Does combined antioxidant vitamin supplementation blunt repeated bout effect?

We investigated the effect of antioxidant supplementation on markers of muscle damage, antioxidant status, and delayed onset of muscle soreness (DOMS) after repeated downhill runs. Moderately-trained males (n=22) were randomly assigned to a supplement (S) or placebo (P) group. Capsules (vitamin C:1 000 mg/d; vitamin E: 400 IU/d) were ingested daily for 2 weeks. before the first (1D) and second (2D) downhill runs, and for 2 additional days following each run. Creatine kinase (CK) activity and oxygen radical absorbance capacity (ORAC) were measured pre-exercise and at 0 (immediately), 6, 24 and 48 h post-exercise (POST). DOMS was rated for quadriceps, hamstring, gluteus, gastrocnemius, and tibialis anterior at 0, 24, 48 and 72 h POST. CK at 48 h following 1D remained elevated above pre-exercise only in P (P<0.01). Overall, DOMS of the quadriceps was lower in S (1.1±0.3) than P (2.2±0.5) (P<0.05). At 24 h POST in S, CK was lower (P<0.01) and ORAC was higher (P<0.05) following 2D than 1D. CK and ORAC following 2D were blunted and augmented, respectively, in response to 1D and antioxidant supplementation enhanced this protective effect as indicated by an attenuation of biomarkers of muscle damage and a greater antioxidant capacity observed 24 h POST 2D.

Effect of exercise intensity on exercise-induced lymphocyte apoptosis.

Because lymphocyte apoptosis is significantly elevated immediately following high-intensity exercise in humans, it seems intuitive that the cell death process must be initiated at some point during the task. This study was designed to determine whether exercise-induced lymphocyte apoptosis occurs at a threshold level of intensity, or exists only following maximal or near-maximal exercise intensities. Fourteen untrained subjects completed a discontinuous, incremental treadmill test to exhaustion (.VO(2max)). Blood for films was sampled before the test, immediately after each work stage, and for 1-h postexercise. Blood smears were stained with May-Grünwald Giemsa and lymphocytes were evaluated for characteristic features of apoptosis. The apoptotic index (AI) during exercise at 38 % .VO(2max) was similar to pre-exercise but significantly elevated at an intensity approximating 61 % .VO(2max) (p < 0.0001). Significant increases in apoptosis were noted with additional elevations in exercise intensity (i.e., 76 %, 89 %, and 100 %, p < 0.0001). Following 20 min of recovery, AI was significantly lower than values obtained immediately postexercise (p < 0.0001). Forty minutes of recovery resulted in a further significant decrease (p < 0.0001), and by 1-h postexercise, AI was similar to pre-exercise values. Results indicate that the exercise intensity threshold for inducing an increase in lymphocyte apoptosis occurs between 40 and 60 % .VO(2max). In addition, since values return to baseline within 1 h following exhaustive exercise, it is unlikely that factors responsible for the apoptotic response in lymphocytes maintain a prolonged presence once exercise has been terminated.

Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation, migration, and suppression of neointima following vascular injury.

Exaggerated or inappropriate signaling by the platelet-derived growth factor receptor (PDGFR) tyrosine kinase has been implicated in a wide variety of diseases. Thus, a series of piperazinyl quinazoline compounds were identified as potent antagonists of the PDGFR by screening chemical libraries. An optimized analog, CT52923, was shown to be an ATP-competitive inhibitor that exhibited remarkable specificity when tested against other kinases, including all members of the closely related PDGFR family. The PDGFRs and stem cell factor receptor were inhibited with an IC(50) of 100 to 200 nM, while 45- to >200-fold higher concentrations of CT52923 were required to inhibit fms-like tyrosine kinase-3 and colony-stimulating factor-1 receptor, respectively. Other receptor tyrosine kinases, cytoplasmic tyrosine kinases, serine/threonine kinases, or members of the mitogen-activated protein kinase pathway were not significantly inhibited at 100- to 1000-fold higher concentrations. In addition, this compound also demonstrated specificity for inhibition of cellular responses. Platelet-derived growth factor-induced smooth muscle cell migration or fibroblast proliferation was found to be blocked by CT52923 with an IC(50) of 64 and 280 nM, respectively, whereas 50- to 100-fold higher concentrations were required to inhibit these responses when induced with fibroblast growth factor. To investigate the effect of CT52923 on PDGFR signaling, in vivo studies demonstrated that CT52923 could significantly inhibit neointima formation following carotid artery injury by oral administration in the rat. Therefore, PDGFR antagonism by CT52923 could be a viable strategy for the prevention of clinical restenosis or the treatment of other human diseases involving PDGFR signaling.

