Treadmill exercise improves cerebral ischemia injury by regulating microglia polarization via downregulation of MMP12.

BACKGROUD: Exercise training is the main strategy for stroke rehabilitation, and it has shown that shifting microglia toward M2 phenotype is beneficial for the recovery of neurological function after stroke. The mechanisms governing exercise training and inflammatory response after cerebral ischemia remain largely unexplored. Herein, the aim of this study was to investigate the role of exercise training in immune response after cerebral ischemia. METHODS: The transient middle cerebral artery occlusion (MCAO) rat model and primary microglia under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions were used to mimic the ischemic stroke in vivo and in vitro respectively. Treadmill exercise with gradually increased intensity was initiated the second day after MCAO for a maximum of 14 days. The beam balance test, forelimb placement test, cornering test, modified adhesive removal test were used to assess the behavioral recovery. The right peri-infarct cortex was taken from 3 rats per group for RNA sequencing (RNA-seq) analysis. Real-time PCR, western blot, immunofluorescence, and phagocytosis assay was performed after MCAO and/or OGD/R. RESULTS: Treadmill exercise could significantly improve behavioral outcomes and reduce the infarct volumes. In addition, treadmill exercise switched microglia polarization toward M2 phenotype (Iba+/CD206+) in the peri-infarct cortex, and significantly increased the levels of anti-inflammatory factors (TGF-ß, IL10, Arg-1, CD206) and decreased a pool of pro-inflammatory factors (IL-1ß, IL-6, TNF-α, iNOS, CD68) in the peri-infarct areas. RNA-seq analysis and further studies demonstrated that exercise training could significantly reduce the expression of MMP12. Through further immunofluorescence co-labeling analysis, we found that treadmill exercise predominantly reduced the expression of MMP-12 in microglia but not in neuron after MCAO. In primary microglia after OGD/R, MMP12 inhibition switched microglia polarization toward to M2 phenotype, increased the expression of M2 markers, and enhanced its phagocytic capacities. CONCLUSIONS: Our data demonstrate that treadmill exercise could improve the inflammatory microenvironment in the brain after ischemic stroke, which may be caused by inhibition of MMP12 expression. MMP12 suppression in primary microglia could remodel microglia immune functions. In summary, this study may provide novel insights into the immune mechanism of exercise training for stroke and suggests potential targets for therapeutic approaches.

Sequential physical and cognitive training disrupts cocaine-context associations via multi-level stimulation of adult hippocampal neurogenesis.

Cocaine-related contextual cues are a recurrent source of craving and relapse. Extinction of cue-driven cocaine seeking remains a clinical challenge, and the search for adjuvants is ongoing. In this regard, combining physical and cognitive training is emerging as a promising strategy that has shown synergistic benefits on brain structure and function, including enhancement of adult hippocampal neurogenesis (AHN), which has been recently linked to reduced maintenance of maladaptive drug seeking. Here, we examined whether this behavioral approach disrupts cocaine-context associations via improved AHN. To this aim, C57BL/6J mice (N = 37) developed a cocaine-induced conditioned place preference (CPP) and underwent interventions consisting of exercise and/or spatial working memory training. Bromodeoxyuridine (BrdU) was administered during early running sessions to tag a subset of new dentate granule cells (DGCs) reaching a critical window of survival during spatial learning. Once these DGCs became functionally mature (∼ 6 weeks-old), mice received extinction training before testing CPP extinction and reinstatement. We found that single and combined treatments accelerated CPP extinction and prevented reinstatement induced by a low cocaine priming (2 mg/kg). Remarkably, the dual-intervention mice showed a significant decrease of CPP after extinction relative to untreated animals. Moreover, combining the two strategies led to increased number and functional integration of BrdU+ DGCs, which in turn maximized the effect of spatial training (but not exercise) to reduce CPP persistence. Together, our findings suggests that sequencing physical and cognitive training may redound to decreased maintenance of cocaine-context associations, with multi-level stimulation of AHN as a potential underlying mechanism.

Treadmill exercise prevents recognition memory impairment in VD rat model and enhancement of hippocampal structural synaptic plasticity.

