A novel poly-naphthol compound ST104P suppresses angiogenesis by attenuating matrix metalloproteinase-2 expression in endothelial cells.

Angiogenesis, the process of neovascularization, plays an important role in physiological and pathological conditions. ST104P is a soluble polysulfated-cyclo-tetrachromotropylene compound with anti-viral and anti-thrombotic activities. However, the functions of ST104P in angiogenesis have never been explored. In this study, we investigated the effects of ST104P in angiogenesis in vitro and in vivo. Application of ST104P potently suppressed the microvessels sprouting in aortic rings ex vivo. Furthermore, ST104P treatment significantly disrupted the vessels' development in transgenic zebrafish in vivo. Above all, repeated administration of ST104P resulted in delayed tumor growth and prolonged the life span of mice bearing Lewis lung carcinoma. Mechanistic studies revealed that ST104P potently inhibited the migration, tube formation and wound closure of human umbilical endothelial cells (HUVECs). Moreover, ST104P treatment inhibited the secretion and expression of matrix metalloproteinase-2 (MMP-2) in a dose-dependent manner. Together, these results suggest that ST104P is a potent angiogenesis inhibitor and may hold potential for treatment of diseases due to excessive angiogenesis including cancer.

Upregulated protein arginine methyltransferase 1 by IL-4 increases eotaxin-1 expression in airway epithelial cells and participates in antigen-induced pulmonary inflammation in rats.

Protein arginine methyltransferases (PRMTs), catalyzing methylation of both histones and other cellular proteins, have emerged as key regulators of various cellular processes. This study aimed to identify key PRMTs involved in Ag-induced pulmonary inflammation (AIPI), a rat model for asthma, and to explore the role of PRMT1 in the IL-4-induced eosinophil infiltration process. E3 rats were i.p. sensitized with OVA/alum and intranasally challenged with OVA to induce AIPI. The expressions of PRMT1-6, eotaxin-1, and CCR3 in lungs were screened by real-time quantitative PCR. Arginine methyltransferase inhibitor 1 (AMI-1, a pan-PRMT inhibitor) and small interfering RNA-PRMT1 were used to interrupt the function of PRMT1 in A549 cells. In addition, AMI-1 was administrated intranasally to AIPI rats to observe the effects on inflammatory parameters. The results showed that PRMT1 expression was mainly expressed in bronchus and alveolus epithelium and significantly upregulated in lungs from AIPI rats. The inhibition of PRMTs by AMI-1 and the knockdown of PRMT1 expression were able to downregulate the expressions of eotaxin-1 and CCR3 with the IL-4 stimulation in the epithelial cells. Furthermore, AMI-1 administration to AIPI rats can also ameliorate pulmonary inflammation, reduce IL-4 production and humoral immune response, and abrogate eosinophil infiltration into the lungs. In summary, PRMT1 expression is upregulated in AIPI rat lungs and can be stimulated by IL-4. Intervention of PRMT1 activity can abrogate IL-4-dependent eotaxin-1 production to influence the pulmonary inflammation with eosinophil infiltration. The findings may provide experimental evidence that PRMT1 plays an important role in asthma pathogenesis.

PRO-2000, an antimicrobial gel for the potential prevention of HIV infection.

Indevus Pharmaceuticals Inc, under license from Paligent Inc, is developing PRO-2000, an antimicrobial gel for the prevention of HIV infection. The company is also investigating its potential to prevent the transmission of other sexually transmitted diseases. In February 2005, Indevus launched a pivotal phase III trial for the prevention of HIV infection in women. At that time, further phase III trials in 12,000 African women were scheduled to begin in 2005. A second phase III trial began for the prevention of sexually transmitted infections, including HIV, herpes, Chlamydia and gonorrhea, in Africa in October 2005.

Intravitreal injection of the heparin analog 5-amino-2-naphthalenesulfonate reduces retinal neovascularization in mice.

The effect of the heparin analog 5-amino-2-naphthalenesulfonate (5-amino-2-NMS) on retinal neovascularization was investigated in the mouse model for oxygen-induced retinopathy (OIR). From postnatal day 7 (P7) until P12, mice were kept in a 75% oxygen environment. On P12, they received an intravitreal injection of 10mM 5-amino-2-NMS in one eye and PBS as control substance in the fellow eye. The animals were intracardially perfused with fluorescein-dextran solution on P17. Retinal whole mounts were prepared and ischemic retinopathy was evaluated in 30 animals using a standardized retinopathy score. A single intravitreal injection of 5-amino-2-NMS reduces significantly angioproliferative changes (blood vessel tufts, extra-retinal neovascularization, and blood vessel tortuosity) compared to the contralateral control eye (p=0.025). The median retinopathy score (maximal 13) for the 5-amino-2-NMS treated eyes was 6 versus 8 for the control eyes. 5-Amino-2-NMS binds to the heparin-binding site of FGF1 and FGF2 and thus may be a promising substance for the local treatment of retinal neovascularization.

