Development of Perfluoro Decalin/Fluorinated Polyimide Core-Shell Microparticles via SPG Membrane Emulsification Using Methyl Perfluoropropyl Ether Cosolvent.

Red blood cell-inspired perfluorocarbon-encapsulated core-shell particles have been developed for biomedical applications. Although the use of perfluorodecalin (FDC) is expected for core-shell particles owing to its high oxygen solubility, the low solubility of FDC in any organic solvent, owing to its fluorous properties, prevents its use in core-shell particles. In this study, a new cosolvent system composed of dichloromethane (DCM) and heptafluoropropyl methyl ether (HFPME) was found to dissolve both FDC and fluorinated polyimide (FPI) based on a systematic study using a phase diagram, achieving a homogeneous disperse phase for emulsification composed of oxygen-permeable FPI and oxygen-soluble FDC. Using this novel cosolvent system and Shirasu porous glass (SPG) membrane emulsification, FDC-encapsulated FPI shell microparticles were successfully prepared for the first time. In addition to oxygenation, demonstrated using hypoxia-responsive HeLa cells, the fabricated core-shell microparticles exhibited monodispersity, excellent stability, biocompatibility, and oxygen capacity.

Balance of antiperitoneal adhesion, hemostasis, and operability of compressed bilayer ultrapure alginate sponges.

In surgery, both antiperitoneal adhesion barriers and hemostats with high efficiency and excellent handling are necessary. However, antiadhesion and hemostasis have been examined separately. In this study, six different ultrapure alginate bilayer sponges with thicknesses of 10, 50, 100, 200, 300, and 500 µm were fabricated via lyophilization and subsequent mechanical compression. Compression significantly enhanced mechanical strength and improved handling. Furthermore, it had a complex effect on dissolution time and contact angle. Therefore, the 100 µm compressed sponge showed the highest hemostatic activity in the liver bleeding model in mice, whereas the 200 µm sponge demonstrated the highest antiadhesion efficacy among the compressed sponges in a Pean crush hepatectomy-induced adhesion model in rats. For the first time, we systematically evaluated the effect of sponge compression on foldability, fluid absorption, mechanical strength, hemostatic effect, and antiadhesion properties. The optimum thickness of an alginate bilayer sponge by compression balances antiperitoneal adhesion and hemostasis simultaneously.

Role of cervical cancer screening during prenatal checkups for infectious diseases: A retrospective, descriptive study.

OBJECTIVE: This study was conducted to evaluate the status and role of cervical cytology affected by human papillomavirus infection and other infectious diseases screened during routine prenatal checkups. METHODS: We retrospectively examined medical records containing the screening results for infectious diseases and cervical cancer in women who delivered neonates in our hospital from 2014 to 2017. RESULTS: Among 3393 deliveries, 18.8% of women underwent a regular cervical cancer screening within 1 year of becoming pregnant, and 2641 women underwent a cervical cytology screening during this pregnancy. The cytological diagnostic results showed that 2562 women (97.0%) were negative for intraepithelial lesions or malignancy, whereas 79 (3.0%) had abnormal results. Of those with abnormal cytology results, 70 had abnormal cytology that was newly detected in this pregnancy, and 42 had grade ≥1 cervical intraepithelial neoplasia lesions. Spatulas were the most frequently used cytological sampling instruments, followed by cotton swabs. Cervical cytology revealed no major adverse reactions during these pregnancies. CONCLUSIONS: Our results confirm the importance of screening for infectious diseases during pregnancy. Only 20% of the women underwent a regular pre-pregnancy cervical cytology screening. Cervical cytology screening during pregnancy may currently be playing a crucial role in preventing cervical cancer in Japan.

The role of S126 in the Staphylococcus equorum MnSOD activity and stability.

