Nutritional research has shifted recently from alleviating nutrient deficiencies to chronic disease prevention. We investigated the activity of indicaxanthin, a bioavailable phytochemical of the betalain class from the edible fruit of Opuntia ficus-indica (L. Miller) in a rat model of acute inflammation. Rat pleurisy was achieved by injection of 0.2 mL of λ-carrageenin in the pleural cavity, and rats were killed 4, 24, and 48 h later; exudates were collected to analyze inflammatory parameters, such as nitric oxide (NO), prostaglandin E(2) (PGE(2)), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α); cells recruited in pleura were analyzed for cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) expression, and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation. Indicaxanthin (0.5, 1, or 2 μmol/kg), given orally before carrageenin, time- and dose-dependently, reduced the exudate volume (up to 70%) and the number of leukocytes recruited in the pleural cavity (up to 95%) at 24 h. Pretreatment with indicaxanthin at 2 μmol/kg inhibited the carrageenin-induced release of PGE(2) (91.4%), NO (67.7%), IL-1β (53.6%), and TNF-α (71.1%), and caused a decrease of IL-1β (34.5%), TNF-α (81.6%), iNOS (75.2%), and COX2 (87.7%) mRNA, as well as iNOS (71.9%) and COX-2 (65.9%) protein expression, in the recruited leukocytes. Indicaxanthin inhibited time- and dose- dependently the activation of NF-κB, a key transcription factor in the whole inflammatory cascade. A pharmacokinetic study with a single 2 μmol/kg oral administration showed a maximum 0.22 ± 0.02 μmol/L (n = 15) plasma concentration of indicaxanthin, with a half-life of 1.15 ± 0.11 h. When considering the high bioavailability of indicaxanthin in humans, our findings suggest that this dietary pigment has the potential to improve health and prevent inflammation-based disorders.

Although thiazolidinediones were designed as specific peroxisome proliferator-activated receptor (PPAR)-gamma-ligands, there is evidence for some off-target effects mediated by a non-PPARgamma mechanism. Previously we have shown that rosiglitazone has antiinflammatory actions not explicable by activation of PPARgamma,but possibly by the glucocorticoid receptor (GR). Rosiglitazone induces nuclear translocation both of GR-green fluorescent protein, and endogenous GR in HeLa and U20S cells but with slower kinetics than dexamethasone. Rosiglitazone also induces GR phosphorylation (Ser211), a GR ligand-binding-specific effect. Rosiglitazone drives luciferase expression from a simple glucocorticoid-response element containing reporter gene in a GR-dependent manner (EC50 4 microm), with a similar amplitude response to the partial GR agonist RU486. Rosiglitazone also inhibits dexamethasone-driven reporter gene activity (IC50 2.9 microm) in a similar fashion to RU486, suggesting partial agonist activity. Importantly we demonstrate a similar effect in PPARgamma-null cells, suggesting both GR dependence and PPARgamma independence. Rosiglitazone also activates a GAL4-GR chimera, driving a upstream activating sequence promoter, demonstrating DNA template sequence independence and furthermore enhanced steroid receptor coactivator-1-GR interaction, measured by a mammalian two-hybrid assay. Both ciglitazone and pioglitazone, structurally related to rosiglitazone, show similar effects on the GR. The antiproliferative effect of rosiglitazone is increased in U20S cells that overexpress GR, suggesting a biologically important GR-dependent component of rosiglitazone action. Rosiglitazone is a partial GR agonist, affecting GR activation and trafficking to influence engagement of target genes and affect cell function. This novel mode of action may explain some off-target effects observed in vivo. Additionally, antagonism of glucocorticoid action may contribute to the antidiabetic actions of rosiglitazone.

Lipopolysaccharide (LPS) or endotoxin, the major constituent of the outer membrane of Gram negative bacteria, has been implicated as the bacterial product responsible for the clinical syndrome of sepsis. LPS binding to the host receptor Toll-like receptor 4 (TLR4) triggers an inflammatory reaction characterised by the release of large number of inflammatory mediators that allow the host to respond to the invading pathogen. When this production becomes un-controlled and excessive, it leads to the development of septic shock. Despite decades of efforts in supporting therapies, sepsis remains the leading cause of death amongst critically ill patients. Unfortunately, the major factor contributing to the high morbidity and mortality of sepsis is the lack of the effective targeted treatment. Indeed, over 30 drugs for the treatment of sepsis have been developed: many of these target specific inflammatory mediators and have thus been, in general, unsuccessful since sepsis relies on the cross talk of several cytokines and the block of a single factor has been proven to be ineffective. More successful strategies include those modulating the early phase of LPS signalling such as the ones that prevent the binding of LPS to host cells and the subsequent cascade of detrimental events. In this light, effective LPS antagonists would represent invaluable tools to efficaciously manage sepsis. This review discusses the evolution of naturally occurring and synthetic LPS antagonists with emphasis on the development of several natural new molecules.

No abstract

Malignant melanoma is a highly aggressive tumor that frequently resists chemotherapy, so the search for new agents for its treatment is of great importance. In the present study, the antiproliferative propensity against human melanoma cell lines of lauroside B (1), a megastigmane glycoside isolated from Laurus nobilis (bay laurel) leaves, was investigated. This compound suppressed the proliferation of three human melanoma cell lines, namely, A375, WM115, and SK-Mel-28. The 1-induced inhibition of human melanoma cell proliferation was due to the induction of apoptosis, as demonstrated by FACS analysis with annexin V/PI staining and confirmed by activation of caspase-3 and by the cleavage of poly(ADP-ribose) polymerase (PARP). Growing evidence implicates NF-κB as an important contributor to metastasis and increased chemoresistance of melanoma. Thus, it was hypothesized that 1-induced apoptosis could be associated with suppression of NF-κB activation. The results showed that exposure of human melanoma cells to 1 inhibited IκB-α degradation and constitutive NF-κB DNA-binding activity as well as the expression, regulated by NF-κB, of two antiapoptotic genes, XIAP and c-FLIP. Induction of apoptosis by 1 in human aggressive melanoma cell lines has a potential high biological value.