Long-term moderate exercise accelerates the recovery of stress-evoked cardiovascular responses.

Psychological stress is an important global health problem. It is well documented that stress increases the incidences of various cardiovascular disorders. Regular exercise is known to reduce resting blood pressure (BP) and heart rate (HR). This study was designed to clarify the effects of long-term exercise on stress-evoked cardiovascular responses and to emphasize post-stress recovery effects. Male Wistar rats underwent 8 weeks of moderate treadmill training, with cardiovascular responses, autonomic nervous system activities and local Fos reactivity changes in the cardiovascular regulation center were monitored before, during and after immobilization stress. A spectral analysis of cardiovascular parameters was used to examine autonomic nervous activities. We found that long-term exercise (i) lowered resting BP, HR and sympathetic activity, but increased resting parasympathetic activity and baroreflex sensitivity (BRS); (ii) accelerated post-stress recovery of stress-evoked cardiovascular and sympathetic responses along with increased BRS and (iii) accelerated post-stress recovery of stress-evoked neuron activations in the paraventricular nucleus, but delayed it in the nucleus of the tractus solitarius. We conclude that, in rats, long-term exercise accelerated recovery of stress-evoked cardiovascular responses differentially altering hypothalamic and medullar neuron activities.

Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer's disease (APP/PS1) transgenic mice.

Alzheimer's disease (AD) is an age-related neurodegenerative disease. Post-mortem examination and brain imaging studies indicate that neurodegeneration is evident in the hippocampus and amygdala of very early stage AD patients. Exercise training is known to enhance hippocampus- and amygdala-associated neuronal function. Here, we investigated the effects of exercise (running) on the neuronal structure and function of the hippocampus and amygdala in APP/PS1 transgenic (Tg) mice. At 4-months-old, an age before amyloid deposition, the amygdala-associated, but not the hippocampus-associated, long-term memory was impaired in the Tg mice. The dendritic complexities of the amygdalar basolateral neurons, but not those in the hippocampal CA1 and CA3 neurons, were reduced. Furthermore, the levels of BDNF/TrkB signaling molecules (i.e. p-TrkB, p-Akt and p-PKC) were reduced in the amygdala, but not in the hippocampus of the 4-month-old Tg mice. The concentrations of Aß40 and Aß42 in the amygdala were higher than those in the hippocampus. Ten weeks of treadmill training (from 1.5- to 4-month-old) increased the hippocampus-associated memory and dendritic arbor of the CA1 and CA3 neurons, and also restored the amygdala-associated memory and the dendritic arbor of amygdalar basolateral neurons in the Tg mice. Similarly, exercise training also increased the levels of p-TrkB, p-AKT and p-PKC in the hippocampus and amygdala. Furthermore, exercise training reduced the levels of soluble Aß in the amygdala and hippocampus. Exercise training did not change the levels of APP or RAGE, but significantly increased the levels of LRP-1 in both brain regions of the Tg mice. In conclusion, our results suggest that tests of amygdala function should be incorporated into subject selection for early prevention trials. Long-term exercise protects neurons in the amygdala and hippocampus against AD-related degeneration, probably via enhancements of BDNF signaling pathways and Aß clearance. Physical exercise may serve as a means to delay the onset of AD.

Early postinjury exercise reverses memory deficits and retards the progression of closed-head injury in mice.

Closed-head injury (CHI) usually involves both physical damage of neurons and neuroinflammation. Although exercise promotes neuronal repair and suppresses neuroinflammation, CHI patients currently often remain resting during the post-traumatic period. This study aimed to investigate whether and how postinjury exercise benefited the brain structure and function in mice after CHI. Closed-head injury immediately caused an elevated neurological severity score, with rapid loss of object recognition memory, followed by progressive location-dependent brain damage (neuronal loss and activation of microglia in the cortex and hippocampus). An early exercise protocol at moderate intensity (starting 2 days postimpact and lasting for 7 or 14 days) effectively restored the object recognition memory and prevented the progressive neuronal loss and activation of microglia. However, if the exercise started 9 days postimpact, it was unable to recover recognition memory deficits. In parallel, early exercise intervention drastically promoted neurite regeneration, while late exercise intervention was much less effective. We also tested the possible involvement of brain-derived neurotrophic factor (BDNF) and mitogen-activated protein kinase phosphatase-1 (MKP-1) in the exercise-induced beneficial effects. Exercise gradually restored the impact-abolished hippocampal expression of BDNF and MPK-1, while oral administration of triptolide (a synthesis inhibitor of MKP-1 and an antagonist of nuclear factor-B) before each bout of exercise blocked the restorative effects of exercise on MKP-1 and recognition memory, as well as the exercise-induced retardation of neuronal loss. Although triptolide treatment alone inhibited activation of microglia and maintained neuronal numbers, it did not recover the injury-hampered recognition memory. Overall, moderate exercise shortly after CHI reversed the deficits in recognition memory and prevented the progression of brain injury.

