-substituted-1H-pyrazol-5-ol derivatives was synthesized and evaluated as prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors to obtain a novel anti-prostate cancer drug. After modifying 1-(1H-benzimidazol-2-yl)-3,4-dimethyl-1H-pyrazol-5-ol (1), a hit compound found during random screening using a recombinant PCA-1/ALKBH3, 1-(1H-5-methylbenzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol (35, HUHS015), was obtained as a potent PCA-1/ALKBH3 inhibitor both in vitro and in vivo. The bioavailability (BA) of 35 was 7.

Inhibition of virulence potential of Vibrio cholerae by natural compounds.

The rise in multi-drug resistant Vibrio cholerae strains is a big problem in treatment of patients suffering from severe cholera. Only a few studies have evaluated the potential of natural compounds against V. cholerae.

Capsaicin, a potential inhibitor of cholera toxin production in Vibrio cholerae.

The use of natural compounds as inhibitory agents for virulence factor production is a new approach to overcome increased antimicrobial resistance in pathogenic bacteria. In this study, we examined whether red chilli (Capsicum annuum) contains any such compound(s) that can repress the cholera toxin (CT) production in Vibrio cholerae. We found that the methanol extract of red chilli could inhibit CT production in recently emerged V.

Smenospongine, a sesquiterpene aminoquinone from a marine sponge, induces G1 arrest or apoptosis in different leukemia cells.

Smenospongine, a sesquiterpene aminoquinone isolated from the marine sponge Dactylospongia elegans, was previously reported by us to induce erythroid differentiation and G1 phase arrest of K562 chronic myelogenous leukemia cells. In this study, we investigated the effect of smenospongine on the cell cycles of other leukemia cells, including HL60 human acute promyelocytic leukemia cells and U937 human histiocytic lymphoma cells by flow cytometric analysis. Smenospongine induced apoptosis dose-dependently in HL60 and U937 cells.

Structure-activity relationships study of bastadin 6, an anti-angiogenic brominated-tyrosine derived metabolite from marine sponge.

A structure-activity relationship (SAR) study of bastadin 6 (1), a brominated tyrosine-derived metabolite from Indonesian marine sponge having a potent anti-angiogenic activity, was executed. The syntheses and their biological evaluation of the oxime-modified analogues and bromine-modified analogues revealed that both the oxime moieties and bromine atoms in bastadin 6 (1) play an important role to show the potent and selective anti-proliferative activity against human umbilical vein endothelial cells (HUVECs).

The plant alkaloid cryptolepine induces p21WAF1/CIP1 and cell cycle arrest in a human osteosarcoma cell line.

We previously established a bioassay method to screen for compounds that activate the promoter activity of p21(WAF1/CIP1), a potent inhibitor of cyclin-dependent kinases, in a p53-independent manner. As an activator of p21(WAF1/CIP1) promoter activity, we isolated cryptolepine (CLP: 5-methyl indolo (2,3b)-quiniine), an indoloquinoline alkaloid, from the traditional Ayurvedic medicinal plant Sida cordifolia. We show here that CLP induces the expression of p21(WAF1/CIP1) with growth arrest in p53-mutated human osteosarcoma MG63 cells.

Structure-activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids.

Previously, bioassay-guided separation led us to isolate eleven novel steroidal alkaloids named cortistatins from the marine sponge Corticium simplex. These cortistatins were classified into three types based on the chemical structure of the side chain part, that is, isoquinoline, N-methyl piperidine or 3-methylpyridine units. From the structure-activity relationship study, the isoquinoline unit in the side chain was found to be crucial for the anti-angiogenic activity of cortistatins.

Novel isomarabarican triterpenes, exhibiting selective anti-proliferative activity against vascular endothelial cells, from marine sponge Rhabdastrella globostellata.

Four novel globostellatic acid X methyl esters (1-4) having isomarabarican-type triterpenoidal skeleton and three related new compounds (5-7) were isolated from the marine sponge Rhabdastrella globostellata, as selective anti-proliferative agents against human umbilical vein endothelial cells (HUVECs). Those chemical structures were elucidated by the detailed 2D NMR analysis. Two globostellatic acid X methyl esters (3 and 4) having 13E-geometry were found to inhibit proliferation of HUVECs, 80- to 250-fold selectively in comparison with several other cell lines.

Synthesis of 15,20-triamide analogue with polar substituent on the phenyl ring of arenastatin A, an extremely potent cytotoxic spongean depsipeptide.

In order to increase metabolic stability and water solubility of arenastatin A, an extremely potent cytotoxic depsipeptide from the Okinawan marine sponge of Dysidea arenaria, several 15,20-triamide analogues with a polar substituent on the phenyl ring were synthesized. The 15,20-triamide analogues with a polar substituent (24, 30, and 31) showed increased solubility to MeOH and stronger cytotoxicity against KB cells in comparison with the parental 15,20-triamide analogue (2). Furthermore, the diethylamine analogue (30) exhibited in vivo anti-tumor activity against subcutaneously implanted murine sarcoma.

A functional role of intracellular loops of human multidrug resistance protein 1.

