Intestinal inflammatory cytokine response in relation to tumorigenesis in the Apc(Min/+) mouse.

The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental factors. However, only about 20% have a familial basis with the largest fraction being attributed to environmental causes that can lead to chronic inflammation. While the link between inflammation and colon cancer is well established, the temporal sequence of the inflammatory response in relation to tumorigenesis has not been characterized. We examined the timing and magnitude of the intestinal inflammatory cytokine response in relation to tumorigenesis in the Apc(Min/+) mouse. Apc(Min/+) mice and wildtype mice were sacrificed at one of 4 time-points: 8, 12, 16, and 20 weeks of age. Intestinal tissue was analyzed for polyp burden (sections 1, 4 and 5) and mRNA expression and protein concentration of MCP-1, IL-1ß, IL-6 and TNF-α (sections 2 and 3). The results show that polyp burden was increased at 12, 16 and 20 weeks compared to 8 weeks (P<0.05). Gene expression (mRNA) of MCP-1, IL-1ß, IL-6 and TNF-α was increased in sections 2 and 3 starting at week 12 (P<0.05), with further increases in MCP-1, IL-1ß and IL-6 at 16 weeks (P<0.05). Protein concentration for these cytokines followed a similar pattern in section 3. Similarly, circulating MCP-1 was increased at 12 weeks (P<0.05) and then again at 20 weeks (P<0.05). In general, overall polyp number and abundance of large polyps were significantly correlated with the inflammatory cytokine response providing further support for a relationship between polyp progression and these markers. These data confirm the association between intestinal cytokines and tumorigenesis in the Apc(Min/+) mouse and provide new information on the timing and magnitude of this response in relation to polyp development. These findings may lead to the development of inflammatory mediators as important biomarkers for colon cancer progression. Further, these data may be relevant in the design of future investigations of therapeutic interventions to effectively target inflammatory processes in rodent models.

Quercetin's effects on intestinal polyp multiplicity and macrophage number in the Apc(Min/+) mouse.

Numerous in vitro studies argue for quercetin's chemopreventive potential in colon cancer; however, experimental studies in rodents are limited. Macrophages play a role in tumorigenesis, but the effects of quercetin on macrophage infiltration in colon cancer is unknown. We examined the effects of quercetin on intestinal polyp multiplicity and macrophage number in Apc(Min/+) mice. Apc(Min/+) mice were assigned to placebo or quercetin (n = 8/group) groups. Mice were given a placebo or quercetin (0.02%) diet from 4-20 wk of age, after which intestines were analyzed for polyp number and size in the small intestine (Sections 1-4) and colon (Section 5) and for macrophage number in the small intestine (Sections 1 and 3). Spleen weight was determined as a marker of systemic inflammation. Quercetin decreased total intestinal polyps by 67% (P < 0.05). Specifically, quercetin reduced intestinal polyps in categories >2 mm (69%) and 1-2 mm (79%; P < 0.05), and in Sections 2 (75%), 3 (80%), and 4 (79%; P < 0.05). Quercetin also decreased macrophage number in Sections 1 (57%) and 3 (81%), and spleen weight (P < 0.05). These data suggest that quercetin can reduce polyp number and size distribution in the Apc(Min/+) mouse and that these effects may be related to a reduction in macrophage infiltration.

Immune modulating effects of ß-glucan.