Different types of exercise induce differential effects on neuronal adaptations and memory performance.

Different exercise paradigms show differential effects on various forms of memory. We hypothesize that the differential effects of exercises on memory performance are caused by different neuroplasticity changes in relevant brain regions in response to different exercise trainings. We examined the effects of treadmill running (TR) and wheel running (WR) on the Pavlovian fear conditioning task that assesses learning and memory performance associated with the amygdala (cued conditioning) and both the amygdala and hippocampus (contextual conditioning). The skeletal muscle citrate synthase activity, an indicator of aerobic capacity, was elevated in rats received 4 w of TR, but not WR. While both TR and WR elevated the contextual conditional response, only TR facilitated the cued conditional response. Using a single-neuron labeling technique, we found that while both TR and MR enlarged the dendritic field and increased the spine density in hippocampal CA3 neurons, only TR showed these effects in basolateral amygdalar neurons. Moreover, both types of exercise upregulated synaptic proteins (i.e., TrkB and SNAP-25) in the hippocampus; however only TR showed similar effects in the amygdala. Injection of K252a, a TrkB kinase inhibitor, in the dorsal hippocampus or basolateral amygdala abolished the exercise-facilitated contextual or cued fear learning and memory performance, respectively, regardless of the types of exercise. In summary, our results supported that different types of exercise affect the performance of learning and memory via BDNF-TrkB signaling and neuroplasticity in specific brain regions. The brain region-specific neuronal adaptations are possibly induced by various levels of intensity/stress elicited by different types of exercise.

NO signaling in exercise training-induced anti-apoptotic effects in human neutrophils.

Short-lived neutrophils play a predominant role in innate immunity, the effects of exercise training on neutrophil survival is unclear. In this study, we investigated the underlying mechanisms of training effects on human neutrophil apoptosis. Healthy male subjects were trained on a cycling ergometer for 8 weeks and followed by 4 weeks of detraining. Blood neutrophils were collected before exercise, after training, and after detraining. Comparing with pre-exercise specimens, neutrophils collected after training showed reduced apoptosis rate, which partially returned after detraining. Various intracellular proteins, including iNOS, Mcl-1, A1, Grp78, and IL-8, were upregulated by training, and they remained high after detraining. Upregulated iNOS was closely correlated with these anti-apoptotic molecules in neutrophils. Furthermore, the possible mechanism by which iNOS suppressed apoptosis was explored. Neutrophil apoptosis was accelerated by blocking and retarded by stimulating the endogenous iNOS activity. As an anti-apoptosis mediator of NO signaling, the Mcl-1 level dropped by depletion of the major NO downstream molecule cGMP and such loss of Mcl-1 was avoidable when supplying exogenous NO. Upon activation of NO-cGMP signaling, neutrophils held increased Mcl-1 expression and delayed apoptosis. Collectively, our results suggested that exercise training may retard neutrophil apoptosis by upregulating the iNOS-NO-cGMP-Mcl-1 pathway.

Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway.

