Synthesis and electrochemistry of dimanganese(II) complexes of phenol-based dinucleating ligands with four methoxyethyl chelating arms

Dimanganese(II) complexes [Mn2(bonp)(PhCO2)2]PF6 (1) and [Mn2(bocp)(PhCO2)2]PF6 (2) were synthesized with p-nitro- and p-chloro-substituted phenol-based dinucleating ligands bonp- [2,6-bis[bis(2-methoxyethyl)aminomethyl]-4-nitrophenolate anion] and bocp- [4-chloro-2,6-bis[bis(2-methoxyethyl)aminomethyl]phenolate anion], respectively, with the aim of controlling the redox potentials of the dimanganese center by changing the p-substituents in the dinucleating ligands. Cyclic voltammograms of 1 and 2 showed quasi-reversible oxidation processes, assigned to MnIIMnII/MnIIMnIII, at 1.17 and 1.00 V vs. Ag/AgCl, respectively. Compared to the previous p-methyl complex [Mn2(bomp)(PhCO2)2]PF6 (3) [bomp–: 2,6-bis[bis(2-methoxyethyl)aminomethyl]-4-methylphenolate anion] (0.96 V vs. Ag/AgCl), the order of the potentials was 1(-NO2) > 2(-Cl) > 3(-CH3). Thus, the redox potentials of the dimanganese centers were controlled by the p-substituents in the dinucleating ligands

ISOLATION AND CHARACTERIZATION OF A NOVEL HYALURONIDASE INHIBITOR FROM A MARINE ACTINOMYCETES STRAIN

A novel hyaluronidase inhibitor (HI) was isolated from the culture extract of a marine- derived actinomycete strain. This strain MB-PO13 was isolated from ascidian (Molgula manhattensis) in Tokyo Bay. Out of about 1,000 isolates from various marine organisms, strain MB-PO13 had the strongest inhibitory activity and was selected for further study. The strain showed abundant-to-moderate growth on most media, forming a grayish mycelium. On the basis of the taxonomical characteristics, the strain was classified as belonging to the genus of Streptomyces and was named as Streptomyces sp. strain MB-PO13. The structure of HI was elucidated by interpretation of NMR data. HI displayed about 25-fold potent hyaluronidase inhibitory activity against hyaluronidase than glycyrrhizin. Keywords: marine actinomycetes; Streptomyces; hyaluronidase inhibitor

Hyaluromycin, a Novel Hyaluronidase Inhibitor, Attenuates Pancreatic Cancer Cell Migration and Proliferation

Pancreatic ductal adenocarcinoma (PDAC) is characterized by accelerated production and degradation of hyaluronan (HA), a major component of extracellular matrix involved in the malignant phenotype of cancer. In particular, increased hyaluronidase (HYAL) activity plays a critical role in cancer progression, at least in part, by producing low-molecular-weight- (LMW-) HA or small fragments of HA, suggesting HYAL as a target for cancer treatment. Hyaluromycin, a new member of the rubromycin family of antibiotics, was isolated from the culture extract of a marine-derived Streptomyces hyaluromycini as a HYAL inhibitor. We investigated the antitumor effects of hyaluromycin in PDAC cells. We examined the effects of hyaluromycin on the proliferation and migration of PDAC cells. To elucidate the mechanisms underlying the effect of hyaluromycin on PDAC cells, we examined the concentration of LMW-HA in the conditioned media after treating PDAC cells with hyaluromycin. We demonstrate that hyaluromycin inhibits proliferation and migration of PDAC cells. We also found that these antitumor effects of hyaluromycin were associated with a decreased concentration of LMW-HA and a decreased phosphorylation of ribosomal protein S6. Our results suggest that hyaluromycin is a promising new drug against this highly aggressive neoplasm

A comparison of mean winds and gravity wave activity in the northern and southern polar MLT

Mean winds and waves observed in the mesosphere and lower thermosphere with MF radars located at Davis (69°S, 78°E) and Poker Flat (65°N, 147°W) are compared. Measurements covering the period from 1999 to mid 2000 show differences in the strength of the horizontal wind fields. In the southern hemisphere the zonal and meridional winds reach their maximum values near the summer solstice, but are delayed by 2–3 weeks in the northern hemisphere. Gravity wave variances also show significant differences, as do the strength of vertical velocities.Andrew Dowdy and Robert A. Vincent, Kiyoshi Igarashi and Yasuhiro Murayama, Damian J. Murph

Potent and broad anticancer activities of leaf extracts from Melia azedarach L. of the subtropical Okinawa islands