OBJECTIVE: In vascular dementia (VD), memory impairment caused by the damage of synaptic plasticity is the most prominent feature that afflicts patients and their families. Treadmill exercise has proven beneficial for memory by enhancing synaptic plasticity in animal models including stroke, dementia, and mental disorders. The aim of this study was to examine the effects of treadmill exercise on recognition memory and structural synaptic plasticity in VD rat model. METHODS: Male Sprague-Dawley rats were randomly assigned into four groups: control group (C group, n = 6), vascular dementia group (VD group, n = 6), treadmill exercise and vascular dementia group (Exe-VD group, n = 6), and treadmill exercise group (Exe group, n = 6). Four-week treadmill exercise was performed in the Exe-VD and Exe groups. Then, the common carotid arteries of rats in the VD and Exe-VD groups were identified to establish the VD model. Behavior tests (open-field test and novel recognition memory test) were adopted to evaluate anxiety-like behavior and recognition memory. Transmission electron microscopy and Golgi staining were performed to observe synaptic ultrastructure and spine density in the hippocampus. RESULTS: Our study demonstrated that VD rat exhibited significantly anxiety-like behavior and recognition impairment (p < .01), while treadmill exercise significantly alleviated anxiety-like behavior and improved recognition memory in VD rat (p < .01). Transmission electron microscopy revealed that hippocampal synapse numbers were significantly decreased in the VD group compared to the control group (p < .05). These alterations were reversed by treadmill exercise, and the rats exhibited healthier synaptic ultrastructure, including significantly increased synapse (p < .05). Meanwhile, golgi staining revealed that the spine numbers of the hippocampus were significantly decreased in the VD group compared to the control group (p < .05). When compared with the VD group, hippocampal spine numbers were significantly increased in the Exe-VD group (p < .05). CONCLUSION: The improvement of VD-associated recognition memory by treadmill exercises is associated with enhanced structural synaptic plasticity in VD rat model.

Effects of different combinations of mechanical loading intensity, duration, and frequency on the articular cartilage in mice.

BACKGROUND: Understanding how healthy articular cartilage responds to mechanical loading is critical. Moderate mechanical loading has positive effects on the cartilage, such as maintaining cartilage homeostasis. The degree of mechanical loading is determined by a combination of intensity, frequency, and duration; however, the best combination of these parameters for knee cartilage remains unclear. This study aimed to determine which combination of intensity, frequency, and duration provides the best mechanical loading on healthy knee articular cartilage in vitro and in vivo. METHODS AND RESULTS: In this study, 33 male mice were used. Chondrocytes isolated from mouse knee joints were subjected to different cyclic tensile strains (CTSs) and assessed by measuring the expression of cartilage matrix-related genes. Furthermore, the histological characteristics of mouse tibial cartilages were quantified using different treadmill exercises. Chondrocytes and mice were divided into the control group and eight intervention groups: high-intensity, high-frequency, and long-duration; high-intensity, high-frequency, and short-duration; high-intensity, low-frequency, and long-duration; high-intensity, low-frequency, and short-duration; low-intensity, high-frequency, and long-duration; low-intensity, high-frequency, and short-duration; low-intensity, low-frequency, and long-duration; low-intensity, low-frequency, and short-duration. In low-intensity CTSs, chondrocytes showed anabolic responses by altering the mRNA expression of COL2A1 in short durations and SOX9 in long durations. Furthermore, low-intensity, low-frequency, and long-duration treadmill exercises minimized chondrocyte hypertrophy and enhanced aggrecan synthesis in tibial cartilages. CONCLUSION: Low-intensity, low-frequency, and long-duration mechanical loading is the best combination for healthy knee cartilage to maintain homeostasis and activate anabolic responses. Our findings provide a significant scientific basis for exercise and lifestyle instructions.