Novel tricyclic benzothiazolo[2,3-c]thiadiazine antagonists of the platelet ADP receptor (P2Y(12)).

Novel non-nucleoside tricyclic platelet ADP receptor (P2Y(12)) antagonists have been discovered that bind reversibly and with high affinity to the platelet receptor. Condensation of various 2-aminobenzothiazoles with chlorosulfonylacetyl chloride affords these novel tricyclic heterocycles, which are novel and unpredicted products of this reaction.

Impact of exercise on bone health and contraindication of oral contraceptive use in young women.

PURPOSE: The effect of quantified resistance and high impact exercise training on bone mass as modified by age and oral contraceptive (OCont) use in young women was studied. METHODS: Women were categorized by age (18-23 vs 24-31 yr) and OCont use, and were then randomized into either three sessions of resistance exercise plus 60 min.wk-1 of jumping rope or a control group for 24 months. Total body, spine, femoral neck, greater trochanter, Ward's area, and radial bone mineral density (BMD) and/or content (BMC), biochemical markers of bone turnover, dietary intake of calcium, lean body mass, maximal oxygen uptake, and strength were determined at baseline and every 6 months. RESULTS: Total body (TB) BMC percent change from baseline was higher in exercisers compared with nonexercisers at 6 and 24 months. OCont users had lower bone turnover at baseline and a decrease in TBBMC from baseline compared with non-OCont users at 24 months. Spine BMC and BMD decreased in the exercise and OCont group at 6 months and remained significantly below nonexercisers who used oral contraceptives at 2 yr. Femoral neck BMD also decreased in the exercise and oral contraceptive group at 6 months. CONCLUSIONS: Exercise prevented a decline in TBBMC seen in the nonexercisers. On the other hand, exercise in oral contraceptive users prevented the increase observed in the spine of the nonexercise plus OCont group.

Kyphosis in active and sedentary postmenopausal women.

UNLABELLED: EAGAN, M. S., and D. A. SEDLOCK. Kyphosis in active and sedentary postmenopausal women. Med. Sci. Sports Exerc., Vol. 33, No. 5, 2001, pp. 688-695. PURPOSE: This study examined kyphosis in relation to self-reported activity level (sedentary, active) and activity type (weight-bearing land, nonweight-bearing water) in 61 postmenopausal women aged 60-78 yr. METHODS: Specifically, we measured kyphosis, muscle strength (defined as back extensor (BES) and grip (GS) strength), total calcium intake, body fat, height lost since age 30 (HtLost), current activity level for household, leisure and sport activities and their total, as well as occupational and physical activity history and their total. RESULTS: No significant differences (P > 0.05) were found for any variables when subjects were divided into sedentary (N = 18), land (N = 29), and water (N = 14) groups; exercisers (N = 43) and nonexercisers (N = 18); or between the top and bottom tertiles of lifetime active (N = 20) and inactive (N = 20) women. Stepwise multiple regression yielded body fat as the single best predictor of kyphosis accounting for 6.9% of the total variance (P < 0.04) with the resulting equation: kyphosis (degrees) = 22.919 + 0.627*body fat (%) + 0.852*HtLost (cm) + 2.881E-0.03*total calcium intake (mg) (r2 = 0.22, SEE = 7.7). Significant relationships (P < 0.05) included kyphosis with body fat (r = 0.26) and HtLost with age (r = 0.50). Relationships (P < 0.05) regarding muscle strength included: GS and BES with age (r = -0.38, -0.30), HtLost (r = -0.39, -0.36), and occupational activity history (r = 0.28, 0.35), as well as BES with household activity and total activity history (r = 0.28, 0.30). Physical activity history was related (P < 0.05) to current sport, leisure, and total activity history (r = 0.37, 0.42, 0.93, respectively). CONCLUSION: Women who are active when younger seem to be active and stronger as older adults. However, this does not seem to impact kyphosis. The measured variables accounted for a small proportion of kyphosis variance, suggesting that more potent causative factors of this spinal malformation exist.