The dimeric form of manganese superoxide dismutase is instrumental for activity because each of the monomers provides amino acid residues participating in the enzymatic reaction. Hence, preventing dissociation of the dimer would maintain the enzymatic activity in detrimental conditions e.g. high temperature. To prevent dissociation of the dimer, a disulphide (S-S) bond was introduced at the dimer interface. In the wild type structure, S126 interacts with S126 of the other monomer. In the presented work, a mutant was designed with an S126C substitution. The crystal structure of the S126C mutant showed that only 50-70% of monomers formed the S-S bond. This observed imperfect S-S bonding was likely caused by photolytic S-S bond breakage mediated by the neighbouring tryptophan residue. In the wild type, S126 is located facing W163 and forms a water-mediated hydrogen bond with E164; W163 and E164 are crucial in the enzyme's activity. The replacement of S126 by a cysteine residue lowered the activity of the enzyme by ~70%. S126 has never been considered to play a role in the enzyme's activity or stability, thus the finding showed the importance of this residue.

Improving Time to Antibiotics for Pediatric Oncology Patients With Suspected Infections: An Emergency Department-Based Quality Improvement Intervention.

OBJECTIVE: Studies in pediatric patients with fever and neutropenia demonstrate that shorter time to antibiotics is associated with a decrease in pediatric intensive care unit admissions and in-hospital mortality. In 2012, a 2-phase quality improvement intervention was implemented in a pediatric emergency department (ED) to improve care for this high-risk patient population.The objective was to determine if the introduction of (1) a rapid absolute neutrophil count (ANC) test and (2) a standardized prearrival process decreased time to antibiotics for febrile hematology/oncology(heme/onc) patients presenting to the ED. METHODS: The rapid ANC test introduced in February 2012 decreased turn-around-times in the laboratory from 60 to 10 minutes. The standardization of the prearrival communication between the heme/onc team and ED was implemented in August 2012 as part of a clinical standard work pathway for heme/onc patients who presented to the ED with fever and possible neutropenia. Time from arrival to the ED to administration of first antibiotic was measured.Data from January 2011 to December 2013 were analyzed using statistical process control. RESULTS: Seven hundred eighteen encounters for 327 patients were included. After the rapid ANC test, the proportion of patients who received antibiotics within 60 minutes of arrival increased from 47% to 60%. There was further improvement to 69% with implementation of the clinical standard work pathway. Mean time to antibiotics decreased from 83 to 65 minutes (21% decrease). CONCLUSION: This 2-phase quality improvement intervention increased the proportion of patients who received antibiotics within 60 minutes of arrival to the ED. Similar processes may be implemented in other pediatric EDs to improve timeliness of antibiotic administration.

X-ray structure of Clostridium perfringens sortase B cysteine transpeptidase.

The pathogenesis and infectivity of Gram-positive bacteria are mediated by many surface proteins that are covalently attached to peptidoglycans of the cell wall. The covalent attachment of these proteins is catalyzed by sortases (Srts), a family of cysteine transpeptidases, which are classified into six classes, A - F, based on their amino acid sequences and biological roles. Clostridium perfringens, one of the pathogenic clostridial species, has a class B sortase (CpSrtB) with 249 amino acid residues. X-ray structures of CpSrtB and its inactive mutant form were determined at 2.2 Å and 1.8 Å resolutions, respectively. CpSrtB adopts a typical sortase-protein fold, and has a unique substrate-binding groove formed by three ß-strands and two helices creating the sidewalls of the groove. The position of the catalytic Cys232 of CpSrtB is significantly different from those commonly found in Srts structures. The modeling study of the CpSrtB/peptide complex suggested that the position of Cys232 found in CpSrtB is preferable for the catalytic reaction to occur. Structural comparison with other class B sortases demonstrated that the catalytic site likely converts between two forms. The movement of Cys232 between the two forms may help His136 deprotonate Cys232 to be activated as a thiolate, which may the catalytic Cys-activated mechanism for Srts.

X-ray structure of a protease-resistant mutant form of human galectin-9 having two carbohydrate recognition domains with a metal-binding site.