Parkinson's disease (PD) is characterized by a progressive and selective loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although the etiology of PD remains unclear, neuroinflammation has been implicated in the development of PD. Running exercise (Ex) promotes neuronal survival and facilitates the recovery of brain functions after injury. Therefore, we hypothesize that Ex protects the DA neurons against inflammation-induced injury in the SN. An intraperitoneal lipopolysaccharide (LPS, 1 mg/kg) injection induced microglia activation in the SN within hours, followed by a reduction in the number of DA neurons. LPS reduced the level of dopamine in the striatum and impaired the performance of motor coordination. Furthermore, the levels of the brain-derived neurotrophic factor (BDNF) were reduced in the SN by the LPS treatment. Four weeks of Ex before LPS treatment completely prevented the LPS-induced loss of DA neurons, reduction of dopamine levels and dysfunction of motor movement. Ex did not change the LPS-induced status of microglia activation or the levels of cytokines/chemokines, but restored the levels of LPS-reduced BDNF-TrkB signaling molecules. Blocking the action of BDNF, through its receptor TrkB antagonist, abolished the Ex-induced protection against LPS-induced DA neuron loss. Intrastriatal perfusion of BDNF alone was sufficient to counteract the LPS-induced DA neuron loss. Altogether, our results show that Ex protects DA neurons against inflammation-induced insults. The neuroprotective effects of Ex are not due to the modulation of inflammation status, but rather to the activation of the BDNF-TrkB signaling pathway.

Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I.

Chronic exercise has been reported to improve cognitive function. However, whether and how different types of exercise affect various learning and memory tasks remain uncertain. To address this issue, male BALB/c mice were trained for 4 weeks under two different exercise protocols: moderate treadmill running or voluntary wheel running. After exercise training, their spatial memory and aversive memory were evaluated by a Morris water maze and by one-trial passive avoidance (PA), respectively. Levels of neural plasticity-related proteins, i.e. brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and synaptotagmin I (Syt I), in hippocampus and amygdala were determined by ELISA or immunoblotting. Finally, the functional roles of these proteins in the basolateral amygdala were verified by locally blocking them with K252a (a TrkB kinase inhibitor), or lentivirus expressing Syt I shRNA. We found that (1) although both moderate treadmill running and wheel running improved the Morris water maze performance, only the former improved PA performance; (2) likewise, both exercise protocols upregulated the BDNF-TrkB pathway and Syt I in the hippocampus, whereas only treadmill exercise upregulated their expression levels in the amygdala; (3) local injection of K252a abolished the treadmill exercise-facilitated PA performance and upregulation of amygdalar TrkB and Syt I; and (4) local administration of Syt I shRNA abolished the treadmill exercise-facilitated PA performance and upregulation of amygdalar Syt I. Therefore, our results support the notion that different forms of exercise induce neuroplasticity changes in different brain regions, and thus exert diverse effects on various forms of learning and memory.

Glucocorticoid signaling and exercise-induced downregulation of the mineralocorticoid receptor in the induction of adult mouse dentate neurogenesis by treadmill running.

Physical exercise is known to promote adult neurogenesis, although the underlying mechanisms remain unclear. Glucocorticoid (corticosterone in rodents) is a factor that is known to affect neurogenesis. As physical exercise modulates corticosterone secretion, we hypothesized that corticosterone signaling is involved in exercise-induced adult neurogenesis. We chose treadmill running (TR) to accurately define the intensity and duration of exercise. Our results showed that 5 weeks of TR increased the doublecortin (DCX)-positive neuronal progenitor cells (NPCs) in adult hippocampus and transiently increased the serum corticosterone level at the end of the TR protocol. This protocol reduced the levels of hippocampal mineralocorticoid receptor (MR); however, glucocorticoid receptor levels were unaltered. We then investigated whether reducing corticosterone levels by bilateral adrenalectomy (ADX) attenuated the TR-enhanced adult neurogenesis. Our results showed that ADX not only blocked the TR-induced downregulation of MR, but also reduced the number of TR-enhanced NPCs. In order to examine the role of MR downregulation in TR-induced adult neurogenesis, animals were treated repeatedly with a selective MR antagonist, spironolactone, for 3 weeks. The results revealed that spironolactone increased the number of spontaneously occurring and TR-induced NPC in the dentate area. Further analysis revealed that spironolactone treatment did not alter precursor cell proliferation, but increased the number of DCX-positive NPCs, suggesting that blockage of MR signaling either facilitates the differentiation of progenitor cells towards neurons and/or enhances the survival of NPCs. Taken together, the data indicated that induction of NPCs in the dentate area of adult hippocampus by TR is partly due to the downregulation of glucocorticoid/MR signaling, which subsequently enhances differentiation along a neuronal lineage and/or NPC survival.

Upregulation of hippocampal TrkB and synaptotagmin is involved in treadmill exercise-enhanced aversive memory in mice.

