Eugene P. Mayer

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.

Effects of Oat β-glucan on Innate Immunity and Infection after Exercise Stress

ABSTRACTDAVIS, J. M., E. A. MURPHY, A. S. BROWN, M. D. CARMICHAEL, A. GHAFFAR, and E. P. MAYER. Effects of Oat β-Glucan on Innate Immunity and Infection after Exercise Stress. Med. Sci. Sports Exerc., Vol. 36, No. 8, pp. 1321–1327, 2004. Exhaustive exercise has been associated with an increased risk

Antiinflammatory Properties of the Muscadine Grape (Vitis rotundifolia)

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.

Selective adhesion of macrophages to denatured forms of type I collagen is mediated by scavenger receptors

Macrophages (Mφs) are multifunctional immune cells which are involved in the regulation of immune and inflammatory responses, as well as in tissue repair and remodeling. In tissues, Mφs reside in areas which are rich in extracellular matrix (ECM), the structural component which also plays an essential role in regulating a variety of cellular functions. A major ECM protein encountered by Mφs is type I collagen, the most abundant of the fibril-forming collagens. In this study, the adhesion of RAW 264.7 murine Mphis to native fibrillar, monomeric, and denatured type I collagen was investigated. Using atomic force microscopy, structural differences between fibrillar and monomeric type I collagen were clearly resolved. When cultured on fibrillar type I collagen, Mphis adhered poorly. In contrast, they adhered significantly to monomeric, heat-denatured, or collagenase-modified type I collagen. Studies utilizing anti-beta1 and -beta2 integrin adhesion-blocking antibodies, RGD-containing peptides, or divalent cation-free conditions did not inhibit Mphi; adhesion to monomeric or denatured type I collagen. However, macrophage scavenger receptor (MSR) ligands and anti-MSR antibodies significantly blocked Mphi; adhesion to denatured and monomeric type I collagen strongly suggesting the involvement of the MSR as an adhesion molecule for denatured type I collagen. Further analysis by Western blot identified the MSR as the primary receptor for denatured type I collagen among Mphi; proteins purified from a heat-denatured type I collagen affinity column. These findings indicate that Mphis adhere selectively to denatured forms of type I collagen, but not the native fibrillar conformation, via their scavenger receptors.

Anti-inflammatory activity of select sorghum (Sorghum bicolor) brans.

The bran fractions of certain varieties of sorghum (Sorghum bicolor) grain are rich sources of phytochemicals and antioxidants. In this article, the anti-inflammatory actions of extracts of select sorghum brans were evaluated in two experimental inflammatory systems: (1) the release of cytokines by lipopolysaccharide-activated peripheral blood mononuclear cells and (2) 12-O-tetradecanoylphorbol acetate (TPA)-induced ear edema in mice. A 1:200 dilution of a 10% (wt/vol) ethanol extract of black sorghum bran significantly inhibited the secretion of the pro-inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha. Ethanolic extracts of both black and sumac varieties of sorghum bran significantly reduced edema in inflamed ears as measured by ear thickness and ear punch weight 6 hours following TPA application. The degree of inhibition was similar to that observed with indomethacin. Black sorghum bran significantly diminished the increase in myeloperoxidase activity 24 hours following the application of TPA. No anti-inflammatory activity was observed with white and Mycogen sorghum bran varieties or with oat, wheat, or rice brans in the mouse ear model. The anti-inflammatory activity observed with these brans correlated with their phenolic content and antioxidant activity. These results demonstrate that select sorghum bran varieties possess significant anti-inflammatory activity.

Effects of exercise on the immune response to cancer

This study examined the effects of two doses of exercise on tumor incidence and progression, and the number and activity of intratumoral phagocytic cells (80% macrophages [M phis]). Male mice were randomly assigned to control (CON), moderate (MOD) or exhaustive (EXH) treadmill running. Mice were inoculated subcutaneously with 2.5 x 10(5) mammary adenocarcinoma cells after 3 d of running (3 h after the last run at a point when enhancement in M phi cytotoxicity is observed). This tumor was chosen due to its susceptibility to M phi inhibition in vitro and in vivo. Mice continued daily running for 14 d. Food intakes were higher during the last 3 d in MOD and EXH, but body weights were no different. Flow cytometer analysis of tumor masses revealed that MOD had greater numbers of phagocytic cells (vs EXH) with slightly higher phagocytic activities (vs CON and EXH) (P < 0.05). However, no group differences in tumor appearance were seen except on day 7 when CON had less observable tumors than MOD and EXH (P < 0.05). Tumor size was also not different between groups at any point. These results indicate that moderate exercise can increase the phagocytic capacity of intratumoral phagocytic cells, but these changes had no apparent effect on tumor incidence or progression in this study.