Galectin-9 (G9) is a tandem-repeat type ß-galactoside-specific animal lectin having N-terminal and C-terminal carbohydrate recognition domains (N-CRD and C-CRD, respectively) joined by a linker peptide that is involved in the immune system. G9 is divalent in glycan binding, and structural information about the spatial arrangement of the two CRDs is very important for elucidating its biological functions. As G9 is protease sensitive due to the long linker, the protease-resistant mutant form of G9 (G9Null) was developed by modification of the linker peptide, while retaining its biological functions. The X-ray structure of a mutant form of G9Null with the replacement of Arg221 by Ser (G9Null_R221S) having two CRDs was determined. The structure of G9Null_R221S was compact to associate the two CRDs in the back-to-back orientation with a large interface area, including hydrogen bonds and hydrophobic interactions. A metal ion was newly found in the galectin structure, possibly contributing to the stable structure of protein. The presented X-ray structure was thought to be one of the stable structures of G9, which likely occurs in solution. This was supported by structural comparisons with other tandem-repeated galectins and the analyses of protein thermostability by CD spectra measurements.

Suppression of allergic and inflammatory responses by essential oils derived from herbal plants and citrus fruits.

The aim of the present study was to investigate the biological activity of 20 essential oils (EOs) derived from herbal plants and citrus fruits. The in vitro anti-allergic and anti-inflammatory activities of these oils were investigated, and the EO which was found to have the strongest activity of the 20 EOs examined, was investigated further to identify its components and bioactive compounds. The in vitro anti-allergic activity was determined by measuring the release of ß-hexosaminidase from rat basophilic leukemia (RBL-2H3) cells treated with the calcium ionophore, A23187. The in vitro anti-inflammatory activity was determined by measuring the production of tumor necrosis factor-α (TNF-α) in RAW264.7 murine macrophages treated with lipopolysaccharide. Among the EOs examined, lemongrass [Cymbopogon citratus (DC.) Stapf] elicited the strongest anti-allergic and anti-inflammatory effects. A principal component of this EO is citral (3,7-dimethyl-2,6-octadien-1-al) (74.5%), a mixture of the stereoisomers, geranial (trans-citral, 40.16%) and neral (cis-citral, 34.24%), as determined by chromatography-mass spectrometry analysis. The activities of citral and geranial are similar to those of lemongrass EO. These compounds elicited significant in vivo anti-allergic and anti-inflammatory effects, suppressing an immunoglobulin E (IgE)-induced passive cutaneous anaphylactic reaction in mice and a 12-O-tetradecanoylphorbol-13-acetate-induced inflammatory mouse ear edema, respectively. Our data demonstrate that lemongrass EO and its constituents, citral and geranial, may be a therapeutic candidate for allergic and inflammatory diseases.

Anti-tumor effects of novel 5-O-acyl plumbagins based on the inhibition of mammalian DNA replicative polymerase activity.

We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase γ (pol γ). In this study, we focused on plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), and chemically synthesized novel plumbagins conjugated with C2:0 to C22:6 fatty acids (5-O-acyl plumbagins). These chemically modified plumbagins enhanced mammalian pol inhibition and their cytotoxic activity. Plumbagin conjugated with chains consisting of more than C18-unsaturated fatty acids strongly inhibited the activities of calf pol α and human pol γ. Plumbagin conjugated with oleic acid (C18:1-acyl plumbagin) showed the strongest suppression of human colon carcinoma (HCT116) cell proliferation among the ten synthesized 5-O-acyl plumbagins. The inhibitory activity on pol α, a DNA replicative pol, by these compounds showed high correlation with their cancer cell proliferation suppressive activity. C18:1-Acyl plumbagin selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols and DNA metabolic enzymes tested. This compound inhibited the proliferation of various human cancer cell lines, and was the cytotoxic inhibitor showing strongest inhibition towards HT-29 colon cancer cells (LD50 = 2.9 µM) among the nine cell lines tested. In an in vivo anti-tumor assay conducted on nude mice bearing solid tumors of HT-29 cells, C18:1-acyl plumbagin was shown to be a promising tumor suppressor. These data indicate that novel 5-O-acyl plumbagins act as anti-cancer agents based on mammalian DNA replicative pol α inhibition. Moreover, the results suggest that acylation of plumbagin is an effective chemical modification to improve the anti-cancer activity of vitamin K3 derivatives, such as plumbagin.