VO2peak and the gas-exchange anaerobic threshold during incremental arm cranking in able-bodied and paraplegic men.

Resting energy expenditure, peak oxygen uptake (VO2peak) and the gas-exchange anaerobic threshold (Than) were measured during incremental arm cranking (15 W x min(-1)) in six able-bodied (AB) and six paraplegic (P) subjects. Only male subjects with traumatic spinal cord injuries in the area of the 10-12th thoracic segment were included in the P group. All AB and P subjects were physically active. Mean (SE) values for age and body mass were 28 (2) years and 78.9 (3.9) kg for the AB group and 32 (4) years and 70.8 (7.9) kg for the P group (P>0.05). Resting energy expenditure values were not found to be significantly different between AB [5.8 (0.2) kJ x min(-1)] and P [5.1 (0.3) kJ min(-1)] subjects. Mean VO2peak values were 29.3 (2.4) ml x kg(-1) min(-1) and 29.6 (2.2) ml x kg(-1) x min(-1) for the AB and P groups, respectively (P>0.05). Absolute oxygen uptake values measured at two gas-exchange anaerobic threshold (Than) were not significantly different between the two groups. However, the Than occurred at a significantly higher percentage of VO2peak in the P [58.9 (1.7)%] group than in the AB [50.0 (2.8)%] group (P<0.05). Moreover, respiratory exchange ratio (R) values obtained at the Than and at 15, 45, 60, 75 and 90 W of incremental exercise were significantly lower in the P group than in the AB group. Heart rates were significantly elevated at every submaximal work stage (15-120 W) in the P group compared to the AB group (P<0.05). These findings suggest that chronic daily wheelchair activity produces local adaptations in the functional upper-body musculature, which reduce glycogenolysis and increase the rate of lipid utilization (lower R) during arm exercise. These local adaptations may be in part responsible for the significantly higher Than observed for arm exercise in P subjects, even though VO2peak values were essentially the same for both groups.

Antimycins, inhibitors of ATP-citrate lyase, from a Streptomyces sp.

A related group of compounds belonging to the antimycin class of antibiotics was found in culture broth produced by a Streptomyces species. The group includes known antimycins A1, A2, A3 and A4, and new antimycins A7 and A8. These compounds inhibit ATP-citrate lyase with Ki values of 4 to 60 microM against the substrate magnesium citrate. The structures of the new antimycins were determined by spectroscopic analyses.

Excess postexercise oxygen consumption and recovery rate in trained and untrained subjects.

The purpose of this study was to determine whether aerobic fitness level would influence measurements of excess postexercise oxygen consumption (EPOC) and initial rate of recovery. Twelve trained [Tr; peak oxygen consumption (VO2 peak) = 53.3 +/- 6.4 ml . kg-1 . min-1] and ten untrained (UT; VO2 peak = 37.4 +/- 3.2 ml . kg-1 . min-1) subjects completed two 30-min cycle ergometer tests on separate days in the morning, after a 12-h fast and an abstinence from vigorous activity of 24 h. Baseline metabolic rate was established during the last 10 min of a 30-min seated preexercise rest period. Exercise workloads were manipulated so that they elicited the same relative, 70% VO2 peak (W70%), or the same absolute, 1.5 l/min oxygen uptake (VO2) (W1.5), intensity for all subjects, respectively. Recovery VO2, heart rate (HR), and respiratory exchange ratio (RER) were monitored in a seated position until baseline VO2 was reestablished. Under both exercise conditions, Tr had shorter EPOC duration (W70% = 40 +/- 15 min, W1.5 = 21 +/- 9 min) than UT (W70% = 50 +/- 14 min; W1.5 = 39 +/- 14 min), but EPOC magnitude (Tr: W70% = 3.2 +/- 1.0 liters O2, W1.5 = 1.5 +/- 0.6 liters O2; UT: W70% = 3.5 +/- 0.9 liters O2, W1.5 = 2.4 +/- 0.6 liters O2) was not different between groups. The similarity of Tr and UT EPOC accumulation in the W70% trial is attributed to the parallel decline in absolute VO2 during most of the initial recovery period. Tr subjects had faster relative decline during the fast-recovery phase, however, when a correction for their higher exercise VO2 was taken. Postexercise VO2 was lower for Tr group for nearly all of the W1.5 trial and particularly during the fast phase. Recovery HR kinetics were remarkably similar for both groups in W70%, but recovery was faster for Tr during W1.5. RER values were at or below baseline throughout much of the recovery period in both groups, with UT experiencing larger changes than Tr in both trials. These findings indicate that Tr individuals have faster regulation of postexercise metabolism when exercising at either the same relative or same absolute work rate.

