Structural mutations in the p53 gene are seen in virtually every form of human cancer. To determine whether such mutations are important for initiating tumorigenesis, we have been studying hepatocellular carcinoma, in which most cases are associated with chronic hepatitis B virus infections. Using a transgenic mouse model where expression of a single HBV gene product, the HBx protein, induces progressive changes in the liver, we show that tumour development correlates precisely with p53 binding to HBx in the cytoplasm and complete blockage of p53 entry into the nucleus. Analysis of tumour cell DNA shows no evidence for p53 mutation, except in advanced tumours where a small proportion of cells may have acquired specific base substitutions. Our results suggest that genetic changes in p53 are late events which may contribute to tumour progression.

Downhill running is associated with fiber damage, inflammation, delayed-onset muscle soreness, and various functional deficits. Curcumin, a constituent of the Indian spice turmeric has been investigated for its anti-inflammatory activity and may offset some of the damage and functional deficits associated with downhill running. This study examined the effects of curcumin on inflammation and recovery of running performance following downhill running in mice. Male mice were assigned to downhill placebo (Down-Plac), downhill curcumin (Down-Cur), uphill placebo (Up-Plac), or uphill curcumin (Up-Cur) groups and run on a treadmill at 22 m/min at -14% or +14% grade, for 150 min. At 48 h or 72 h after the up/downhill run, mice (experiment 1) underwent a treadmill performance run to fatigue. Another subset of mice was placed in voluntary activity wheel cages following the up/downhill run (experiment 2) and their voluntary activity (distance, time and peak speed) was recorded. Additional mice (experiment 3) were killed at 24 h and 48 h following the up/downhill run, and the soleus muscle was harvested for analysis of inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), and plasma was collected for creatine kinase analysis. Downhill running decreased both treadmill run time to fatigue (48 h and 72 h) and voluntary activity (24 h) (P < 0.05), and curcumin feedings offset these effects on running performance. Downhill running was also associated with an increase in inflammatory cytokines (24 h and 48 h) and creatine kinase (24 h) (P < 0.05) that were blunted by curcumin feedings. These results support the hypothesis that curcumin can reduce inflammation and offset some of the performance deficits associated with eccentric exercise-induced muscle damage.

The results of this study indicate that extracts of E. angustifolia root, either alone or in combination, do not have clinically significant effects on infection with a rhinovirus or on the clinical illness that results from it.

Exercise stress is associated with increased risk for upper respiratory tract infection. We have shown that exercise stress can increase susceptibility to infection. Quercetin, a flavonoid present in a wide variety of fruits and vegetables, has been reported to inhibit infectivity and replication of a broad spectrum of viruses and may offset the increase in susceptibility to infection associated with stressful exercise. This study examined the effects of quercetin feedings on susceptibility to the influenza virus A/Puerto Rico/8/34 (H1N1) following stressful exercise. Mice were randomly assigned to one of four treatment groups: exercise-placebo, exercise-quercetin, control-placebo, or control-quercetin. Exercise consisted of a run to fatigue (approximately 140 min) on a treadmill for 3 consecutive days. Quercetin (12.5 mg/kg) was administered via gavage for 7 days before viral challenge. At 30 min after the last bout of exercise or rest, mice (n=23-30) were intranasally inoculated with a standardized dose of influenza virus (0.04 hemagglutinating units). Mice were monitored daily for morbidity (time to sickness), symptom severity, and mortality (time to death) for 21 days. Exercise stress was associated with an increased susceptibility to infection [morbidity, mortality, and symptom severity on days 5-7 (P<0.05)]; quercetin offset the increase in susceptibility to infection [morbidity, mortality, and symptom severity on days 5-7 (P<0.05)] that was associated with stressful exercise. These data suggest that short-term quercetin feedings may prove to be an effective strategy to lessen the impact of stressful exercise on susceptibility to respiratory infection.