Synthesis, structure, and cytotoxicity studies of some fungal isochromanes.

Ustusorane D and penicisochromans B-D are natural isochromans isolated from Aspergillus ustus 094102 and Penicillium sp. PSU-F40, respectively. Herein, we report the syntheses of (-)-ustusorane D and (+)-penicisochroman B and the structures of penicisochromans C and D. The relative configuration of natural ustusorane D and the absolute configuration of natural penicisochroman B were determined. Two plausible structures for penicisochroman C were evaluated through synthesis, but their ¹H and ¹³C NMR data were not in agreement with those of the natural product. The structural revision and the determination of the absolute configuration of natural penicisochroman D were achieved. Structure-activity relationship studies of the synthetic compounds as well as a series of related isochromans indicated that the enone of the furanone moiety was essential for the cytotoxicity of these compounds toward HCT116 human colon cancer cells. Pseudodeflectusin, the related natural isochroman, suppressed cell growth and induced apoptosis in HCT116 cells.

Inhibitory effects of a major soy isoflavone, genistein, on human DNA topoisomerase II activity and cancer cell proliferation.

The inhibitory activity of 3 soy isoflavones (daidzein, genistein and glycitein) and their glycosides (daidzin, genistin and glycitin) on mammalian DNA polymerases (pols) and topoisomerases (topos) was investigated. Of the compounds tested, only genistein selectively inhibited human topo II activity and had an IC50 value of 37.5 µM. These isoflavones had no effect on the activity of human topo I; mammalian pols α, ß, γ and κ; or on any other DNA metabolic enzyme tested. Thermal transition analysis indicated that genistein did not influence the direct binding to double-stranded DNA. Genistein prevented the proliferation of HCT116 human colon carcinoma cells with an LD50 of 94.0 µM and it halted the cell cycle in G2/M phase. These results suggest that decreases in cell proliferation due to genistein may result from the inhibition of cellular topo II and that genistein, a major soy isoflavone, may be an anticancer food component. The relationship between the structures and these bioactivities of soy isoflavones is discussed.

Inhibitory effects of α-mangostin on mammalian DNA polymerase, topoisomerase, and human cancer cell proliferation.

We found that the ethanol extract of mangosteen (Garcinia mangostana L.) fruit rind had a strong inhibitory effect on mammalian DNA polymerase (pol) activity and isolated α-mangostin as a potent pol inhibitor from the extract. In this study, the inhibitory activities against mammalian pols by α-mangostin and its related five compounds, 3-isomangostin, xanthone, 9,10-anthraquinone, 9-anthracenecarboxylic acid, and anthracene, were investigated. α-Mangostin was the most potent inhibitor of the mammalian pol species among the tested compounds, with IC50 values of 14.8-25.6 µM. This compound also inhibited human DNA topoisomerases (topos) I and II activities with IC50 values of 15.0 and 7.5 µM, respectively, but did not inhibit the activities of other DNA metabolic enzymes tested. α-Mangostin also did not directly bind to double-stranded DNA as determined by thermal transition analysis. α-Mangostin was found to suppress human colon HCT116 carcinoma cell proliferation with an LC50 of 18.5 µM, inhibit the activity of cellular topos, halt cell cycle in the G2/M phase, and induce apoptosis. These results suggest that decreased proliferation by α-mangostin may be a result of the inhibition of cellular topos rather than pols, and α-mangostin might be an anticancer chemotherapeutic agent.