The effect of upper body exercise intensity and duration on post-exercise oxygen consumption.

This study assessed excess post-exercise oxygen consumption (EPOC) following upper body exercise (UBE) of different intensity and duration. Ten subjects, 5 male and 5 female (age: 26.7 +/- 4.9 yr; peak UBE oxygen uptake [VO2peak]: 1.78 +/- 0.57 l. min-1, 25.6 +/- 5.8 ml.kg-1. min-1) performed three randomized tests on an arm crank ergometer: 1) low intensity, short duration (LS) = 35% VO2peak for 15 min; 2) low intensity, long duration (LL) = 35% VO2peak for 30 min; 3) high intensity, short duration (HS) = 70% VO2peak for 15 min. Subjects reported for all tests in the morning and in a fasted and rested state. Exercise was preceded by a 30 min seated baseline. Recovery VO2 was continuously monitored until baseline was re-established. EPOC duration (p < 0.01) and magnitude (p < 0.01) were significantly greater following HS, while LL and LS did not differ in response (duration and magnitude: HS = 14.0 +/- 6.5 min, 32.5 +/- 24.6 kJ; LL = 5.5 +/- 4.4 min, 12.3 +/- 8.6 kJ; LS = 5.7 +/- 4.9 min, 10.3 +/- 5.3 kJ). HS also had higher HR (73 +/- 10 b.min-1, p < 0.01) at end-EPOC compared to LL (64 +/- 8 b.min-1) and LS (66 +/- 8 b.min-1), and baseline HS values (63 +/- 8 b. min-1). Results from this study indicate that UBE intensity has a greater effect on EPOC than exercise duration under these conditions. UBE appears to have similar EPOC patterns as lower body exercise.

Previous physical activity relates to bone mineral measures in young women.

Exercise may increase accretion of bone, potentially reducing the risk of osteoporosis. Previous physical activity was assessed in 204 minimally active young women (18-31 yr). Bone mineral content (BMC) and bone mineral density (BMD) for the total body, femoral neck, and spine were assessed by a dual x-ray absorptiometer, and the radius by a single photon absorptiometer. Self-reported occupation and leisure activity for the 5 yr before enrollment in the study, as well as high school and college sports participation, were assigned energy expenditure (EE) values. From this information, EE variables were created as follows: 1) occupation EE + leisure EE + high school sport and/or college sport EE if within prior 5 yr (5-yr EE); 2) occupation EE + leisure EE (occupation + leisure EE); and 3) high school sport EE (high school EE). These variables were correlated with bone mineral measures and significant results follow (P < 0.05). Five-year EE and occupation + leisure EE correlated with all measures of bone health (r from 0.13 to 0.39). High school EE correlated with total body BMD (r = 0.25) and BMC (r = 0.28), femoral neck BMD (r = 0.28), radius BMC (r = 0.20), as well as spine BMD (r = 0.20) and BMC (r = 0.27). When weight was controlled, 5-yr EE and occupation + leisure EE remained correlated with all BMC measures (r from 0.14 to 0.22). When controlled for weight, high school EE remained associated with femoral neck BMD (r = 0.24), total body BMD (r = 0.20) and BMC (r = 0.26), and spine BMC (r = 0.17). To partially control for selection bias, data were also controlled for total body BMD. Five-year EE and occupation + leisure EE remained positively correlated with all measures of BMC. High school EE remained correlated both with femoral neck BMD and total body BMC. In multiple regression analyses, 5-yr EE or occupation + leisure EE were significant predictors of all measures of bone health, except femoral neck BMD. High school EE was a significant predictor for total body BMD and BMC, femoral neck BMD, and spine BMC.