PURPOSE OF REVIEW: To examine the recent scientific literature on the immune modulating effects of ß-glucans and subsequent benefits on infection and cancer. RECENT FINDINGS: ß-Glucans have been investigated for their ability to protect against infection and cancer and more recently for their therapeutic potential when combined with cancer therapy. Their immune modulating effects are attributed to the ability to bind to pattern recognition receptors including complement receptor 3, scavenger receptors, lactosylceramide, and dectin-1 that results in activation of different aspects of the immune response depending on the cell types and species involved although there is some controversy about the relative importance of each of these receptors. Most of the available evidence comes from preclinical data and human studies are just now beginning to appear in the literature, therefore firm conclusions on its clinical importance cannot yet be made. Perhaps the most promising evidence to date in human trials has come from recent studies on a benefit of ß-glucan on quality of life and survival when given in combination with cancer treatment. We identify the need for future studies that compare purified forms of ß-glucans from different sources to further the understanding of the mechanisms of action and aid in the development of clinical studies. SUMMARY: ß-Glucans appear to be effective at enhancing immune function and reducing susceptibility to infection and cancer. A better understanding of the mechanisms of ß-glucan recognition and subsequent immune activation is necessary for the design of effective treatment approaches in future clinical trials.

Role of brain macrophages on IL-1beta and fatigue following eccentric exercise-induced muscle damage.

Fatigue associated with recovery from muscle damage has recently been linked to increases in brain and muscle proinflammatory cytokines. However, little is known regarding the origin of these cytokines. Since macrophage-like cells in the brain are a primary source of cytokines, we used a brain specific macrophage depletion technique involving liposome encapsulated clodronate (CLD) to examine the role of macrophages on brain IL-1beta and fatigue following eccentric exercise-induced muscle damage. Mice were assigned to six groups: Downhill saline (DWNSAL), downhill clodronate (DWNCLD), uphill saline (UPSAL), uphill clodronate (UPCLD), non-running saline (CONSAL) or non-running clodronate (CONCLD). Mice were given intracerebroventricular (ICV) (10 microL) injections of clodronate-filled liposomes (CLD) to deplete macrophages, or saline-filled liposomes (SAL) and run on a treadmill at 22m/min and -14% (DWN) or 14% (UP) grade for 150 min. A subset of uphill and downhill running mice (n=40) was then run to fatigue on a treadmill at 36m/min, 8% grade at 24h after the uphill and downhill runs. A second subset of uphill, downhill, and control mice (n=30) was sacrificed 24h after the run for analysis of brain IL-1beta concentration. Histological examination confirmed previous reports that CLD administration reduced perivascular and meningeal macrophage subsets in the brain. CLD reduced IL-1beta concentration in the cortex of DWN mice (P<0.05), which was associated with enhanced treadmill performance 24h after both uphill and downhill runs (P<0.05) although the magnitude was greater following the downhill run. These results suggest that brain macrophages can contribute to the increase in brain IL-1beta and fatigue that are associated with recovery from exercise-induced muscle damage.

Benefits of oat beta-glucan and sucrose feedings on infection and macrophage antiviral resistance following exercise stress.

Oat beta-glucan can counteract the exercise-induced increased risk for upper respiratory tract infection (URTI) in mice, which is at least partly mediated by its effects on lung macrophages. Substantial evidence in humans indicates that carbohydrate-containing sports drinks can offset the decreased immune function associated with stressful exercise. However, no studies in animals or humans have directly examined their effects on URTI using a controlled virus-challenge model. We examined the effects of sucrose feedings alone and in combination with oat beta-glucan on susceptibility to infection and on macrophage antiviral resistance in mice following stressful exercise. These effects were also examined in rested, nonimmunocompromised control mice. Mice were assigned to one of four groups: H(2)O (water), sucrose (S), oat beta-glucan (ObetaG), and sucrose + oat beta-glucan (S+ObetaG). ObetaG and S treatments consisted of a solution of 50% ObetaG and 6% sucrose, respectively, and were administered in drinking water for 10 consecutive days. Exercise consisted of a treadmill run to fatigue performed on three consecutive days. Mice were then intranasally inoculated with a standardized dose of herpes simplex virus 1 (HSV-1) and monitored for morbidity and mortality for 21 days. Additional mice were used to determine macrophage antiviral resistance. In the exercise experiment, S, ObetaG, and S+ObetaG all reduced morbidity (P < 0.05), while only S+ObetaG reduced mortality (P < 0.05). Macrophage antiviral resistance was also increased in S, ObetaG, and S+ObetaG treatments (P < 0.05). In resting controls, S and S+ObetaG reduced morbidity and mortality (P < 0.05) and showed a trend toward increased macrophage antiviral resistance. There was no significant additive effect of S and ObetaG in either control or exercised animals. These data extend our previous work on the benefits of oat beta-glucan to show that sucrose feedings have similar effects on susceptibility to respiratory infection and macrophage antiviral resistance in both resting controls and following exercise stress.