Inhibitory effects of low molecular weight polyphenolics from Inonotus obliquus on human DNA topoisomerase activity and cancer cell proliferation.

Low molecular weight (LMW) polyphenolics containing a polyhydroxylated benzyl moiety are abundant in medicinal plants. In the present study, we report on the activities of seven LMW polyphenolics isolated from Inonotus obliquus, a medicinal mushroom. The isolated compounds included caffeic acid (CA), 3,4-dihydroxybenzalacetone (DBL), gallic acid, syringic acid, protocatechuic acid, 3,4-dihydroxybenzaldehyde and 2,5-dihydroxyterephthalic acid. We analyzed their inhibitory effects on DNA polymerase (pol) and DNA topoisomerase (topo), and their effects on human cancer cell growth. All isolated compounds inhibited human topo II activity; the most potent were DBL and CA, which contain a catechol propanoid moiety. CA and DBL inhibited the activity of human topo I, whereas other compounds had no effect. No compound modulated the activities of 11 mammalian pol species or other DNA metabolic enzymes, including T7 RNA polymerase, mouse IMP dehydrogenase (type II), T4 polynucleotide kinase and bovine deoxyribonuclease I. CA and DBL markedly suppressed the proliferation of human colon HCT116 carcinoma cells with an LD50 of 70.0 and 49.4 µM, respectively, and halted the cell cycle in the G2/M phase. The suppressive effect of these compounds on cancer cell growth correlated with their ability to inhibit topo II. These results suggest that CA- and DBL-dependent decreases in cell proliferation are due to the inhibition of cellular topo II. The mechanism of action of these catechol propanoid compounds and the implication for their use as anticancer agents are discussed.

Inhibitory effects of myricetin on mammalian DNA polymerase, topoisomerase and human cancer cell proliferation.

In this study, the inhibitory activities against mammalian DNA polymerases (pols) of 16 major bioflavonoids were investigated. Myricetin (3,3',4',5,5',7-hexahydroxyflavone) was the most potent inhibitor of pols amongst the compounds tested, with IC50 values of 21.3-40.9 µM. This compound did not affect the activities of plant (cauliflower) pol α or prokaryotic pols. Myricetin also inhibited human DNA topoisomerase II (topo II) activity with an IC50 value of 27.5 µM, but did not inhibit the activities of other DNA metabolic enzymes tested. Myricetin also did not influence the direct binding to double stranded DNA as determined by thermal transition analysis. It was found to prevent the proliferation of human colon HCT116 carcinoma cells with an LD50 of 28.2 µM, halt the cell cycle in G2/M phase, and induce apoptosis. These results suggest that the decrease of proliferation may be a result of the inhibition of cellular topoisomerase (topo) II rather than pols.

Inhibition of repair-related DNA polymerases by vitamin Ks, their related quinone derivatives and associated inflammatory activity (Review).

Vitamin Ks (VKs) are fat-soluble quinone compounds known to have various bioactivities. This review describes the inflammatory effects of VKs and their related quinone derivatives based on DNA polymerase (pol) inhibition. VK3, but not VK1 or VK2 (=MK-4), inhibited the activity of human pol γ, which is the DNA replicative pol in mitochondria. Of the intermediate compounds between VK2 and VK3 (namely MK-3, MK-2 and MK-1), MK-2 was the strongest inhibitor of mammalian pols α, κ and λ, which belong to the B-, Y- and X-families of pols, respectively. Among the VK3 based quinone derivatives, such as 1,4-naphthoquinone (NQ), 2-dimethyl-1,4-naphthoquinone (1,2-dimethyl-NQ), 1,4-benzoquinone (BQ), 9,10-anthraquinone (AQ) and 5,12-naphthacenequinone (NCQ), NQ was the strongest inhibitor of mammalian pols α and λ, in particular, DNA repair-related pol λ. Among the all compounds tested, NQ displayed the strongest suppression of tumor necrosis factor (TNF)-α production induced by lipopolysaccharide (LPS) in a cell culture system using RAW264.7 mouse macrophages. NQ also suppressed the expression of pol λ protein in these cells, after LPS-treated RAW264.7 cells were stimulated to induce pol λ expression. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of NQ into mice suppressed TNF-α production in peritoneal macrophages and serum. In an in vivo colitis mouse model induced using dextran sulfate sodium (DSS), NQ markedly suppressed DSS-evoked colitis. The promising anti-inflammatory candidates based on the inhibition of DNA repair-related pols, such as pol λ, by VKs quinone derivatives, such as NQ, are discussed.