Plant extracts have been traditionally used for various therapeutic applications. By conducting an initial screening of several subtropical plants, in this study, we evaluated the anticancer activities of Melia azedarach L. The extract from Melia azedarach L. leaves (MLE) show high cytotoxic effects on cancer cells and in vivo mouse and dog tumor models. During the initial screening, MLE showed strong antiproliferative activity against HT-29 colon, A549 lung, and MKN1 gastric cancer cells. In subsequent tests, using 39 human tumor cell lines, we confirmed the potent anticancer activities of MLE. The anticancer activity of MLE was also confirmed in vivo. MLE markedly inhibited the growth of transplanted gastric MKN1 cancer xenografts in mice. To elucidate the mechanism underlying the anticancer effects of MLE, MLE-treated MKN1 cells were observed using an electron microscope; MLE treatment induced autophagy. Furthermore, western blot analysis of proteins in lysates of MLE-treated cells revealed induction of light chain 3 (LC3)-II autophagosomal proteins. Thus, MLE appeared to suppress MKN1 cell proliferation by inducing autophagy. In addition, in the mouse macrophage cell line J774A.1, MLE treatment induced TNF-alpha production, which might play a role in tumor growth suppression in vivo. We also performed a preclinical evaluation of MLE treatment on dogs with various cancers in veterinary hospitals. Dogs with various types of cancers showed a mean recovery of 76% when treated with MLE. Finally, we tried to identify the active substances present in MLE. All the active fractions obtained by reverse-phase chromatography contained azedarachin B-related moieties, such as 3-deacetyl-12-hydroxy-amoorastatin, 12-hydroxy-amoorastatin, and 12-hydroxyamoorastaton. In conclusion, MLE contains substances with promising anticancer effects, suggesting their future use as safe and effective anticancer agents

Two new aromatic polyketides from a sponge-derived Fusarium

Two new aromatic polyketides from a sponge-derived Fusariu

Carbohydrate-Binding Non-Peptidic Pradimicins for the Treatment of Acute Sleeping Sickness in Murine Models

Current treatments available for African sleeping sickness or human African trypanosomiasis (HAT) are limited, with poor efficacy and unacceptable safety profiles. Here, we report a new approach to address treatment of this disease based on the use of compounds that bind to parasite surface glycans leading to rapid killing of trypanosomes. Pradimicin and its derivatives are non-peptidic carbohydrate-binding agents that adhere to the carbohydrate moiety of the parasite surface glycoproteins inducing parasite lysis in vitro. Notably, pradimicin S has good pharmaceutical properties and enables cure of an acute form of the disease in mice. By inducing resistance in vitro we have established that the composition of the sugars attached to the variant surface glycoproteins are critical to the mode of action of pradimicins and play an important role in infectivity. The compounds identified represent a novel approach to develop drugs to treat HAT.Funding: This work was supported by grants from the VI Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008-2011, Instituto de Salud Carlos III - Subdirección General de Redes y Centros de Investigación Cooperativa, Red de Investigación Cooperativa en Enfermedades Tropicales (RICET) (RD06/0021), the Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (SAF2013-48999-R) (http://www.idi.mineco.gob.es), and the Junta de Andalucía (BIO-199, P09-CVI-5367) to DGP. Research of JB and SL was supported by the Katholieke Universiteit Leuven (PF 10/18). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Important parameters in the detection of left main trunk disease using stress myocardial perfusion imaging

SummaryObjectivesWe sought noninvasively to diagnose left main trunk (LMT) disease using myocardial perfusion imaging (MPI).MethodsFive hundred and eight patients with suspected coronary artery disease (CAD) underwent both stress MPI and coronary angiography. The extent and severity of perfusion abnormalities were assessed using a 20-segment model. In addition, perfusion defects in both left anterior descending and left circumflex arterial territories were defined as a left main (LM) pattern defect, and those in 3-coronary arterial territories as a 3-vessel pattern defect.ResultsIn 42 patients with LMT disease, a summed stress score (19.4±10.0 vs. 13.5±10.0; p<0.0001) and a summed rest score (12.1±9.7 vs. 7.0±7.8; p=0.002) were greater than in 466 patients without LMT disease, while a summed difference score was similar (7.3±7.7 vs. 6.5±6.1; p=NS). The prevalence of an LM-pattern defect was low in both groups (12% vs. 8%; p=NS). However, a 3-vessel pattern defect (33% vs. 7%; p<0.0001), lung uptake of radiotracers (38% vs. 11%; p<0.0001), and transient ischemic dilation (31% vs. 13%; p=0.003) were more frequently observed in patients with LMT disease than in those without. Logistic regression analysis showed that a 3-vessel pattern defect (OR=3.5, 95% CI=1.4–8.8; p=0.007), lung uptake of radiotracers (OR=2.5, 95% CI=1.1–5.7; p=0.03), and previous myocardial infarction (MI) (OR=2.4, 95% CI=1.0–5.7; p=0.05) were the most important parameters to detect LMT disease. After excluding 163 patients with previous MI, a repeat analysis revealed that lung uptake of radiotracers (OR=8.2, 95% CI=2.3–29.2; p=0.001) and an LM-pattern defect (OR=6.3, 95% CI=1.4–27.2; p<0.02) were independent predictors for LMT disease.ConclusionIn the identification of LMT disease, lung uptake of radiotracers was a single best parameter, which was independent of the presence or absence of previous MI

Nocapyrones: α- and γ-Pyrones from a Marine-Derived Nocardiopsis sp.

One new α-pyrone (nocapyrone R (1)), and three known γ-pyrones (nocapyrones B, H and L (2–4)) were isolated from the culture extract of a Nocardiopsis strain collected from marine sediment. Structures of these compounds were determined on the basis of spectroscopic data including NMR and MS. γ-Pyrones 2–4 were found to induce adiponectin production in murine ST-13 preadipocyte cells but the α-pyrone 1 had no activity. The absolute configuration of the anteiso-methyl branching in 4 was determined by HPLC comparison of a degraded product of 4 with standard samples as a 2:3 enantiomeric mixture of (R)- and (S)-isomers