Successive bouts of cycling stimulates genes associated with mitochondrial biogenesis.

Exercise increases mRNA for genes involved in mitochondrial biogenesis and oxidative enzyme capacity. However, little is known about how these genes respond to consecutive bouts of prolonged exercise. We examined the effects of 3 h of intensive cycling performed on three consecutive days on the mRNA associated with mitochondrial biogenesis in trained human subjects. Forty trained cyclists were tested for VO(2max) (54.7 +/- 1.1 ml kg(-1) min(-1)). The subjects cycled at 57% watts(max) for 3 h using their own bicycles on CompuTrainer Pro Model trainers (RacerMate, Seattle, WA) on three consecutive days. Muscle biopsies were obtained from the vastus lateralis pre- and post-exercise on days one and three. Muscle samples were analyzed for mRNA content of peroxisome proliferator receptor gamma coactivator-1 alpha (PGC-1alpha), sirtuin 1 (Sirt-1), cytochrome c, and citrate synthase. Data were analyzed using a 2 (time) x 2 (day) repeated measures ANOVA. Of the mRNA analyzed, the following increased from pre to post 3 h rides: cytochrome c (P = 0.006), citrate synthase (P = 0.03), PGC-1alpha (P < 0.001), and Sirt-1 (P = 0.005). The following mRNA showed significant effects from days one to three: cytochrome c (P < 0.001) and citrate synthase (P = 0.01). These data show that exhaustive cycling performed on three consecutive days resulted in both acute and chronic stimuli for mRNA associated with mitochondrial biogenesis in already trained subjects. This is the first study to illustrate an increase in sirtuin-1 mRNA with acute and chronic exercise. These data contribute to the understanding of mRNA expression during both acute and successive bouts of prolonged exercise.

Effects of the dietary flavonoid quercetin upon performance and health.

There is increased interest among such diverse groups as the military, athletes, and the aged for novel plant-derived dietary supplements to enhance performance and maintain/improve health. Quercetin, a flavonoid found in fruits and vegetables, has unique biological properties that are likely to improve mental/physical performance and reduce infection risk during intense exercise. These properties include antiinflammatory, antioxidant, and psychostimulant activity, as well as the ability to stimulate mitochondrial biogenesis, and they form the basis for potential benefits to overall health and disease resistance. However, most information regarding quercetin is based upon in vitro and animal studies. Therefore, there is a pressing need for well-designed clinical trials to evaluate this novel dietary supplement further. This article will examine the recent scientific literature concerning the role of quercetin in mental and physical performance and health.

Quercetin ingestion does not alter cytokine changes in athletes competing in the Western States Endurance Run.

