Antifungal activity of lichen extracts and lichenic acids

Acetone extracts of the threelichen species Evernia prunastri, Hypogymnia physodes and Cladoniaportentosa were investigated for activityagainst eight plant pathogenic fungi: Pythium ultimum, Phytophthorainfestans, Rhizoctonia solani, Botrytis cinerea, Colletotrichumlindemuthianum, Fusarium solani, Stagonospora nodorum and Ustilagomaydis. Particularly, E. prunastriand H. physodes exhibit total or stronginhibition on P. ultimum, U.maydis and P. infestans growth. Incontrast, Cladonia extracts were lessactive to reduce growth of these fungi.Lichenic acids were also examined forantifungal activity. P. infestans growthwas severely inhibited by evernic acid. P.ultimum and P. infestans growth wereslightly but significantly inhibited by evernicacid and (–) usnic acid, respectively. Growthinhibition of U. maydis was also observedfor the latter lichenic acid. These resultsconfirm the previously observed activities oflichen extracts. This suggests that secondarylichen metabolites might be of potential use asantifungal agents.     

Umbelliprenin from Ferula szowitsiana inhibits the growth of human M4Beu metastatic pigmented malignant melanoma cells through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis.

Metastatic malignant melanoma have a bad prognosis (median survival: 6-8 months) mainly due to the development of lung, hepatic and brain metastases. In this study we have used the resazurin reduction test and FACS analysis to assess the cytostatic and cytotoxic effect of umbelliprenin from Ferula szowitsiana (Apiaceae) on human solid cancer cells and human primary fibroblasts. We have observed that the cell susceptibility to umbelliprenin decreases in the order M4Beu (metastatic pigmented malignant melanoma)>A549 (nonsmall cell lung carcinoma) approximately PC3 (androgen-resistant prostate carcinoma)>PA1 (ovary teratocarcinoma)>human primary fibroblasts approximately MCF7 (breast adenocarcinoma)>DLD1 (colon adenocarcinoma). M4Beu cell-proliferation is inhibited through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis. The finding that the cytotoxic effect of umbelliprenin is markedly more pronounced in M4Beu cells than in primary fibroblasts, suggests a therapeutic margin. As M4Beu cell proliferation is more potently inhibited by umbelliprenin (IC50 12.3 microM) than by the citrus coumarin auraptene (7-geranyloxycoumarin, IC50 17.1 microM) previously reported capable of inhibiting the prevalence of lung metastasis in mice bearing B16BL6 murine melanoma, our data suggest that umbelliprenin orally administered and foods and folk medicines containing this coumarin, may afford protection against the development and early recurrence of malignant melanoma. In vivo investigations are needed to test these hypotheses.     

The acetate recovery factor to correct tracer-derived dietary fat oxidation in humans

When using (13)C tracer to measure plasma fat oxidation, an acetate recovery factor should be determined in every subject to correct for label sequestration. Less is known regarding the acetate recovery factor for dietary fatty acid oxidation. We compiled data from six studies to investigate the determinants of the dietary acetate recovery factor (dARF) at rest and after physical activity interventions and compared the effects of different methods of dARF calculation on both the fat oxidation and its variability. In healthy lean subjects, dARF was 50.6 +/- 5.4% dose (n = 56) with an interindividual coefficient of variation of 10.6% at rest and 9.2% after physical activity modifications. The physical activity interventions did not impact dARF, and the intraindividual coefficient of variation was 4.6%. No major anthropological or physiological determinants were detected except for resting metabolic rate, which explains 7.4% of the dARF variability. Applying an individual or an average group dARF did not affect the mean and the variability of the derived dietary lipid oxidation at rest or after physical activity interventions. Using a mean dARF for a group leads to over- or underestimation of fat oxidation of less than 10% in individual subjects. Moreover, the use of a group or individual correction did not affect the significant relationship found between fasting respiratory exchange ratio and dietary fat oxidation. These data indicate that an average dARF can be applied for longitudinal and cross-sectional studies investigating dietary lipid metabolism.     