Cognitive functions usually involve various synaptic proteins and neurotrophic factors in the hippocampus. However, whether treadmill exercise can improve learning and memory by upregulating some of these molecules remain unraveled. To address this question, male BALB/c mice were divided into control and exercise groups, the latter group went through 4 weeks of treadmill exercise training. At the end of exercise training period, they were either tested for passive avoidance (PA) performance or sacrificed for quantifying the hippocampal levels of brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB, the BDNF receptor), synaptotagmin (a Ca(2+)-dependent synaptic vesicle protein), and SNAP-25 (a presynaptic vesicular fusion protein). Our results showed that treadmill exercise training (1) increased the retention latency without affecting the fear acquisition in the PA test, (2) transiently increased the hippocampal BDNF level at 1, 2, and 4h after the completion of exercise training, and (3) persistently increased the hippocampal protein levels of full-length TrkB, phosphorylated TrkB and synaptotagmin, but not truncated TrkB or SNAP-25. Moreover, the protein expression level of full-length TrkB or synaptotagmin was positively correlated with PA performance in mice. Finally, inhibition of TrkB signaling by K252a abolished the exercise-facilitated PA performance and upregulation of TrkB and synaptotagmin. Taken together, these data suggest that the upregulation of TrkB and synaptotagmin in the hippocampus contributes to the exercise-facilitated aversive memory.

Treadmill exercise enhances passive avoidance learning in rats: the role of down-regulated serotonin system in the limbic system.

While serotonin (5-HT) may impair learning and memory, exercise has been reported to improve them. Whether chronic exercise can facilitate fear memory via regulating the serotonin system is unknown. We examined the effects of 4-week treadmill exercise training on levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), the protein expression of its receptor 5-HT(1A) and transporter in the amygdala, hippocampus and prefrontal cortex of male Sprague-Dawley rats. Our results demonstrated that treadmill exercise (1) improved the passive avoidance learning performance; (2) decreased the 5-HT level in the hippocampus; (3) decreased the expression of 5-HT(1A) receptor in the amygdala without altering the transporter expression. Moreover, pretreatment with 0.1 mg/kg 8-hydroxy-di-n-propylamino tetralin, a selective 5-HT(1A) receptor agonist, impaired the passive avoidance performance and completely abolished the exercise-enhanced fear memory. Our results suggest that down-regulation of the 5-HT system in the limbic system, i.e., the reduction of the hippocampus 5-HT content and the amygdala 5-HT(1A) receptor expression, may be involved in the exercise-enhanced fear memory.

Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice.

Aging is an important determinant of adult hippocampal neurogenesis as the proliferation of neural stem/precursor cells (NSCs) declines dramatically before middle age. Contrary to this, physical exercise is known to promote adult hippocampal neurogenesis. The objective of this study is to investigate the effects of mandatory treadmill running (TR) on neurogenesis, including 1) NSCs proliferation, 2) neurite outgrowth of neuronal progenitor cells, and 3) the survival of newborn neurons in dentate area of middle-aged animals. Compared with 3-mo-old mice, numbers of mitotic cells and neuronal progenitor cells decreased dramatically by middle age and remained at low levels after middle age. Five weeks of TR not only increased NSC proliferation and the number of immature neurons but also promoted the maturation and survival of immature neurons in middle-aged mice. The neurogenic and neurotrophic effects of TR were not due to the reduction of the age-related elevation of serum corticosterone. Significantly, 5 wk of TR restored the age-dependent decline of brain-derived neurotrophic factor and its receptor, TrkB, which are known to promote neuronal differentiation and survival. Taken together, mandatory running exercise alters the brain chemistries of middle-aged animals toward an environment that is favorable to NSC proliferation, survival, and maturation.

Long-term compulsive exercise reduces the rewarding efficacy of 3,4-methylenedioxymethamphetamine.