Inhibitory effect of novel somatostatin peptide analogues on human cancer cell growth based on the selective inhibition of DNA polymerase ß.

The present study was designed to investigate the anticancer activity of novel nine small peptides (compounds 1-9) derived from TT-232, a somatostatin structural analogue, by analyzing the inhibition of mammalian DNA polymerase (pol) and human cancer cell growth. Among the compounds tested, compounds 3 [tert-butyloxycarbonyl (Boc)-Tyr-Phe-1-naphthylamide], 4 (Boc-Tyr-Ile-1-naphthylamide), 5 (Boc-Tyr-Leu-1-naphthylamide) and 6 (Boc-Tyr-Val-1-naphthylamide) containing tyrosine (Tyr) but no carboxyl groups, selectively inhibited the activity of rat pol ß, which is a DNA repair-related pol. Compounds 3-6 strongly inhibited the growth of human colon carcinoma HCT116 p53(+/+) cells. The influence of compounds 1-9 on HCT116 p53(-/-) cell growth was similar to that observed for HCT116 p53(+/+) cells. These results suggest that the cancer cell growth suppression induced by these compounds might be related to their inhibition of pol. Compound 4 was the strongest inhibitor of pol ß and cancer cell growth among the nine compounds tested. This compound specifically inhibited rat pol ß activity, but had no effect on the other 10 mammalian pols investigated. Compound 4 combined with methyl methane sulfonate (MMS) treatment synergistically suppressed HCT116 p53(-/-) cell growth compared with MMS alone. This compound also induced apoptosis in HCT116 cells with or without p53. From these results, the influence of compound 4, a specific pol ß inhibitor, on the relationship between DNA repair and cancer cell growth is discussed.

Oral administration of monogalactosyl diacylglycerol from spinach inhibits colon tumor growth in mice.

Previously, we observed that purified monogalactosyl diacylglycerol (MGDG), a major glycoglycerolipid from spinach, selectively inhibits the activities of mammalian replicative DNA polymerases (α, δ and ε). However, the function of MGDG following ingestion is not well-known. In the present study, spinach MGDG suppressed the proliferation of Colon26 mouse colon cancer cells with an LD(50) of 24 µg/ml in vitro. γ-cyclodextrin (CD)-MGDG complex was prepared and administered orally following Colon26 mouse tumor adhesion for 26 days. It was observed that 20 mg/kg equivalent (eq.) of the CD-MGDG complex reduced tumor volume by ∼60% compared with that of the vehicle-treated controls. In immunohistochemical analysis, the CD-MGDG complex group showed a decreased number of proliferating cell nuclear antigen (PCNA)-positive cells and reduction of mitosis in the tumor cells compared with the control group. In addition, the CD-MGDG complex increased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive apoptotic cells and inhibited CD31-positive tumor blood vessel growth significantly. These results suggest that MGDG has the potential for cancer prevention and health promotion.

Monogalactosyl diacylglycerol, a replicative DNA polymerase inhibitor, from spinach enhances the anti-cell proliferation effect of gemcitabine in human pancreatic cancer cells.