Exercise and tumor development in a mouse predisposed to multiple intestinal adenomas.

UNLABELLED Epidemiological evidence suggests that physical activity may be protective against the development of colon cancer. Potential mechanisms remain largely unexplored due to the paucity of appropriate experimental models. PURPOSE The purpose of this study was to examine the effect of exercise training on polyp development in an induced mutant mouse strain predisposed to multiple intestinal neoplasia (Min mouse). METHODS Three-week-old male and female heterozygotes were randomly assigned to control (CON; 10 males, 6 females) or exercise (EX; 11 males, 11 females) groups. In the first week, EX mice were acclimated to treadmill running at 10-18 m x min(-1) for 15-60 min x d(-1). From 4-10 wk of age, mice ran at 18-21 m x min(-1) for 60 min. CON mice sat in Plexiglas lanes suspended above the treadmill for the same time periods. At 10 wk of age, the mice were sacrificed and the intestines removed, opened, and counted for polyps. RESULTS Skeletal muscle oxidative capacity increased with training as shown by a 64% increase in citrate synthase activity in the gastrocnemius/soleus muscle of EX compared with CON (P = 0.009). There were no significant effects of exercise in the males and females combined on small intestine, colon, or total intestinal polyps (P > 0.05). When analyzed separately, however, there were fewer colon and total polyps in the EX than in the CON males, although the difference was not statistically significant (P = 0.06). CONCLUSIONS These results suggest that seven weeks of exercise training do not affect the development of intestinal polyps in the Min mouse. Further studies are required to determine if a true sex difference exists or if variations on the current training protocol may affect tumor outcomes.

The collagenous domain of class A scavenger receptors is involved in macrophage adhesion to collagens

Class A macrophage scavenger receptors (MSRs) have a remarkably broadligand specificity and are well‐known for their roles in atherogenesisand host defense. Recently, we demonstrated that these receptors alsorecognize and mediate adhesion to denatured forms of type I collagen.In this study, the involvement of the collagenous domain of MSRs inbinding to denatured type I collagen was investigated. Transientexpression of full‐length, native type II MSR in COS‐1 cells conferredadhesion to denatured type I collagens, whereas expression of atruncated receptor lacking the distal portion of the collagenous domaindid not. Further, a synthetic peptide derived from the collagenousdomain was effective in abrogating Mφ adhesion to denatured forms oftype I collagen. We also addressed collagen‐type specificity byexamining MSR affinity for type III and type IV collagens. As with typeI collagen, Mφs adhered only to denatured forms of type III collagen.Moreover, the adhesion was mediated by MSRs. In contrast, adhesion todenatured type IV collagen was not shown to be MSR‐dependent, butadhesion to the native form was. MSR‐mediated adhesion to types III andIV collagens was also shown to be dependent on the collagenous domain.Taken together, these data strongly suggest that the collagenous domainis involved in MSR‐mediated adhesion to denatured forms of types I andIII collagens and native, but not denatured, type IV collagen.

Drug targeting: anti-HSV-1 activity of mannosylated polymer-bound 9-(2-phosphonylmethoxyethyl)adenine.

The antiviral drug, 9-(2-phosphonylmethoxyethyl) adenine (PMEA) was linked to a synthetic and neutral polymer bearing mannosyl residues to allow its internalization by macrophages via membrane lectins. PMEA bound to the mannosylated polymer was more efficient in vitro than free PMEA in preventing lysis of human macrophages by herpes virus.

Poly I:C-induced anti-herpes simplex virus type 1 activity in inflammatory macrophages is mediated by induction of interferon-β

We examined the mechanism by which Polyriboinosinic:Polyribocytidylic acid (Poly l:C) augments resistance of thioglycolate‐elicited inflammatory macrophages to infection with herpes simplex virus type 1 (HSV‐1). We show that Poly l:C‐induced antiviral activity is completely abrogated by antibodies to interferon‐β (IFN‐β) whereas antibodies to other interferons or to other cytokines have no effect. Furthermore, treatment of inflammatory macrophages with exogenous IFN renders them resistant to HSV‐1, whereas treatment with other cytokines does not. In addition, we demonstrate that supernatants from macrophages treated with Poly l:C contain IFN‐β but not IFN‐α. Taken together these data indicate that the antiviral effects of Poly l:C in inflammatory macrophages are mediated solely by IFN‐β, which acts in an autocrine manner to induce resistance to HSV‐1.