The purpose of this study was to measure the influence of quercetin on plasma cytokines, leukocyte cytokine mRNA, and related variables in ultramarathoners competing in the 160-km Western States Endurance Run (WSER). Sixty-three runners were randomized to quercetin and placebo groups and under double-blinded methods ingested 1000 mg/day quercetin for 3 weeks before the WSER. Thirty-nine of the 63 subjects (n = 18 for quercetin, n = 21 for placebo) finished the race and provided blood samples the morning before the race and 15-30 min postrace. Significant prerace to postrace WSER increases were measured for nine proinflammatory and anti-inflammatory plasma cytokines, cortisol (quercetin = 94%, placebo = 96%), serum C-reactive protein (CRP) (mean +/- SE absolute increase, quercetin = 31.8 +/- 4.2, placebo = 38.2 +/- 5.0 mg/L), and creatine kinase (CK) (quercetin = 21,575 +/- 3,977, placebo = 19,455 +/- 3,969 U/L), with no significant group differences. Interleukin-6 (IL-6) mRNA did not change post-WSER, with a significant decrease measured for leukocyte IL-8 mRNA (0.21 +/- 0.03-fold and 0.25 +/- 0.04-fold change from rest, quercetin and placebo, respectively) and significant increases for IL-1Ra mRNA (1.43 +/- 0.18-fold and 1.40 +/- 0.16-fold change, quercetin and placebo, respectively) and IL-10 mRNA (12.9 +/- 3.9-fold and 17.2 +/- 6.1-fold change, quercetin and placebo, respectively), with no significant differences between groups. In conclusion, quercetin ingestion (1 g/day) by ultramarathon athletes for 3 weeks before a competitive 160-km race significantly increased plasma quercetin levels but failed to attenuate muscle damage, inflammation, increases in plasma cytokine and hormone levels, and alterations in leukocyte cytokine mRNA expression.

Quercetin's influence on exercise-induced changes in plasma cytokines and muscle and leukocyte cytokine mRNA.

Trained male cyclists (n = 40) ingested quercetin (Q; n = 20) (1,000 mg/day) or placebo (P; n = 20) supplements under randomized, double-blinded methods for 3 wk before and during a 3-day period in which subjects cycled for 3 h/day at approximately 57% maximal work rate. Blood samples were collected before and after each exercise session and assayed for plasma IL-6, IL-10, IL-1ra, IL-8, TNF-alpha, and monocyte chemoattractant protein 1, and leukocyte IL-10, IL-8, and IL-1ra mRNA. Muscle biopsies were obtained before and after the first and third exercise sessions and assayed for NF-kappaB and cyclooxygenase-2 (COX-2), IL-6, IL-8, IL-1beta, and TNF-alpha mRNA. Postexercise increases in plasma cytokines did not differ between groups, but the pattern of change over the 3-day exercise period tended to be lower in Q vs. P for IL-8 and TNF-alpha (P = 0.094 for both). mRNA increased significantly postexercise for each cytokine measured in blood leukocyte and muscle samples. Leukocyte IL-8 and IL-10 mRNA were significantly reduced in Q vs. P (interaction effects, P = 0.019 and 0.012, respectively) with no other leukocyte or muscle mRNA group differences. Muscle NF-kappaB did not increase postexercise and did not differ between Q and P. Muscle COX-2 mRNA increased significantly postexercise but did not differ between Q and P. In summary, 1 g/day quercetin supplementation by trained cyclists over a 24-day period diminished postexercise expression of leukocyte IL-8 and IL-10 mRNA, indicating that elevated plasma quercetin levels exerted some effects within the blood compartment. Quercetin did not, however, influence any of the muscle measures, including NF-kappaB content, cytokine mRNA, or COX-2 mRNA expression across a 3-day intensified exercise period.

Oat beta-glucan effects on neutrophil respiratory burst activity following exercise.

UNLABELLED: Fatiguing exercise has been associated with a decrease in certain functions of neutrophils, whereas moderate exercise has generally been associated with an increase. Consumption of oat beta-glucan (ObetaG), a soluble fiber and mild immune system enhancer, may offset the immunosuppression associated with intense training and perhaps further enhance the benefits of moderate exercise. PURPOSE: To test the effects of ObetaG consumption on neutrophil function and number after both moderate and fatiguing exercise. METHODS: Male mice were assigned to one of six treatment groups. Fatiguing exercise mice (Ftg-ObetaG and Ftg-H2O) ran to volitional fatigue on a treadmill for three consecutive days, and moderate exercise mice (Mod-ObetaG and Mod-H2O) ran for six consecutive days for 1 h. Control mice (Con-ObetaG and Con-H2O) were exposed to the treadmill environment but did not run. ObetaG was consumed in the drinking water (approximately 0.6 mL x d(-1)) for 10 consecutive days. After rest or exercise on the last day of training, mice were given a 1-mL i.p. injection of thioglycollate. Mice were sacrificed 3 h later; neutrophils were harvested from the peritoneal cavity and counted, and their respiratory burst activity was measured using flow cytometry. RESULTS: Both moderate exercise and ObetaG increased neutrophil burst activity, whereas fatiguing exercise had no effect. Neutrophil number was increased by fatiguing exercise and ObetaG, but not moderate exercise. There were no additive effects of exercise and ObetaG on either of these variables. CONCLUSION: These data suggest that although not additive in their effects, both ObetaG and exercise can alter overall neutrophil respiratory burst activity (number and/or function), but only ObetaG increased both number and function, which may have important ramifications for defense against infection.