Multidrug resistance protein 1 (MRP1) is a human ATP-binding cassette (ABC) transporter in the plasma membrane. It confers multidrug resistance to tumor cells by actively effluxing intracellular drugs. To examine the functional significance of intracellular loops (ICLs) in MRP1, we determined the effect of mutation of the amino acid sequence EXXXG, which is conserved in ICL5 and ICL7 of human MRP1, 2 and 3, sulfonylurea receptor (SUR) 1 and 2, and mouse MRP1 and 2.

Bastadins, cyclic tetramers of brominated-tyrosine derivatives, selectively inhibit the proliferation of endothelial cells.

Eight bastadins, tetramers of brominated-tyrosine derivatives, were isolated from the marine sponge Ianthella basta, and their anti-proliferative activities against endothelial cells were examined. A structure-activity relationship study of these compounds revealed that a macrocyclic structure was crucial, and a bastarane-type skeleton was important for the selective activity of these bastadins against endothelial cells. A conformational analysis of the bastadins was also carried out by molecular mechanics calculation.

A novel synthetic drug, LB-18, closely related to lembehyne-A derived from a marine sponge, induces caspase-independent cell death to human neuroblastoma cells.

Neuroblastoma is a common solid tumor of children that arises from the sympathetic nervous system. Much work has consequently focused on the possibility of inducing marked cell death in neuroblastoma, and the new effective drugs are required. We have newly synthesized LB-18, closely related to lembehyne A (LB-A), a polyacetylene derived from a kind of marine sponge.

Cortistatins A, B, C, and D, anti-angiogenic steroidal alkaloids, from the marine sponge Corticium simplex.

Four novel steroidal alkaloids named cortistatins A (1), B (2), C (3), and D (4) consisting of a 9(10-19)-abeo-androstane and isoquinoline skeleton have been isolated from the marine sponge Corticium simplex. The absolute stereostructures of 1-4 were elucidated by detailed 2D NMR, CD, and X-ray crystallographic analyses. Cortistatins A-D inhibited proliferation of human umbilical vein endothelial cells (HUVECs) with high selectivity.

Bastadin 6, a spongean brominated tyrosine derivative, inhibits tumor angiogenesis by inducing selective apoptosis to endothelial cells.

Bastadin 6, a macrocyclic tetramer of a brominated tyrosine derivative, was isolated from a marine sponge and its anti-angiogenic activity was evaluated. Bastadin 6 was found to inhibit vascular endothelial growth factor (VEGF)- or basic fibroblast growth factor (bFGF)-dependent proliferation (IC50=0.052 micromol/l) of human umbilical vein endothelial cells (HUVECs) 20- to 100-fold selectively in comparison with normal fibroblast (3Y1) or several tumor cells (KB3-1, K562 and Neuro2A).

Aaptamine, a spongean alkaloid, activates p21 promoter in a p53-independent manner.

Aaptamine, a benzonaphthyridine alkaloid was isolated from a marine sponge on the guidance of a bioassay using the transfected human osteosarcoma MG63 cells (MG63luc(+)). Aaptamine activated p21 promoter stably transfected in MG63 cells dose-dependently at the concentrations of 20-50microM. Expression of p21 and its mRNA in the wild-type MG63 cells also increased by aaptamine-treatment.

GSH inhibits trypsinization of the C-terminal half of human MRP1.

MRP1 is a 190-kDa membrane glycoprotein that confers multidrug resistance to tumor cells. The accumulated evidence has proved that GSH interacts with MRP1 and stimulates drug transport. However, the mechanism of GSH-dependent drug transport by MRP1 remains unclear.

Erythroid differentiation in K562 chronic myelogenous cells induced by crambescidin 800, a pentacyclic guanidine alkaloid.

The differentiation induction of K562 chronic myelogenous leukemia (CML) cells by crambescidin 800, a pentacyclic guanidine alkaloid isolated from a marine sponge, was examined. Crambescidin 800 increased hemoglobin production in K562 cells at concentrations of 0.15-1 microM and arrested the cell cycle of K562 cells at the S-phase.

Sesquiterpene aminoquinones, from a marine sponge, induce erythroid differentiation in human chronic myelogenous leukemia, K562 cells.

A new sesquiterpene aminoquinone, 5-epi-smenospongorine, together with nine known sesquiterpene quinone/phenols, was isolated as differentiation-inducing substances to K562 cells into erythroblast from the marine sponge Dactylospongia elegans. The structure-activity relationship study of these compounds clarified that the quinone skeleton is indispensable and the amino group plays an important role for their differentiation-inducing activity to K562 cells into erythroblast.

Function of the ABC signature sequences in the human multidrug resistance protein 1.

Human multidrug resistance protein 1 (MRP1) is a membrane ATP-binding cassette transporter that confers multidrug resistance to tumor cells by effluxing intracellular drugs in an ATP-dependent manner. The mechanisms by which transport occurs and by which ATP hydrolysis is coupled to drug transport are not fully elucidated. In particular, the function of the signature sequences in the nucleotide binding domains (NBDs) of MRP1 is unknown.