Moderate aerobic training enhances the effectiveness of insulin therapy through hypothalamic IGF1 signaling in rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurological condition that is connected with a decline in a person's memory as well as their cognitive ability. One of the key topics of AD research has been the exploration of metabolic causes. We investigated the effects of treadmill exercise and intranasal insulin on learning and memory impairment and the expression of IGF1, BDNF, and GLUT4 in hypothalamus. The animals were put into 9 groups at random. In this study, we examined the impact of insulin on spatial memory in male Wistar rats and analyzed the effects of a 4-week pretreatment of moderate treadmill exercise and insulin on the mechanisms of improved hypothalamic glucose metabolism through changes in gene and protein expression of IGF1, BDNF, and GLUT4. We discovered that rat given Aß25-35 had impaired spatial learning and memory, which was accompanied by higher levels of Aß plaque burden in the hippocampus and lower levels of IGF1, BDNF, and GLUT4 mRNA and protein expression in the hypothalamus. Additionally, the administration of exercise training and intranasal insulin results in the enhancement of spatial learning and memory impairments, the reduction of plaque burden in the hippocampus, and the enhancement of the expression of IGF1, BDNF, and GLUT4 in the hypothalamus of rats that were treated with Aß25-35. Our results show that the improvement of learning and spatial memory due to the improvement of metabolism and upregulation of the IGF1, BDNF, and GLUT4 pathways can be affected by pretreatment exercise and intranasal insulin.

Effects of short-term dietary nitrate supplementation on exercise and coronary blood flow responses in patients with peripheral artery disease.

Background: Peripheral arterial disease (PAD) is a prevalent vascular disorder characterized by atherosclerotic occlusion of peripheral arteries, resulting in reduced blood flow to the lower extremities and poor walking ability. Older patients with PAD are also at a markedly increased risk of cardiovascular events, including myocardial infarction. Recent evidence indicates that inorganic nitrate supplementation, which is abundant in certain vegetables, augments nitric oxide (NO) bioavailability and may have beneficial effects on walking, blood pressure, and vascular function in patients with PAD. Objective: We sought to determine if short-term nitrate supplementation (via beetroot juice) improves peak treadmill time and coronary hyperemic responses to plantar flexion exercise relative to placebo (nitrate-depleted juice) in older patients with PAD. The primary endpoints were peak treadmill time and the peak coronary hyperemic response to plantar flexion exercise. Methods: Eleven PAD patients (52-80 yr.; 9 men/2 women; Fontaine stage II) were randomized (double-blind) to either nitrate-rich (Beet-IT, 0.3 g inorganic nitrate twice/day; BRnitrate) or nitrate-depleted (Beet-IT, 0.04 g inorganic nitrate twice/day, BRplacebo) beetroot juice for 4 to 6 days, followed by a washout of 7 to 14 days before crossing over to the other treatment. Patients completed graded plantar flexion exercise with their most symptomatic leg to fatigue, followed by isometric handgrip until volitional fatigue at 40% of maximum on day 4 of supplementation, and a treadmill test to peak exertion 1-2 days later while continuing supplementation. Hemodynamics and exercise tolerance, and coronary blood flow velocity (CBV) responses were measured. Results: Although peak walking time and claudication onset time during treadmill exercise did not differ significantly between BRplacebo and BRnitrate, the diastolic blood pressure response at the peak treadmill walking stage was significantly lower in the BRnitrate condition. Increases in CBV from baseline to peak plantar flexion exercise after BRplacebo and BRnitrate showed a trend for a greater increase in CBV at the peak workload of plantar flexion with BRnitrate (p = 0.06; Cohen's d = 0.56). Conclusion: Overall, these preliminary findings suggest that inorganic nitrate supplementation in PAD patients is safe, well-tolerated, and may improve the coronary hyperemic and blood pressure responses when their calf muscles are most predisposed to ischemia.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT02553733.

Multisensory Fusion Training and 7, 8-Dihydroxyflavone Improve Amyloid-ß-Induced Cognitive Impairment, Anxiety, and Depression-Like Behavior in Mice Through Multiple Mechanisms.