Quercetin reduces illness but not immune perturbations after intensive exercise.

PURPOSE: To investigate the effects of quercetin supplementation on incidence of upper respiratory tract infections (URTI) and exercise-induced changes in immune function. METHODS: Trained male cyclists (N=40) were randomized to quercetin (N=20) or placebo (N=20) groups and, under double-blind procedures, received 3 wk quercetin (1000 mg.d(-1)) or placebo before, during, and for 2 wk after a 3-d period in which subjects cycled for 3 h.d(-1) at approximately 57% Wmax. Blood and saliva samples were collected before and after each of the three exercise sessions and assayed for natural killer cell activity (NKCA), PHA-stimulated lymphocyte proliferation (PHA-LP), polymorphonuclear oxidative-burst activity (POBA), and salivary IgA output (sIgA). RESULTS: Pre- to postexercise changes in NKCA, PHA-LP, POBA, and sIgA did not differ significantly between quercetin and placebo groups. URTI incidence during the 2-wk postexercise period differed significantly between groups (quercetin=1/20 vs placebo=9/20, Kaplan-Meier analysis statistic=8.31, P=0.004). CONCLUSION: Quercetin versus placebo ingestion did not alter exercise-induced changes in several measures of immune function, but it significantly reduced URTI incidence in cyclists during the 2-wk period after intensified exercise.

Gender differences in macrophage antiviral function following exercise stress.

INTRODUCTION: In male mice, exhaustive exercise increases susceptibility to respiratory infection following intranasal inoculation with herpes simplex virus-1 (HSV-1), whereas moderate exercise decreases the risk of infection. These responses have been linked with altered macrophage antiviral resistance, among other immune mechanisms. Female mice appear to be better protected from death than male mice following HSV-1 infection, although their response to exercise stress is similar. The possible immune mechanisms, however, have not been explored. PURPOSE: This study was conducted to examine gender differences in macrophage antiviral resistance following repeated moderate and exhaustive treadmill exercise. METHODS: Male (M, N = 36) and female (F, N = 36) CD-1 mice were randomly assigned to moderate exercise (Mod), exhaustive exercise (Exh), or control (C) groups. Exercise was done daily for 3 d; moderate exercise consisted of treadmill running for 90 min, whereas exhaustive exercise consisted of running to volitional fatigue (approximately 50 min). RESULTS: Females had greater macrophage antiviral resistance to HSV-1 than males in C and Mod (P < 0.05), but not Exh; Mod increased resistance, whereas Exh decreased resistance similarly in both genders (P < 0.001). CONCLUSIONS: These data suggest that altered macrophage antiviral resistance to HSV-1 may contribute to gender differences in in vivo resistance to HSV-1 respiratory infection at rest, as well as following moderate and exhaustive exercise.

Carbohydrate feedings during team sport exercise preserve physical and CNS function.