Alkamides are suspected to contribute to the activity of Echinacea preparations. They are mainly derived from undeca- and dodecanoic acid and differ in the degree of unsaturation and the configuration of the double bonds. In total, 6 alkamides have been isolated from the roots of Echinacea angustifolia as major lipophilic constituents and have been investigated regarding their pharmacokinetics. A sensitive and specific method has been developed for the identification and quantification of these alkamides in human plasma using liquid chromatography electrospray ionization ion-trap mass spectrometry. The method was applied to analyze plasma samples obtained from a randomized, open, single-dose, crossover study after oral administration of a 60% ethanolic extract from the roots of E. angustifolia to 11 healthy subjects. The maximum concentration of dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides, the main alkamides in the roots of E. angustifolia, appeared already after 30 minutes and was 10.88 ng/mL for the 2.5-mL dose.

The purpose of this study was to assess the effectiveness of echinacea for the prevention of experimental rhinovirus colds. Infection occurred in 44 and 57% and illness occurred in 36 and 43% of the echinacea-and placebo-treated subjects, respectively. This preparation of echinacea had no significant effect on either the occurrence of infection or the severity of illness.Since the Dietary Supplement Health and Education Act was enacted by Congress in 1994 to modify the Food and Drug Administration regulation of dietary supplements, there has been a dramatic increase in the marketing and sale of these products. Echinacea is one of the most popular herbal remedies and is reported to have immunomodulatory activity that is beneficial for the treatment of common cold symptoms. Clinical studies on the effect of echinacea on the common cold have used a variety of different echinacea preparations and study designs (8,13,16). Different preparations of echinacea differ in chemical composition due variation in the plant species or the part of the plant that is used as the starting material or because of differences in the manufacturing process or dosage form (1, 3). The purpose of this study was to use the experimental cold model to evaluate the effectiveness of an echinacea preparation with a defined chemical profile for the prevention of rhinovirus colds.Subjects Ն18 years of age were recruited for these studies from the university community of the Medical University of South Carolina. Volunteers with a serum titer of neutralizing antibody to the study virus of Յ1:4 were treated with echinacea (300 mg) or a placebo three times each day for 14 days prior to virus challenge. All volunteers were challenged with 100 to 300 50% tissue culture-infective doses of rhinovirus type 23, and then the treatment was continued for 5 days after the virus challenge. Virus infection was documented by virus cultures and antibody responses, and illness severity was assessed by a modification of a previously published method (12,14). The echinacea preparation used in this study was analyzed by reversed-phase high-pressure liquid chromatography by Rudolf Bauer (Institut für Pharmazeutische Biologie, Düsseldorf, Germany) using published methods (2-6) and found to contain 0.16% cichoric acid with almost no echinacosides or alkamides. Written informed consent was obtained prior to study participation, and subjects were compensated for participation.One hundred seventeen subjects were enrolled in the trial and treated with either echinacea (63 subjects) or a placebo (54 subjects) for 2 weeks. Sixteen subjects (eight active, eight placebo) had a respiratory illness on day 0 and were not challenged with rhinovirus, four subjects in each group withdrew from the study prior to challenge, and one subject treated with echinacea was removed from the study due to an adverse event. The remaining 92 subjects were challenged with rhinovirus type 23 and continued on study medication as outpatients for an additional 5 days. On day 0 prior to virus challenge, ...

The muscadine grape possesses one of the highest antioxidant levels among fruits; yet, the effect of this fruit on mammalian metabolic systems has not received significant attention. To examine the antiinflammatory properties of the muscadine, grape skins were dried, pulverized, and extracted (10% w/v) with 50% ethanol. The extract was then tested in two different assays: the release of superoxide in phorbol myristate acetate-activated neutrophils and the release of cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-beta), and interleukin-6 (IL-6)] by lipopolysaccharide-activated peripheral blood mononuclear cells. The release of superoxide and cytokines was inhibited by increasing concentrations of the extract. A 1:100 dilution of the extract inhibited superoxide release by approximately 60% while the release of TNF-alpha and IL-1beta was reduced at a dilution of 1:200 by approximately 15 and 90%, respectively (all P < 0.05). The inhibition pattern on the release of IL-6 was similar to that seen with TNF-alpha. In a related in vivo study, rats were fed a diet containing 5% (wt/wt) dried muscadine grape skins for 14 days and then were injected with carrageenan in the foot pad. After 3 h, paw edema was measured and the rats on the grape skin diet had approximately 50% less paw edema than controls (P < 0.05). These results demonstrate that the muscadine grape skin powder possesses significant in vitro and in vivo antiinflammatory properties.

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