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Hit, Lead & Candidate Discovery Antiangiogenesis therapy is a promising way for treatment of solid cancers, and many angiogenesis inhibitors that target vascular endothelial growth factor (VEGF) or its receptors have been developed. We explored novel antiangiogenic compounds other than anti‐VEGF drugs by screening our synthetic compound library and found that 6‐thiophen‐3‐yl‐2‐methoxy‐1,4‐naphthoquinone (6‐TMNQ) had potential as a novel angiogenesis inhibitor. This paper describes the effects of 6‐TMNQ on angiogenesis and tumor growth in vitro and in vivo. 6‐TMNQ inhibited serum‐, VEGF‐, and basic fibroblast growth factor (bFGF)‐stimulated proliferation of endothelial cells in a concentration‐dependent manner, but had no effect on the proliferation of fibroblasts. VEGF‐induced activation of VEGF receptor‐2 in endothelial cells was not affected by the compound. 6‐TMNQ markedly abrogated both migration and tube formation of endothelial cells. Orally administered 6‐TMNQ inhibited angiogenesis in response to VEGF or bFGF in mice in a dose‐dependent manner. Furthermore, when tumor‐bearing mice were treated with 6‐TMNQ, increase in tumor size was significantly prevented due to inhibition of angiogenesis in the tumor tissues. These results demonstrate that 6‐TMNQ is an orally available compound that selectively inhibits endothelial cell proliferation and migration, and abrogates angiogenesis, resulting in the prevention of tumor growth. The mechanism of 6‐TMNQ action is different from that of conventional anti‐VEGF drugs. [ABSTRACT FROM AUTHOR]

Abstract: Cyclophosphamide (CPA) is one of the therapeutic agents for systemic inflammatory disorders. In murine dermal endothelial cells (F-2), 4-hydroxycyclophosphamide (4-HC), which is active metabolite of CPA, enhanced TNF-α-induced DNA fragmentation. In addition, 4-HC was shown to elevate TNF-α-induced caspase-3 activation. Caspase-8 activation was identified by the treatment of TNF-α, whereas 4-HC was no effect. In contrast, only when treated with 4-HC, caspase-9 activation and the increase in the intracellular expression of Bax were detected. These results suggest that CPA may sensitize endothelial cells to TNF-α-induced apoptosis through a mitochondria-dependent pathway and clinically may contribute to the limitation of inflammatory process. [Copyright &y& Elsevier]

Rat peritoncal mast cells incubated with a histamine liberator, compound 48/80, showed a significantly reduced capacity for releasing histamine following in vitro treatment with 0. 1 μg/ml of 8-methoxypsoralen (8-MOP) plus 1-5 J/cm² of long-wave ultraviolet (UVA) irradiation (PUVA). No remarkable inhibition in histamine release was observed in the cells treated with 8-MOP only. Irradiation with 5 J/cm² of UVA alone exerted an inhibitory effect on histamine release, to a lesser extent than PUVA. PUVA irradiation did not bring any decrease in cell viability or any spontaneous release of histamine from irradiated cells as shown by phase-contrast microscopy and by histamine assay, respectively. These results suggest that PUVA treatment may cause a noncytotoxic disturbance at mast cell membranes or on surface receptors, leading to a decreased capacity for secreting chemical mediators. [ABSTRACT FROM AUTHOR]

The possible relationship between lichen striatus and atopy was studied. Twenty-six patients with typical lichen striatus were studied, and 22 (84.6%) had a positive history of atopic disorders. This might indicate that the pathogenesis of lichen striatus has a close relationship to that of a topic disorders. [ABSTRACT FROM AUTHOR]

Cysteine-rich motor neuron 1 (CRIM1) is upregulated only in extracellular matrix gels by angiogenic factors such as vascular endothelial growth factor (VEGF). It then plays a critical role in the tube formation of endothelial cells. In the present study, we investigated the effects of increased CRIM1 on other endothelial functions such as proliferation and migration. Knock down of CRIM1 had no effect on VEGF-induced proliferation or migration of human umbilical vein endothelial cells (HUVECs), indicating that basal CRIM1 is not involved in the proliferation or migration of endothelial cells. Stable CRIM1-overexpressing endothelial F-2 cells, termed CR1 and CR2, were constructed, because it was difficult to prepare monolayer HUVECs that expressed high levels of CRIM1. Proliferation was reduced and migration was accelerated in both CR1 and CR2 cells, compared with normal F-2 cells. Furthermore, the transient overexpression of CRIM1 resulted in decreased proliferation and increased migration of bovine aortic endothelial cells. In contrast, neither proliferation nor migration of COS-7 cells were changed by the overexpression of CRIM1. These results demonstrate that increased CRIM1 reduces the proliferation and accelerates the migration of endothelial cells. These CRIM1 effects might contribute to tube formation of endothelial cells. CRIM1 induced by angiogenic factors may serve as a regulator in endothelial cells to switch from proliferating cells to morphological differentiation. [ABSTRACT FROM AUTHOR]

Endothelial cell injury is a critical event in tissue damage accompanying inflammation, in which both inflammatory cytokines and reactive oxygen species may play pivotal roles, although the exact mechanism has not yet been clarified. We found that combined stimulation with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) induced both cytotoxicity to murine vascular endothelial cell line F-2 and an increase in nitric oxide (NO). Therefore, in the present study, the implication of NO in cytotoxicity was examined. A potent iNOS-specific inhibitor ONO-1714 completely blocked both cytokine-induced cytotoxicity and NO production. NO scavengers such as carboxy-PTIO and hemoglobin blocked cytotoxicity. Moreover, exogenous NO from NOC 18 also caused cytotoxicity. These results together demonstrated that cytotoxicity of IFN-γ and TNF-α for endothelial cell F-2 was mediated by NO, suggesting a pathogenic role of cytokine-induced NO production in endothelial damage under inflammatory conditions. [Copyright &y& Elsevier]