PURPOSE: This study was designed to examine the effect of carbohydrate (CHO) feedings on physical and central nervous system (CNS) function during intermittent high-intensity exercise with physical demands similar to those of team sports such as basketball. METHODS: Twenty active men (N = 10) and women (N = 10), with experience competing in team sports, performed three practice sessions before two experimental trials during which they were fed either a 6% CHO solution or a flavored placebo (PBO). Experimental trials consisted of four 15-min quarters of shuttle running with variable intensities ranging from walking (30% VO(2max)), to running (120% VO(2max)), to maximal sprinting, and 40 jumps at a target hanging at 80% of their maximum vertical jump height. Subjects received 5 mL.kg(-1) of fluid before exercise and 3 mL.kg(-1) after exercise, in addition to 3 mL.kg(-1) over a 5-min span after the first and third quarters, and 8 mL.kg(-1) during a 20-min halftime. During each break, the subjects performed a battery of tests measuring peripheral and CNS function, including 20-m sprints, a 60-s maximal jumping test, internal and external mood evaluation, cognitive function, force sensation, tests of motor skills, and target-jumping accuracy. RESULTS: Compared with PBO, CHO feedings during exercise resulted in faster 20-m sprint times and higher average jump height in the fourth quarter (P < 0.05). CHO feedings also reduced force sensation, enhanced motor skills, and improved mood late in exercise versus PBO (P < 0.05). CONCLUSION: These results suggest that CHO feedings during intermittent high-intensity exercise similar to that of team sports benefited both peripheral and CNS function late in exercise compared with a flavored placebo.

Gender differences in viral infection after repeated exercise stress.

UNLABELLED: Fatiguing exercise can increase susceptibility to respiratory infection after intranasal inoculation with herpes simplex virus-1 (HSV-1) in male mice. Although gender differences in susceptibility to certain pathogens do exist, it is unknown whether female mice will respond differently than males in response to strenuous exercise and HSV-1 infection. PURPOSE: To test the effects of gender on susceptibility to HSV-1 respiratory infection after repeated exhaustive exercise. METHODS: Male (N = 86) and female (N = 89) CD-1 mice (approximately 60 d old) were randomly assigned to exercise (Ex) or control (C) groups. Exercise consisted of 3 d of treadmill running at 36 m x min(-1) at 8% grade until volitional fatigue (135 +/- 5min). Fifteen minutes after the last bout of exercise, Ex and C mice were inoculated intranasally with a standard dose (LD30) of HSV-1. Mice were monitored for 21 d for morbidity (time to sickness and symptom severity) and mortality. RESULTS: Run time to fatigue was significantly longer in females than males (P = 0.027). Significant gender differences in susceptibility to infection were found after exercise stress. In males, exercise stress resulted in increased morbidity (66%, P < 0.05) and mortality (30%, P < 0.05) whereas in females, exercise stress only resulted in increased morbidity (66%, P < 0.05). CONCLUSION: Results suggest that although males and females have similar morbidity rates after infection and exercise stress, females recover to a greater extent and are ultimately better protected from death.

Effects of oat beta-glucan on innate immunity and infection after exercise stress.

PURPOSE: To test the effects of oat beta-glucan (ObetaG) on respiratory infection, macrophage antiviral resistance, and NK cytotoxicity. METHODS: Mice were randomly assigned to one of four groups: Ex-H2O, Ex-ObetaG, Con-H2O, or Con-ObetaG. ObetaG was fed in the drinking water for 10 d before intranasal inoculation of HSV-1 or sacrifice. Exercise consisted of treadmill running to volitional fatigue (approximately 140 min) for three consecutive days. Fifteen minutes after the last bout of exercise or rest, mice (N = 24) were intranasally inoculated with a standardized dose of HSV-1. Mice were monitored twice daily for morbidity and mortality. Additional mice were sacrificed after exercise, peritoneal macrophages were obtained via i.p. lavage and assayed for antiviral resistance to HSV-1 (N = 18), and spleens were harvested and assayed for NK cell cytotoxicity (N = 12). RESULTS: Exercise stress was associated with a 28% increase in morbidity (P = 0.036) and 18% increase in mortality (P = 0.15). Ingestion of ObetaG before infection prevented this increase in morbidity (P = 0.048) and mortality (P = 0.05). Exercise stress was associated with a decrease in macrophage antiviral resistance (P = 0.007), which was blocked by ingestion of ObetaG (P < 0.001). There were no effects of exercise or ObetaG on NK cytotoxicity. CONCLUSION: These data suggest that daily ingestion of ObetaG may offset the increased risk of URTI associated with exercise stress, which may be mediated, at least in part, by an increase in macrophage antiviral resistance.