Background: There is growing interest in the role of physical activity in patients with of Alzheimer's disease (AD), particularly regarding its impact of cognitive function, gut microbiota, metabolites, and neurotrophic factors. Objective: To investigate the impact of multisensory fusion training (MSFT) combined with 7, 8-dihydroxyflavone (DHF) on the behavioral characteristics, protein expression, microbiome, and serum metabolome using the AD model in mice induced with amyloid-ß (Aß). Methods: We assessed cognitive ability, anxiety-like and depression-like behaviors in Aß mice using behavioral measures. Western blotting was employed to detect the expression of relevant proteins. The 16S rRNA gene sequencing and metabolomics were used to analyze changes in the intestinal microbial composition and serum metabolic profile, respectively, of Aß mice. Results: The behavioral outcomes indicated that a 4-week intervention combining DHF and MSFT yielded remarkable improvements in cognitive function and reduced anxiety and depression-like behaviors in Aß mice. In the hippocampus of Aß mice, the combined intervention increased the levels of BDNF, VGF, PSD-95, Nrf2, p-GSK3ß and p-CREB proteins. Analyses of sequence and metabolomic data revealed that Bacteroides and Ruminococcaceae were remarkably more abundant following the combined intervention, influencing the expression of specific metabolites directly linked to the maintenance of neuronal and neurobehavioral functions. These metabolites play a crucial role in vital processes, such as amino acid metabolism, lipid metabolism, and neurotransmitter metabolism in mice. Conclusion: Our study highlighted that MSFT combined with DHF improves cognitive impairment, anxiety, and depression-like behavior in Aß mice through multiple mechanisms, and further validated the correlation between the gut microbiome and serum metabolome. These findings open up a promising avenue for future investigations into potential treatment strategies for AD.

Effects of conventional versus virtual reality-simulated treadmill exercise on fatigue, cognitive function, and participant satisfaction in post-COVID-19 subjects. A randomized trial.

Background/objective: Post-COVID-19 subjects typically experience symptoms of fatigue, cognitive impairment, and sleep difficulty, which can be relieved by conventional aerobic exercise. Virtual Reality (VR) technology to support conventional exercise has recently gained much attention. Therefore, this study aimed to assess the effects of traditional treadmill exercise compared to virtual reality-simulated treadmill exercise on fatigue, cognitive function, sleep quality, and participant satisfaction with the exercise program in post-COVID-19 subjects. Methods: This single-centered, randomized, parallel-group intervention study was conducted between December 2021 and March 2022. Sixteen of twenty post-COVID-19 subjects completed this study (n1 = 8, n2 = 8). Inclusion criteria were persistent dyspnea/fatigue, mild cognitive problems, and age from 30-60 years. Exclusion criteria were previous severe COVID-19 infection and ICU admission, concomitant respiratory or cardiovascular disease, and musculoskeletal or neurological disease. Eligible subjects were assigned randomly to two groups: a non-VR group that received traditional treadmill aerobic exercise only and a VR group that received treadmill exercise with non-immersive VR. Both groups received moderate-intensity exercise on a treadmill at [50-60 % (peak HR－resting HR) + resting HR] for 30-45 min, three times per week, and for four weeks. The outcome measures were the Chalder Fatigue Scale, Montreal Cognitive Assessment (MoCA) questionnaire, Pittsburgh Sleep Quality Index (PSQI), and participant satisfaction with the exercise program rated on a 5-point Likert scale. Results: Both groups showed significant improvements in the Chalder Fatigue Scale, the MoCA questionnaire, and the PSQI scores after training compared to baseline (p < 0.05), without significant differences between them (p > 0.05). However, participant satisfaction with the exercise program was significantly higher in the VR group than in the non-VR group (p = 0.037). Conclusion: A moderate-intensity 4-week treadmill exercise program with and without non-immersive VR may improve fatigue, cognitive function, and sleep quality to the same extent in COVID-19 survivors. However, participant satisfaction with the exercise program could be greater after conventional treadmill training assisted by non-immersive VR than after conventional treadmill training alone in this cohort. Trial registration: Pan African Clinical Trials Registry, PACTR202311561948428, retrospectively registered.

Comparing prophylactic effect of exercise and metformin on cognitive brain functions in rats with type 3 diabetes mellitus.