Vitamin D signaling in immune-mediated disorders: Evolving insights and therapeutic opportunities

1,25(OH)(2)D(3), the active form of vitamin D, is a central player in calcium and bone metabolism. More recently, important immunomodulatory effects have been attributed to this hormone. The widespread presence of the vitamin D receptor (VDR) in the immune system and the expression of the enzymes responsible for the synthesis of the active 1,25(OH)(2)D(3) regulated by specific immune signals, even suggest a paracrine immunomodulatory role for 1,25(OH)(2)D(3). Additionally, the different molecular mechanisms used by 1,25(OH)(2)D(3) to exert its immunomodulatory effects prove of a broad action radius for this compound. Both, the effects of vitamin D deficiency and/or absence of the VDR as well as intervention with pharmacological doses of 1,25(OH)(2)D(3) or one of its less-calcemic analogs, affects immune system behavior in different animal models of immune-mediated disorders, such as type 1 diabetes. This review aims to summarize the data as they stand at the present time on the role of vitamin D in the pathogenesis of immune-mediated disorders, with special focus on type 1 diabetes, and on the therapeutic opportunities for vitamin D in the prevention and treatment of this autoimmune disease in mouse models and humans.     

Unusual intracellular trafficking of Salmonella typhimurium in human melanoma cells

Salmonella spp. are enterobacteria capable of invading and replicating in both professional and non‐professional phagocytes. Here, we investigate the fate of S. typhimurium in human melanoma MelJuSo cells. The bacterium entered MelJuSo cells by a trigger mechanism and resided within a unique organelle, the Salmonella‐containing vacuole (SCV). The SCV acquired early endosomal markers transiently and then underwent a series of membrane modifications. In HeLa cells, vacuole maturation is characterized by the simultaneous acquisition of the lysosomal membrane glycoproteins (Lgps) Lamp1, CD63 and vacuolar (v)‐ATPase; in MelJuSo cells, however, acquisition of CD63 and v‐ATPase preceded that of Lamp1. A very striking event in MelJuSo cells was the arrest of bacterial septation starting from 8 h after infection. Bacteria nevertheless continued to elongate, remained morphologically intact and viable and were eventually exocytosed. This original feature was observed in several skin‐related cells including melanocytes, suggesting that it may provide the basis for an efficient host defence mechanism against Salmonella infection.     

Mode shift of an inhaled aerosol bolus is correlated with flow sequencing in the human lung.

We studied the effects on aerosol bolus inhalations of small changes in convective inhomogeneity induced by posture change from upright to supine in nine normal subjects. Vital capacity single-breath nitrogen washout tests were used to determine ventilatory inhomogeneity change between postures. Relative to upright, supine phase III slope was increased 33 +/- 11% (mean +/- SE, P < 0.05) and phase IV height increased 25 +/- 11% (P < 0.05), consistent with an increase in convective inhomogeneity likely due to increases in flow sequencing. Subjects also performed 0.5-microm-particle bolus inhalations to penetration volumes (V(p)) between 150 and 1,200 ml during a standardized inhalation from residual volume to 1 liter above upright functional residual capacity. Mode shift (MS) in supine posture was more mouthward than upright at all V(p), changing by 11.6 ml at V(p) = 150 ml (P < 0.05) and 38.4 ml at V(p) = 1,200 ml (P < 0.05). MS and phase III slope changes correlated positively at deeper V(p). Deposition did not change at any V(p), suggesting that deposition did not cause the MS change. We propose that the MS change results from increased sequencing in supine vs. upright posture.     

Effects of long-term spaceflight on mechanical properties of muscles in humans

The effects of long-term spaceflight(90-180 days) on the contractile and elastic characteristics ofthe human plantarflexor muscles were studied in 14 cosmonauts beforeand 2-3 days after landing. Despite countermeasures practicedaboard, spaceflight was found to induce a decrease in maximal isometrictorque (17%), whereas an index of maximal shortening velocity wasfound to increase (31%). In addition, maximal muscle activationevaluated during isokinetic tests decreased by 39%. Changes inmusculotendinous stiffness and whole joint stiffness were characterizedby means of quick-release movements and sinusoidal perturbations.Musculotendinous stiffness was found to be increased by 25%. Wholejoint stiffness decreased under passive conditions (21%), whereaswhole joint stiffness under active conditions remained unchanged afterspaceflight (1%). This invariance suggests an adaptive mechanism tocounterbalance the decrease in stiffness of passive structures by anincreased active stiffness. Changes in neural drive could participatein this equilibrium.

     

Synthesis and potential anti-inflammatory activity of some tetrahydrophthalazinones

A solid-phase route for the preparation of 4a,5,8,8a-tetrahydrophthalazinon-1-ones employing the Diels-Alder reaction has been developed. Some of the new compounds have been tested for inhibition of LPS-stimulated TNF-alpha production in human whole blood from patients with chronic obstructive pulmonary disease (COPD). This evaluation revealed two compounds 17 and 18 of interest, incorporating an arylpiperazine moiety, which were found to inhibit LPS-induced TNF-alpha release like the well known anti-inflammatory PDE4 inhibitors, rolipram and roflumilast.