Although exercise has been known to regulate brain plasticity, its impact on psychostimulant reward and the associated mesolimbic dopamine system remained scarcely explored. A psychostimulant, 3,4-methylenedioxymethamphetamine (MDMA), is currently a worldwide abused drug of choice. We decided to examine the modulating effects of long-term, compulsive treadmill exercise on the hedonic value of MDMA in male C57BL/6J mice. MDMA-induced conditioned place preference (CPP) was used as a behavioral paradigm to indicate the reward efficacy of MDMA. We observed that sedentary control mice all demonstrated reliable MDMA-induced CPP with our conditioning protocol. Interestingly, pre-exposure to a treadmill exercise decreased the later MDMA-induced CPP in a running period-dependent manner. Specifically, mice undergoing a 12-week treadmill running exercise did not exhibit any approaching bias toward the MDMA-associated compartment in this CPP paradigm. Twelve weeks of treadmill running did not alter peripheral metabolism of MDMA 30min following single intraperitoneal injection of MDMA (3mg/kg). We further used microdialysis technique to study the underlying mechanisms for the impaired MDMA reward produced by the12-week exercise pre-exposure. We found that acute MDMA-stimulated dopamine release in nucleus accumbens was abolished in the exercised mice, whereas an obvious elevation of accumbal dopamine release was observed in sedentary control mice. Finally, the 12-week exercise program did not alter the protein levels of primary dopamine receptors, vesicular or membrane transporters in this area. We conclude that the long-term, compulsive exercise is effective in curbing the reward efficacy of MDMA possibly via its direct effect on reversing the MDMA-stimulated dopamine release in nucleus accumbens.

Polymorphonuclear leukocyte transverse migration induces rapid alterations in endothelial focal contacts.

Transmigrated polymorphonuclear leukocytes (PMNs) usually undergo subendothelial transverse migration before penetrating into inner tissue layers. Whether or how endothelial cells (ECs) respond to the PMN migrating underneath them is unknown. A tissue flow chamber was used to establish a fMLP gradient and to observe PMN transverse migration along with its associated endothelial responses in culture (on a collagen gel) or in vascular tissues. Our results indicated that transversely migrating PMNs were in direct contact with the basal side of ECs. Contrasting to focal adhesion kinase (FAK) or proteins with phosphorylated tyrosine, paxillin disappeared rapidly (<1 min) from endothelial focal contacts after encountering the leukocyte's leading edge and soon rejoined them after the PMN had left. In addition, FAK moved away or became dephosphorylated when PMNs remained at the same subendothelial location for longer than 10 min, leaving actin filaments apparently unaltered. Unlike PMN transendothelial migration, PMN transverse migration did not induce any detectable endothelial calcium signaling. Taken together, our findings indicated that PMN transverse migration interrupted endothelial-matrix interactions and induced rapid alterations in endothelial focal contact composition.

Treadmill exercise counteracts the suppressive effects of peripheral lipopolysaccharide on hippocampal neurogenesis and learning and memory.

New neurons are continuously generated in hippocampal subgranular zone throughout life, and the amount of neurogenesis is suggested to be correlated with the hippocampus-dependent function. Several extrinsic stimuli are known to modulate the neurogenesis process. Among them, physical exercise has advantageous effects on neurogenesis and brain function, while inflammation shows the opposite. Herein we showed that a moderate running exercise successfully restored the peripheral lipopolysaccharide (LPS)-impaired neurogenesis in the dentate area. LPS treatment obstructed neuronal differentiation, but not proliferation. Exercise training facilitated both the proliferation of the neural stem cells and their differentiation into neurons. Interestingly, exercise replenished the LPS-reduced levels of brain-derived neurotrophic factor and its receptor, TrkB, and rescued the LPS-disturbed performance in water maze; while the LPS-elicited up-regulation of tumor necrosis factor-alpha and interleukin-1beta remained unaltered. In conclusion, our findings suggest that running exercise effectively ameliorates the LPS-disturbed hippocampal neurogenesis and learning and memory performance. Such advantageous effects of running exercise are not due to the alteration of inflammatory response, but possibly by the restoring the LPS-lessened brain-derived neurotrophic factor signaling pathway.

Chronic exercise improves endothelial calcium signaling and vasodilatation in hypercholesterolemic rabbit femoral artery.