Introduction: Type 2 diabetes mellitus (DM) and Alzheimer's disease (AD) are two major medical conditions that constitute a significant financial burden on most healthcare systems. Due to AD sharing "insulin resistance" mechanistic features with DM, some scientists have proposed "type 3 DM" terminology for it. This study aims to compare the prophylactic effect of exercise and metformin on cognitive brain functions in rats with type 3 DM. Material and methods: Two groups of rats were included in the study: the control group (n = 15) and the streptozotocin-induced type 2 diabetic group (n = 45). The diabetic group was subdivided into three equal subgroups: a sedentary non-treated diabetic group, an exercised group, and a metformin-treated group. We estimated step-down avoidance task latency, serum glucose, insulin, free fatty acids (FFA), cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides (TG), brain Aß-42 and glucose, histological changes by toluidine blue, and immunohistochemistry for brain Aß-42 and tau-positive cells. Results: Serum glucose, FFA, TG, cholesterol, LDL, brain Aß-42, brain glucose, the number of hippocampal dark and degenerated cells, and brain Aß-42 and tau-positive cells, were all significantly lower. In contrast, serum insulin and HDL, the number of hippocampal granular cells, and latency of the step-down avoidance task were significantly higher in exercised and metformin-treated groups compared to the diabetic group. There were significantly higher values of serum insulin and brain/plasma glucose ratio and number of brain tau-positive cells in the metformin-treated group than in the exercised group. Conclusions: We can conclude that exercise can be as effective as metformin regarding prophylaxis against the deleterious effects of type 3 DM on cognitive brain functions.

Simultaneous Treatment of 5-Aminosalicylic Acid and Treadmill Exercise More Effectively Improves Ulcerative Colitis in Mice.

Ulcerative colitis (UC) is characterized by continuous mucosal ulceration of the colon, starting in the rectum. 5-Aminosalicylic acid (5-ASA) is the main therapy for ulcerative colitis; however, it has side effects. Physical exercise effectively increases the number of anti-inflammatory and anti-immune cells in the body. In the current study, the effects of simultaneous treatment of treadmill exercise and 5-ASA were compared with monotherapy with physical exercise or 5-ASA in UC mice. To induce the UC animal model, the mice consumed 2% dextran sulfate sodium dissolved in drinking water for 7 days. The mice in the exercise groups exercised on a treadmill for 1 h once a day for 14 days after UC induction. The 5-ASA-treated groups received 5-ASA by enema injection using a 200 µL polyethylene catheter once a day for 14 days. Simultaneous treatment improved histological damage and increased body weight, colon weight, and colon length, whereas the disease activity index score and collagen deposition were decreased. Simultaneous treatment with treadmill exercise and 5-ASA suppressed pro-inflammatory cytokines and apoptosis following UC. The benefits of this simultaneous treatment may be due to inhibition on nuclear factor-κB/mitogen-activated protein kinase signaling activation. Based on this study, simultaneous treatment of treadmill exercise and 5-ASA can be considered as a new therapy of UC.

Treadmill exercise promotes bone tissue recovery in rats subjected to high + Gz loads.

INTRODUCTION: High + Gz loads, the gravitational forces experienced by the body in hypergravity environments, can lead to bone loss in pilots and astronauts, posing significant health risks. MATERIALS AND METHODS: To explore the effect of treadmill exercise on bone tissue recovery, a study was conducted on 72 male Wistar rats. These rats were subjected to four weeks of varying levels of periodic high + Gz loads (1G, 8G, 20G) experiments, and were subsequently divided into the treadmill group and the control group. The treadmill group underwent a continuous two-week treadmill experiment, while the control group rested during this period. The mechanical properties, microstructure, and molecular markers of their tibial bone tissue were measured using three-point bending, micro-CT, and PCR. RESULTS: The results showed that treadmill exercise improved the elastic modulus, ultimate deflection, and ultimate load of rat bone tissue. It also increased the number, density, and volume fraction of bone trabeculae, and decreased their separation. Moreover, treadmill exercise enhanced osteogenesis and inhibited osteoclastogenesis. CONCLUSION: This study demonstrates that treadmill exercise can promote the recovery of bone tissue in rats subjected to high + Gz loads, providing a potential countermeasure for bone loss in pilots and astronauts.

Hepatic kynurenic acid mediates phosphorylation of Nogo-A in the medial prefrontal cortex to regulate chronic stress-induced anxiety-like behaviors in mice.