Effects of long-term moderate exercise on iron status in young women.

The impact of long-term (6-month) moderate exercise on the iron status of previously sedentary women was determined by randomly assigning 62 college-age women into one of the following four groups: 1) 50 mg.d-1 iron supplement, low iron diet (N = 16); 2) Placebo, free choice diet (N = 13); 3) Meat supplement to achieve 15 mg.d-1 iron intake (N = 13); and 4) Control, free choice diet (N = 20). All groups except the Control group exercised 3 d.wk-1 at 60%-75% of their heart rate reserve. VO2max was measured at baseline and week 24. Blood was sampled at baseline and every 4 wk thereafter for 24 wk to measure iron status and to elucidate the causes for alterations in iron status. Subjects had depleted iron stores throughout the study as indicated by their serum ferritin levels (< 15 ng.ml-1). Serum iron, total iron binding capacity and transferrin saturation were not compromised with exercise. Mean hemoglobin level in the Placebo/Ex group was significantly (P < 0.05) lower than the 50 Fe/Ex and the Meat/Ex groups by week 24. However, changes in serum albumin, haptoglobin, and erythropoietin data from the study cannot explain these changes.

Fitness level and postexercise energy expenditure.

This study was designed to investigate the effect of fitness level on excess postexercise oxygen consumption (EPOC) in five endurance trained and five sedentary male volunteers. The possible influence of differences in body weight and exercise energy expenditure were controlled by employing a weight-supported (cycle ergometer), 300 kilocalorie exercise. Exercise intensity was equal to 50% of each subject's previously determined peak oxygen uptake (VO2). VO2 was measured for 1 hr prior to exercise to establish the baseline value, and continuously in the postexercise period until the baseline value was achieved. Duration of EPOC was 16.6 +/- 3.1 minutes and 20.4 +/- 7.8 minutes in the fit and unfit groups, respectively (p > 0.05). Magnitude of EPOC, which was not significantly different between the groups, averaged 12.2 +/- 3.1 kcal in the fit and 12.2 +/- 4.3 kcal in the unfit group. The results suggest that EPOC following a weight-supported exercise of an intensity and duration frequently used by individuals who begin an exercise program for weight control is not compromised by differences in body weight or fitness level.

WIN 66306, a new neurokinin antagonist produced by an Aspergillus species: fermentation, isolation and physico-chemical properties.

WIN 66306 (1a), a cyclic peptide containing a novel amino acid, was isolated as a neurokinin antagonist from an Aspergillus species, labelled SC230. Conditions that maximized the production of 1a were developed, leading also to production of the related compound WIN 68577 (2) and rosellichalasin (3). Both 2 and 3 were more active in the rat NK1 than in the human NK1 receptor binding assay, while 1a was more active at the human receptor with an inhibitor affinity constant of 7 microM.

1'-(2-Phenyl-ethylene)-ditryptophenaline, a new dimeric diketopiperazine from Aspergillus flavus.

A new diketopiperazine dimer, 1'-(2-phenyl-ethylene)-ditryptophenaline [1], was isolated together with ditryptophenaline [2] from the fungus Aspergillus flavus. The structure of 1 was determined by analysis of spectroscopic data. In contrast to the structurally related substance-P antagonist WIN 64821 [3], both 1 and 2 are weak substance-P inhibitors, indicating that stereochemistry at the position of dimerization is an important determinant of biological potency for these molecules.

Benzomalvins, new substance P inhibitors from a Penicillium sp.