Effects of oat ß-glucan on the macrophage cytokine response to herpes simplex virus 1 infection in vitro.

Oat ß-glucan can counteract the increased risk for Herpes Simplex Virus 1 (HSV-1) infection in mice, the effects of which have, at least in part, been attributed to macrophages. However, the specific responses of macrophages to oat ß-glucan treatment in this model have yet to be elucidated. We examined the effects of varying doses of oat ß-glucan on the pro-inflammatory cytokine response in both peritoneal and lung macrophages with and without exposure to HSV-1 infection in vitro. Peritoneal and lung macrophages were obtained from mice and cultured with varying concentrations of oat ß-glucan (0 (control), 10, 100, and 1,000 µg) for 24 h and supernatants were collected. A standardized dose of HSV-1 was added for a second 24 h incubation period after which supernatants were again collected. Samples were analyzed for interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF-α) using enzyme linked immunosorbent assay (ELISA). In most cases, oat ß-glucan resulted in a dose-dependent increase in pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) in lung and peritoneal macrophages with and without exposure to HSV-1 infection. When comparing across macrophage source, this response was greater for IL-1ß and IL-6 in peritoneal macrophages and for TNF-α in lung macrophages. This may be a mechanism for the decreased risk for HSV-1 infection following oat ß-glucan feedings in mice.

Curcumin's effect on intestinal inflammation and tumorigenesis in the ApcMin/+ mouse.

Curcumin's benefits on tumorigenesis are thought to be mediated by its antiinflammatory activity; however, these effects have not been well characterized in a mouse model of colon cancer. We examined the effects of curcumin on intestinal inflammation in the Apc(Min/+) mouse. Apc(Min/+) mice were given a placebo or curcumin (2%) diet from 4 to 18 weeks of age (n = 10/group). C57BL/6 mice were used as a wild-type control (n = 10/group). Intestines were analyzed for polyp burden (sections 1, 4, and 5) and for mRNA expression, and concentration of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, and chemokine ligand 2 (CCL2) (sections 2 and 3). Plasma was collected for concentration of CCL2. Curcumin decreased total intestinal polyps by 75% (P < 0.05) in all size categories [>2 mm (65%), 1-2 mm (72%), <1 mm (82%); P < 0.05]. mRNA expression of IL-1ß, IL-6, tumor necrosis factor-α, and CCL2 was elevated (P < 0.05) and curcumin blunted this increase (P < 0.05). Protein concentration of IL-1ß, IL-6 (section 3), and CCL2 was increased (P < 0.05) and curcumin reduced this response for IL-1ß (section 2) and CCL2 (P < 0.05). Curcumin also offset the increase in plasma CCL2 (P < 0.05). The benefits of curcumin in colon cancer may be at least in part mediated by its antiinflammatory activity.

Exercise training increases mitochondrial biogenesis in the brain.