The non-nucleoside antiviral, BAY 38-4766, protects against cytomegalovirus (CMV) disease and mortality in immunocompromised guinea pigs.

New antiviral drugs are needed for the treatment of cytomegalovirus (CMV) infections, particularly in immunocompromised patients. These studies evaluated the in vitro and in vivo activity of the non-nucleosidic CMV inhibitor, BAY 38-4766, against guinea pig cytomegalovirus (GPCMV). Plaque reduction assays indicated that BAY 38-4766 was active against GPCMV, with an IC(50) of 0.5muM. Yield reduction assays demonstrated an ED(90) and ED(99) of 0.4 and 0.6muM, respectively, of BAY 38-4766 against GPCMV. Guinea pigs tolerated oral administration of 50mg/kg/day of BAY 38-4766 without evidence of biochemical or hematologic toxicity. Plasma concentrations of BAY 38-4766 were high following oral dosing, with a mean peak level at 1-h post-dose of 26.7mg/ml (n=6; range, 17.8-35.4). Treatment with BAY 38-4766 reduced both viremia and DNAemia, as determined by a real-time PCR assay, following GPCMV infection of cyclophosphamide-immunosuppressed strain 2 guinea pigs (p<0.05, Mann-Whitney test). BAY 38-4766 also reduced mortality following lethal GPCMV challenge in immunosuppressed Hartley guinea pigs, from 83% (20/24) in placebo-treated guinea pigs, to 17% (4/24) in BAY 38-4766-treated animals (p<0.0001, Fisher's exact test). Mortality differences were accompanied by reduction in DNAemia in Hartley guinea pigs. Based upon its favorable safety, pharmacokinetic, and therapeutic profiles, BAY 38-4766 warrants further investigation in the GPCMV model.

Inhibition of Neisseria gonorrhoeae genital tract infection by leading-candidate topical microbicides in a mouse model.

The development of effective vaginal microbicides is paramount in the fight against the spread of sexually transmitted infections. Preclinical testing of candidate microbicides for the prevention of gonorrhea has been seriously hindered by the lack of an animal model. We assessed the efficacy of 7 promising formulated agents--CarraGuard, Ushercell, [poly]sodium 4-styrene sulfonate (T-PSS), PRO 2000, ACIDFORM, cellulose acetate phthalate (CAP), and BufferGel--by use of a mouse model of Neisseria gonorrhoeae genital tract infection. Mice received test agent, relevant placebo, or no treatment, followed by intravaginal N. gonorrhoeae challenge. N. gonorrhoeae colonization was tested by vaginal culture. CarraGuard, Ushercell, and T-PSS demonstrated significant protection, compared with control agents and no treatment. PRO 2000, ACIDFORM, and CAP showed significant protection, compared with no treatment but not compared with respective control agents. Mice that received BufferGel were provided significant protection, compared with untreated control mice; no placebo was tested. The findings of the present study suggest that topical agents may effectively reduce N. gonorrhoeae infection and that further evaluation is warranted.

Effects of diet on growth and survival of rats fed toxic levels of tartrazine (FD & C Yellow No. 5) and sunset yellow FCF (FD & C Yellow No. 6).

Tests were conducted on the effects of diet on the response of immature male rats to massive doses of tartrazine (FD&C Yellow No.5) and Sunset Yellow FCF (FD&C Yellow No. 6). When incorporated at a 5% level in a stock diet, tartrazine and Sunset Yellow FCF had no grossly observable toxic effects. When fed with a purified diet, however, both tartrazine and Sunset Yellow FCF at 5% level in the diet resulted in a marked retardation in growth, an unthrifty appearance of the fur and death of 50% or more of the rats within an experimental period of 14 days. The toxic effects obtained by feeding the latter diets were counteracted by the concurrent feeding of blond psyllium seed powder, carrot root powder, alfalfa leaf meal and wheat bran. Supplements of the known nutrients had little if any protective effect. Supplements of purified cellulose were without protective effect for the rats fed tartrazine but had a moderate protective effect for those fed Sunset Yellow FCF.