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Systemic or intratesticular release of TNF alpha and IL1 beta have been implicated in the reduced testosterone biosynthesis and impaired production of competent spermatozoa found in human patients suffering from sepsis or chronic inflammation. Although in vitro and in vivo studies have demonstrated that TNF alpha and IL1 beta intercept the hypothalamic-pituitary testis axis at different levels, the site(s) of action and relative contribution of each cytokine to the overall testicular failure associated to systemic inflammatory processes remains poorly defined. In this study we show that intratesticular delivery of TNF alpha induced a rapid (4 h) and sustained (up to 24 h) reduction in steroidogenic acute regulatory (StAR) protein expression and testosterone biosynthesis in nonstimulated or human chorionic gonadotropin-treated intact or hypophysectomized rats. Bilateral treatment with cell-permeant short-chain ceramides (C2-cer or C6-cer) reproduced the early (4 h) inhibitory action of TNFalpha on testosterone biosynthesis and testicular StAR expression. The inhibitory action of C2-cer or C6-cer was not observed in animals treated with inactive analogs (dihydroceramide), phosphorylcholine, sphingosine, or sphingosine-1P. In sharp contrast to the previously described ability of IL1 beta to prevent human chorionic gonadotropin-stimulated Leydig cell steroidogenesis in vitro, serum testosterone and testicular StAR protein expression remained unchanged in animals bilaterally injected with this cytokine. These data support the concept that TNF alpha triggers different effector mechanisms to directly inhibit Leydig cell StAR expression and steroidogenesis, which ultimately contribute to the global reproductive failure associated with chronic inflammation and sepsis.

Photodynamic therapy (PDT) is a rising and hopeful treatment for solid tumors and others malignancies. PDT uses harmless visible light to activate a tumor-associated photosensitizer (PS). The excited PS generates cytotoxic reactive oxygen species (ROS) that induce damage and death of tumor cells. It is known that certain phytoalexins and phytoanticipins derived from plants often display a PS-like activity due to a phenalenone (PN) moiety-an efficient singlet oxygen photosensitizer-in its skeleton. The aim of this study is to explore the phototoxic properties of PN on the human cell line tumor-derived HL60 (acute promyelocytic leukemia) and to identify the cell-specific targets of ROS involved in the tumor cell death. Our results reveal that PN acts as an excellent PS, showing a potent antitumor cell activity in presence of light. PN-PDT generates intracellular ROS, via oxidation reaction mechanisms type I and II, resulting in an induction of apoptosis. Moreover, both extrinsic (through direct activation of caspase-3) and intrinsic (through mitochondrial depolarization) pathways of apoptosis are induced by PN-PDT. Using pharmacologic inhibitors, we also find that PN-PDT activates caspase-8/tBid and p38-MAPK, triggering the activation of the apoptotic pathways. Although, survival pathways are also promoted through PI3 K/Akt and JNK activation, the net result of PN-PDT is the tumor cell death. The present work identifies to PN, for the first time, as a potent photosensitizer in human tumor cell lines and proposes a mechanism by which ROS induces apoptosis of tumor cell.

Background TLR ligands can promote Th1-biased immune responses, mimicking potent stimuli of viruses and bacteria. Aim To investigate the adjuvant properties of dual TLR2/7 ligands compared to those of the mixture of both single ligands. Methods Dual TLR2/7 ligands: CL401, CL413, and CL531, including CL264 (TLR7-ligand) and Pam2CysK4 (TLR2-ligand), were used. Immune-modulatory capacity of the dual ligands with the individual ligands alone or as a mixture in mouse BMmDCs, BMmDC:TC cocultures, or BMCMCs was compared and assessed in naïve mice and in a mouse model of OVA-induced intestinal allergy. Results CL413 and CL531 induced BMmDC-derived IL-10 secretion, suppressed rOVA-induced IL-5 secretion from OVA-specific DO11.10 CD4+ TCs, and induced proinflammatory cytokine secretion in vivo. In contrast, CL401 induced considerably less IL-10 secretion and led to IL-17A production in BMmDC:TC cocultures, but not BMCMC IL-6 secretion, or IL-6 or TNF-α production in vivo. No immune-modulating effects were observed with single ligands. All dual TLR2/7 ligands suppressed DNP-induced IgE-and-Ag-specific mast cell degranulation. Compared to vaccination with OVA, vaccination with the mixture CL531 and OVA, significantly suppressed OVA-specific IgE production in the intestinal allergy model. Conclusions Based on beneficial immune-modulating properties, CL413 and CL531 may have utility as potential adjuvants for allergy treatment.

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Even though nutritional folate status can be considered minimally acceptable, it may reflect the low level of fruit and vegetable consumption within the Canary Islands population.

The isolation and characterisation of (S)-(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid, a well known synthetic non-steroidal anti-inflammatory drug (naproxene), from a natural source is described for the first time. We evaluated the ability of naproxene and its 7-methoxy isomer to abrogate constitutive COX-1 and inducible COX-2 activity in human A549 cells. Naproxene inhibited COX-1 (IC50 = 3.42 microM) and COX-2 (IC50 = 1.53 microM), whereas the 7-methoxy isomer had no appreciable effect on COX-1 (IC50 >> 100 microM) but also abrogated the activity of COX-2 enzyme (IC50 = 14.42 microM).