Increased muscle mitochondria are largely responsible for the increased resistance to fatigue and health benefits ascribed to exercise training. However, very little attention has been given to the likely benefits of increased brain mitochondria in this regard. We examined the effects of exercise training on markers of both brain and muscle mitochondrial biogenesis in relation to endurance capacity assessed by a treadmill run to fatigue (RTF) in mice. Male ICR mice were assigned to exercise (EX) or sedentary (SED) conditions (n = 16-19/group). EX mice performed 8 wk of treadmill running for 1 h/day, 6 days/wk at 25 m/min and a 5% incline. Twenty-four hours after the last training bout a subgroup of mice (n = 9-11/group) were euthanized, and brain (brain stem, cerebellum, cortex, frontal lobe, hippocampus, hypothalamus, and midbrain) and muscle (soleus) tissues were isolated for analysis of mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α), Silent Information Regulator T1 (SIRT1), citrate synthase (CS), and mitochondrial DNA (mtDNA) using RT-PCR. A different subgroup of EX and SED mice (n = 7-8/group) performed a treadmill RTF test. Exercise training increased PGC-1α, SIRT1, and CS mRNA and mtDNA in most brain regions in addition to the soleus (P < 0.05). Mean treadmill RTF increased from 74.0 ± 9.6 min to 126.5 ± 16.1 min following training (P < 0.05). These findings suggest that exercise training increases brain mitochondrial biogenesis, which may have important implications, not only with regard to fatigue, but also with respect to various central nervous system diseases and age-related dementia that are often characterized by mitochondrial dysfunction.

Susceptibility to infection and inflammatory response following influenza virus (H1N1, A/PR/8/34) challenge: role of macrophages.

The precise role that macrophages play in both influenza-induced pathology and the host's cytokine-mediated response to infection remains largely unknown. We examined the effects of lung macrophage depletion on susceptibility to influenza virus (H1N1, A/PR/8/34) infection and how this relates to the inflammatory cytokine response in the lungs. ICR mice were administered 100 µL of clodronate (CL(2)MDP) or PBS-encapsulated liposomes via an intranasal route 2 days before infection. Then, mice were intranasally inoculated with influenza virus and monitored for morbidity, mortality, and symptom severity for 21 days. Additional mice were sacrificed at 2 and 5 days postinfection, and lung tissue was analyzed for viral replication and for gene expression and protein concentration of interleukin-1ß (IL-1ß), IL-6, and TNF-α. Macrophage depletion increased morbidity, mortality, and symptom severity (P < 0.05) and viral replication at 2 and 5 days postinfection (P < 0.05). IL-1ß, IL-6, and TNF-α mRNA was greater at day 2 (P < 0.05) and IL-6 and TNF-α was greater at day 5 postinfection (P < 0.05) in macrophage depleted mice. Macrophage depletion increased protein concentration of IL-1ß and IL-6 at day 2 postinfection (P < 0.05). These data suggest that macrophages play a necessary role in controlling susceptibility to influenza virus and the host's cytokine-mediated response to influenza infection.

The dietary flavonoid quercetin increases VO(2max) and endurance capacity.

Quercetin, a natural polyphenolic flavonoid substance present in a variety of food plants, has been shown in vitro and in animal studies to have widespread health and performance benefits resulting from a combination of biological properties, including antioxidant and anti-inflammatory activity, as well as the ability to increase mitochondrial biogenesis. Little is known about these effects in humans, however, especially with respect to exercise performance. The authors determined whether quercetin ingestion would enhance maximal aerobic capacity and delay fatigue during prolonged exercise in healthy but untrained participants. Twelve volunteers were randomly assigned to 1 of 2 treatments: (a) 500 mg of quercetin twice daily dissolved in vitamin-enriched Tang or (b) a nondistinguishable placebo (Tang). Baseline VO2max and bike-ride times to fatigue were established. Treatments were administered for a period of 7 days using a randomized, double-blind, placebo-controlled, crossover study design. After treatment both VO2max and ride time to fatigue were determined. Seven days of quercetin feedings were associated with a modest increase in VO2max (3.9% vs. placebo; p < .05) along with a substantial (13.2%) increase in ride time to fatigue (p < .05). These data suggest that as little as 7 days of quercetin supplementation can increase endurance without exercise training in untrained participants. These benefits of quercetin may have important implications for enhancement of athletic and military performance. This apparent increase in fitness without exercise training may have implications beyond that of performance enhancement to health promotion and disease prevention.