The anti-invasive activity of synthetic alkaloid ethoxyfagaronine on L1210 leukemia cells is mediated by down-regulation of plasminogen activators and MT1-MMP expression and activity

Quaternary benzo[c]phenanthridines such as fagaronine are natural substances which have been reported to exhibit anticancer and anti-leukemic properties. However, the therapeutic use of these molecules is limited due to the high dose required to exhibit anti-tumor activity and subsequent toxicity. In this study, we describe the therapeutic potential of a new derivative of fagaronine, Ethoxyfagaronine (N-methyl-12-ethoxy-2hydroxy-3, 8, 9-trimethoxybenzo[c]-phenanthridiniumchlorhydrate) as an anti-leukemic agent. Cytotoxic activity and cell growth inhibition of Ethoxyfagaronine (Etxfag) was tested on murine L1210 leukemia cells using trypan blue assay and MTT assay. At the concentration of 10−7 M, Etxfag induced less than 10% of cell death. Etxfag (10−7 M) was tested on L1210 cell invasiveness using matrigel™ precoated transwell chambers and efficiently reduces the invasive potential of L1210 cells by more than 50% as compared with untreated cells. Western blot and immunofluorescence experiments showed that Etxfag decreased both MT1-MMP expression and activation at the cell surface, decreased plasmin activity by down-regulating u-PAR and uPA expression at the cell surface and increasing PAI-1 secretion in conditioned media. The set of our findings underscore the therapeutic potential of ethoxyfagaronine as a new potential anticancer agent able to prevent leukemic cell dissemination

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†These authors have contributed equally to this work. Specialty section: This article was submitted t

Activation of human Vγ9Vδ2 T cells by a Brucella suis non-peptidic fraction impairs bacterial intracellular multiplication in monocytic infected cells

Human γδ T cells are considered to play an important role in the early response to infection with intracellular pathogens. Evidence has been presented that the percentage of γδ T cells with Vc9Vd2 phenotype is dramatically increased in the peripheral blood of patients with acute brucellosis. This specific γδ T-cell subpopulation is known to be activated by small non-peptidic molecules that can either be produced by the pathogen itself or released from damaged cells after infection. In the present work we provide evidence that Vγ9Vδ2 T lymphocytes from peripheral blood mononuclear cells of healthy donors can be specifically activated by non-peptidic low-molecular-weight compound(s) from Brucella suis lysate. Moreover, we show that Vγ9Vδ2 T cells activated by this B. suis fraction produce tumour necrosis factor-α and interferon-γ, which reduce bacterial multiplication inside infected cells

Elastin-Derived Peptides Are New Regulators of Insulin Resistance Development in Mice

Although it has long been established that the extracellular matrix acts as a mechanical support, its degradation products, which mainly accumulate during aging, have also been demonstrated to play an important role in cell physiology and the development of cardiovascular and metabolic diseases. In the current study, we show that elastin-derived peptides (EDPs) may be involved in the development of insulin resistance (IRES) in mice. In chow-fed mice, acute or chronic intravenous injections of EDPs induced hyperglycemic effects associated with glucose uptake reduction and IRES in skeletal muscle, liver, and adipose tissue. Based on in vivo, in vitro, and in silico approaches, we propose that this IRES is due to interaction between the insulin receptor (IR) and the neuraminidase-1 subunit of the elastin receptor complex triggered by EDPs. This interplay was correlated with decreased sialic acid levels on the β-chain of the IR and reduction of IR signaling. In conclusion, this is the first study to demonstrate that EDPs, which mainly accumulate with aging, may be involved in the insidious development of IRES