In the course of screening microbial broths for neurokinin receptor antagonists, a series of new benzodiazepines, benzomalvins A (1), B (2) and C (3), has been isolated from the culture broth of a fungus identified as a Penicillium sp. Benzomalvin A (1) showed inhibitory activity against substance P with Ki values of 12, 42 and 43 microM at the guinea pig, rat and human neurokinin NK1 receptors, respectively. Benzomalvins B (2) and C (3) were only weakly active. The structures of these compounds were determined by spectroscopic methods including MS measurements and NMR analysis.

WIN 64821, a novel neurokinin antagonist produced by an Aspergillus sp. I. Fermentation and isolation.

WIN 64821, a nonpeptide neurokinin antagonist, was isolated from a strain of Aspergillus sp., SC319. The compound was produced in different fermentation media with greatest yields observed when the culture was grown in a synthetic medium supplemented with L-tryptophan and L-phenylalanine. After 6 days fermentation, yields greater than 600 mg/liter were obtained. Two analogs of WIN 64821 were also identified in the culture extracts and subsequently tested for biological activity. WIN 64821 was the most potent compound isolated from this culture and exhibited activity as a substance P-binding inhibitor with submicromolar potency against the human neurokinin 1 receptor.

WIN 64821, a novel neurokinin antagonist produced by an Aspergillus sp. II. Biological activity.

WIN 64821, a secondary metabolite produced by Aspergillus sp. (ATCC 74177) was found to inhibit radiolabeled substance P (SP) binding in a variety of tissues, including those of human origin. This compound inhibited, in a competitive manner, the binding of SP with Ki values ranging from 0.24 microM in human astrocytoma U-373 MG cells to 7.89 microM in rat submaxillary membranes. Additionally, WIN 64821 was found to inhibit 125I-NKA binding to the NK2 receptor in human tissue at a concentration equivalent to its NK1 activity (0.26 microM). The inhibitory activity of WIN 64821 against an NK3 selective ligand, 3H-senktide, was found to be much weaker (Ki = 15.2 microM). WIN 64821 was also evaluated in NK1 functional assays and was found to be a competitive antagonist of SP-induced contractility in the guinea pig ileum (pA2 = 6.6) as well as an inhibitor of SP-induced 45Ca2+ efflux from human astrocytoma U-373 MG cells (IC50 = 0.6 microM). In a rat vas deferens model, WIN 64821 inhibited eledoisin-induced contractility with an IC50 of 3.4 microM indicating functional antagonism at the NK2 receptor. The data presented in this study provide biochemical, pharmacological and functional evidence supporting WIN 64821 as a competitive neurokinin antagonist.

Iron status in exercising women: the effect of oral iron therapy vs increased consumption of muscle foods.

Forty-seven previously sedentary women participating in a 12-wk moderate aerobic-exercise program were randomly assigned to one of four dietary groups: 50-mg/d iron supplement and a low food-iron diet (50 FE + EX), 10-mg/d iron supplement and a low food-iron diet (10 FE + EX), placebo and unrestricted diet (P + EX), and meat supplement and high food-iron diet (M + EX). A sedentary control group (n = 13) received no dietary interventions. Hematocrit, total iron-binding capacity, and hemoglobin, serum iron, serum ferritin, and serum albumin concentrations were measured every 4 wk. Hemoglobin values decreased at the end of 4 wk in all exercising groups compared with the control group. Iron status in the 50 FE + EX and M + EX groups improved after week 4 as indicated by an increase in serum ferritin, serum iron, and hemoglobin concentrations, and a decline in total iron-binding capacity. Thus, short-term, moderate aerobic exercise resulted in compromised iron status that was offset to varying degrees by ingesting iron or meat supplements. However, meat supplements were more effective in protecting hemoglobin and ferritin status than were iron supplements.

Methylpendolmycin, an indolactam from a Nocardiopsis sp.

Methylpendolmycin, a new indole alkaloid with an N-methylisoleucine moiety incorporated in the nine-membered indolactam ring, has been isolated from an actinomycete culture of Nocardiopsis. Methylpendolmycin exhibited inhibition of phorbol ester binding to protein kinase C. Its structure was assigned on the basis of spectroscopic data.