OBJECTIVE: This study was to investigate the effects of chronic exercise on vasodilatation and endothelial intracellular calcium (EC [Ca2+]i) signaling in atherosclerotic animals. METHODS AND RESULTS: For 8 weeks, male New Zealand White rabbits were fed rabbit chow with or without the addition of 2% cholesterol. They were further divided into control and exercise groups. Animals in the exercise groups ran on a leveled treadmill at 0.88 km/h for 10 to 60 minutes gradually for 5 days per week for a total of 8 weeks. At the end of experiments, femoral arteries were dissected, loaded with fura 2-AM, and mounted in a tissue flow chamber. PE-precontracted vessel specimens were exposed to acetylcholine (ACh). The EC [Ca2+]i elevation and vasorelaxation were determined simultaneously under an epifluorescence microscope equipped with a ratio-imaging capability. Our results showed the following: (1) high cholesterol diet feeding caused lipid deposition on vascular surface, reduced the ACh-evoked EC [Ca2+]i elevation, and impaired endothelium-dependent and endothelium-independent vascular responses, but chronic exercise had the opposite effects; (2) ACh-induced vasorelaxation was associated with EC [Ca2+]i elevation in all groups; and (3) vasorelaxation at high levels of EC [Ca2+]i elevation decreased in hypercholesterolemia. CONCLUSIONS: Our data suggest that hypercholesterolemia induces vascular structural changes and impairs EC [Ca2+]i signaling and vasodilatation, whereas chronic exercise partially reverses these adverse effects.

Topical exposure to carbon disulfide induces epidermal permeability alterations in physiological and pathological changes.

Carbon disulfide (CS2) has been suggested its possible skin toxicity. Neither a dose-response relationship nor any mechanism of CS2-exposure regarding epidermal permeability alterations has been postulated. The objectives of this study were to evaluate the dose-dependent association and the pathological changes with CS2 topically applied to mouse epidermis. Four concentrations of CS2 (0% (controls), 10%, 15%, and 20% in ethanol) were topically applied to a 1.8 cm2 area of the lateral abdomen of female nude mice for 10 min. Time-series transepidermal water loss (TEWL) profile, morphological examinations by both light microscopy (hematoxylin/eosin stain and Nile Red stain) and electronic microscopy, and lipid analysis by high performance thin-layer chromatography (HPTLC) were used to evaluate the epidermal impairment. We found no recovery occurred within 72 h exposure to 20% CS2 in contrast to substantial recovery found in 10% and 15% CS2-exposure. Clear dose-dependent fashions were shown in TEWL elevations, recovery retardation, and lipid extraction across the ethanol (control), 10%, 15%, and 20% CS2 exposures. Two mechanistic pathways were raised to account for CS2-induced epidermal alterations: intercellular lipid depletion and keratinocyte damage. A study with different test animal species is warranted owing to the discrepancies in epidermis between nude mice and other species.

Exercise enhances surfactant-mediated phagocytosis in bronchoalveolar macrophages.

Severe exercise augments the phagocytic capability of bronchoalveolar macrophages (BAMs) in the absence of pulmonary surfactant, a lung immunity modulator in vivo. This study was to investigate whether the exercise effect on BAM phagocytosis is partially mediated by surfactant components. Male BALB/c mice (9-12 wk old) were divided into control and severe exercise groups. Mice in the exercise group received progressive treadmill running exercise until exhaustion. BAMs and lung lavage supernatant were collected under either sedentary or post-severe exercise conditions. Phagocytosis of IgG/C'-opsonized beads by BAMs was determined in the presence of lavage supernatant. Mannose, a monosaccharide competitor for the carbohydrate recognition domain of surfactant protein A (SP-A), and SP-A antibodies were applied to examine the role of SP-A in the exercise-induced facilitating effects on BAM phagocytosis. BAMs from either control or post-exercise animals had elevated phagocytosis of IgG/C'-opsonized beads when incubated with autologous lung lavage supernatant. The supernatant-mediated increase in BAM phagocytosis of IgG/C'-opsonized beads was dose-dependently inhibited by mannose or SP-A antibodies. In addition, higher concentrations of SP-A inhibitors were needed to inhibit BAM phagocytosis in post-exercise group than that in the control group. We also observed that SP-A inhibitors were ineffective in the absence of lung lavage supernatant. Furthermore, post-exercise, but not control, BAMs displayed time-dependent alterations in their membrane-bound SP-A amount during 30-min incubation with autologous lung lavage supernatant. SP-A plays a major role in the severe exercise-enhanced surfactant-mediated BAM phagocytosis.

Short-term exercise training improves vascular function in hypercholesterolemic rabbit femoral artery.