BACKGROUND: Gemcitabine (GEM) is used to treat various carcinomas and represents an advance in pancreatic cancer treatment. In the screening for DNA polymerase (pol) inhibitors, a glycoglycerolipid, monogalactosyl diacylglycerol (MGDG), was isolated from spinach. METHODS: Phosphorylated GEM derivatives were chemically synthesized. In vitro pol assay was performed according to our established methods. Cell viability was measured using MTT assay. RESULTS: Phosphorylated GEMs inhibition of mammalian pol activities assessed, with the order of their effect ranked as: GEM-5'-triphosphate (GEM-TP) > GEM-5'-diphosphate > GEM-5'-monophosphate > GEM. GEM suppressed growth in the human pancreatic cancer cell lines BxPC-3, MIAPaCa2 and PANC-1 although phospholylated GEMs showed no effect MGDG suppressed growth in these cell lines based on its selective inhibition of replicative pol species. Kinetic analysis showed that GEM-TP was a competitive inhibitor of pol alpha activity with nucleotide substrates, and MGDG was a noncompetitive inhibitor with nucleotide substrates. GEM combined with MGDG treatments revealed synergistic effects on the inhibition of DNA replicative pols alpha and gamma activities compared with GEM or MGDG alone. In cell growth suppression by GEM, pre-addition of MGDG significantly enhanced cell proliferation suppression, and the combination of these compounds was found to induce apoptosis. In contrast, GEM-treated cells followed by MGDG addition did not influence cell growth. CONCLUSIONS: GEM/MGDG enhanced the growth suppression of cells based on the inhibition of pol activities. GENERAL SIGNIFICANCE: Spinach MGDG has great potential for development as an anticancer food compound and could be an effective clinical anticancer chemotherapy in combination with GEM.

Effects of essential oils from herbal plants and citrus fruits on DNA polymerase inhibitory, cancer cell growth inhibitory, antiallergic, and antioxidant activities.

In this study, the biological activity of 20 essential oils (EOs) from herbal plants and citrus fruits were investigated in terms of mammalian DNA polymerase (pol) inhibitory activity, cancer cell (human colon carcinoma, HCT116) growth inhibitory activity, antiallergic activity, as anti-ß-hexosaminidase release activity in rat basophilic leukemia RBL-2H3 cells treated with calcium ionophore A23187, and antioxidant activity by a lipophilic-oxygen radical absorbance capacity method. These EOs showed patterns of inhibition of pol α, a DNA replicative pol, similar to their cancer cell growth inhibitory activity, and their inhibitory activity on pol λ, a DNA repair/recombination pol, by the EOs showed correlation with anti-ß-hexosaminidase release activity. Among these EOs, chamomile (Matricaria chamomilla L.) was the strongest inhibitor of pols α and λ and showed significant effects on both cancer cell growth and mast cell degranulation. On the basis of these results, chamomile EO can be recommended as a potentially useful, bioactive candidate for therapeutic applications.

Anti-cancer targeting telomerase inhibitors: ß-rubromycin and oleic acid.

Telomerase is a ribonucleoprotein complex that elongates telomeric DNA and appears to play an important part in the cellular immortalization of cancers. In the screening of potent inhibitors of human telomerase, several inhibitors have been discovered from natural and chemical sources. Some compounds potently inhibit the activity of human telomerase. Rubromycins and fatty acids such as ß-rubromycin and oleic acid, respectively, were found to be inhibitors of human telomerase. The IC(50) values of ß-rubromycin and oleic acid were 8.60 and 8.78 µM, respectively. A kinetic study revealed that these compounds competitively inhibited the activity of telomerase with respect to the substrate of the primer and dNTP. The energy-minimized three-dimensional structure of ß-rubromycin and oleic acid was calculated and designed. The V-shaped curve and molecule length of 18.7-20.3 Å in these compound structures were suggested to be important for telomerase inhibition. The three-dimensional structure of the active site of telomerase (i.e., the binding site of the primer and dNTP substrate) might have a "pocket" that could "join" these compounds. These results appear to suggest a potential structure for the development of more potent inhibitors of human telomerase.