Chronic exercise in healthy or hypercholesteremic animals for at least two months improves their vascular functions. This study is to examine whether short-term exercise training protocols can correct early-stage vascular dysfunction induced by high-cholesterol diet feeding. Male New Zealand White rabbits were fed for 2, 4 or 6 weeks with rabbit chow with or without the addition of 2% (w/w) cholesterol. They were further divided into control and exercise groups. Animals in exercise groups ran on a leveled treadmill for the same time periods as diet intervention. At the end of experiments, femoral arteries were dissected, loaded with fura 2-AM, and mounted in a tissue flow chamber. Phenylephrine-precontracted vessel specimens were exposed to acetylcholine. The endothelial intracellular calcium elevation and vasorelaxation were determined simultaneously under an epifluorescence microscope with ratio imaging capability. En face oil red O staining was used to evaluate fatty streak formation. Our results showed that 1) high-cholesterol diet feeding for > or = 4 weeks caused lipid deposition, reduced the acetylcholine-evoked endothelial calcium signaling, and impaired both endothelium-dependent and endothelium-independent vascular responses in a time-dependent manner; 2) vasorelaxation at given levels of endothelial intracellular calcium elevation decreased in hypercholesterolemia; 3) concomitant exercise program had reverse effects. We conclude that high-cholesterol diet intervention for as short as 4 weeks induces vascular structural changes, impairs endothelial intracellular calcium signaling and vasodilatation in rabbit femoral arteries. Short-term exercise training in parallel completely eliminates these adverse effects so long as the diet intervention is no more than 6 weeks.

Treadmill exercise activates Nrf2 antioxidant system to protect the nigrostriatal dopaminergic neurons from MPP+ toxicity.

Exercise induces oxidative stress, which may activate adaptive antioxidant responses. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in the defense of oxidative stress by regulating the expression of antioxidant enzymes, gamma-glutamylcysteine ligase (γGCL) and heme oxygenase-1 (HO-1). We investigated whether treadmill exercise protects dopaminergic neurons by regulating the Nrf2 antioxidant system in a 1-methyl-4-phenylpyridine (MPP(+))-induced parkinsonian rat model. We found that MPP(+) induced early decreases in total glutathione level and Nrf2/γGCLC (catalytic subunit of γGCL) expression, but late upregulation of HO-1 expression in association with loss of nigral dopaminergic neurons and downregulation of tyrosine hydroxylase and dopamine transporter expression in the striatum. Treadmill exercise for 4weeks induced upregulation of Nrf2 and γGCLC expression, and also prevented the MPP(+)-induced downregulation of Nrf2/γGCLC/glutathione, HO-1 upregulation, and nigrostriatal dopaminergic neurodegeneration. Moreover, the protective effect of exercise was blocked by the knockdown of Nrf2 using a lentivirus-carried shNrf2 delivery system. These results demonstrate an essential role of Nrf2 in the exercise-mediated protective effect that exercise enhances the nigrostriatal Nrf2 antioxidant defense capacity to protect dopaminergic neurons against the MPP(+)-induced toxicity.

Effects of high-cholesterol diet and parallel exercise training on the vascular function of rabbit aortas: a time course study.

It is plausible to assume that exercise training, when applied early enough, can completely correct atherosclerotic defects. Using rabbit aortic specimens, we examined the effects of chronic exercise and high-cholesterol diet feeding on vascular function for different time periods. Male New Zealand White rabbits were divided into four groups: the normal diet groups with or without exercise training and the high-cholesterol diet groups with or without exercise training. Animals in high-cholesterol diet groups were fed 2% cholesterol rabbit chow for 2, 4, or 6 wk. Those in exercise training groups ran on a treadmill at 0.88 km/h for up to 40 min/day, 5 days/wk for the same period of time as the diet feeding. Thoracic aortas were isolated for functional and immunohistochemical analyses. We found that 1). although high-cholesterol diet feeding (>or=2 wk) elevated serum cholesterol levels and impaired acetylcholine-evoked vasorelaxation, only the latter effect was reversed by exercise training; 2). the effects of diet and exercise on acetylcholine-evoked vasorelaxation were mainly due to altered release of nitric oxide and endothelium-derived hyperpolarizing factor; and 3). diet feeding for 4 or 6 wk caused significant lipid deposition and expression of P-selectin, VCAM-1, monocyte chemoattractant protein-1, and inducible nitric oxide synthase, which were largely reduced by exercise training. In conclusion, parallel exercise training almost completely reverses the early-stage endothelial dysfunction caused by high-cholesterol diet feeding.