Exercise training effectively relieves anxiety disorders via modulating specific brain networks. The role of post-translational modification of proteins in this process, however, has been underappreciated. Here we performed a mouse study in which chronic restraint stress-induced anxiety-like behaviors can be attenuated by 14-day persistent treadmill exercise, in association with dramatic changes of protein phosphorylation patterns in the medial prefrontal cortex (mPFC). In particular, exercise was proposed to modulate the phosphorylation of Nogo-A protein, which drives the ras homolog family member A (RhoA)/ Rho-associated coiled-coil-containing protein kinases 1(ROCK1) signaling cascade. Further mechanistic studies found that liver-derived kynurenic acid (KYNA) can affect the kynurenine metabolism within the mPFC, to modulate this RhoA/ROCK1 pathway for conferring stress resilience. In sum, we proposed that circulating KYNA might mediate stress-induced anxiety-like behaviors via protein phosphorylation modification within the mPFC, and these findings shed more insights for the liver-brain communications in responding to both stress and physical exercise.

Aerobic exercise training engages the canonical wnt pathway to improve pulmonary function and inflammation in COPD.

BACKGROUND: We studied whether the exercise improves cigarette smoke (CS) induced chronic obstructive pulmonary disease (COPD) in mice through inhibition of inflammation mediated by Wnt/ß-catenin-peroxisome proliferator-activated receptor (PPAR) γ signaling. METHODS: Firstly, we observed the effect of exercise on pulmonary inflammation, lung function, and Wnt/ß-catenin-PPARγ. A total of 30 male C57BL/6J mice were divided into the control group (CG), smoke group (SG), low-intensity exercise group (LEG), moderate-intensity exercise group (MEG), and high-intensity exercise group (HEG). All the groups, except for CG, underwent whole-body progressive exposure to CS for 25 weeks. Then, we assessed the maximal exercise capacity of mice from the LEG, MEG, and HEG, and performed an 8-week treadmill exercise intervention. Then, we used LiCl (Wnt/ß-catenin agonist) and XAV939 (Wnt/ß-catenin antagonist) to investigate whether Wnt/ß-catenin-PPARγ pathway played a role in the improvement of COPD via exercise. Male C57BL/6J mice were randomly divided into six groups (n = 6 per group): CG, SG, LiCl group, LiCl and exercise group, XAV939 group, and XAV939 and exercise group. Mice except those in the CG were exposed to CS, and those in the exercise groups were subjected to moderate-intensity exercise training. All the mice were subjected to lung function test, lung histological assessment, and analysis of inflammatory markers in the bronchoalveolar lavage fluid, as well as detection of Wnt1, ß-catenin and PPARγ proteins in the lung tissue. RESULTS: Exercise of various intensities alleviated lung structural changes, pulmonary function and inflammation in COPD, with moderate-intensity exercise exhibiting significant and comprehensive effects on the alleviation of pulmonary inflammation and improvement of lung function. Low-, moderate-, and high-intensity exercise decreased ß-catenin levels and increased those of PPARγ significantly, and only moderate-intensity exercise reduced the level of Wnt1 protein. Moderate-intensity exercise relieved the inflammation aggravated by Wnt agonist. Wnt antagonist combined with moderate-intensity exercise increased the levels of PPARγ, which may explain the highest improvement of pulmonary function observed in this group. CONCLUSIONS: Exercise effectively decreases COPD pulmonary inflammation and improves pulmonary function. The beneficial role of exercise may be exerted through Wnt/ß-catenin-PPARγ pathway.

Thyroid hormone deficiency affects anxiety-related behaviors and expression of hippocampal glutamate transporters in male congenital hypothyroid rat offspring.

Thyroid hormones are crucial for brain development and their deficiency during fetal and postnatal periods can lead to mood and cognitive disorders. We aimed to examine the consequences of thyroid hormone deficiency on anxiety-related behaviors and protein expression of hippocampal glutamate transporters in congenital hypothyroid male offspring rats. Possible beneficial effects of treadmill exercise have also been examined. Congenital hypothyroidism was induced by adding propylthiouracil (PTU) to drinking water of pregnant Wistar rats from gestational day 6 until the end of the weaning period (postnatal day 28). Next, following 4 weeks of treadmill exercise (5 days per week), anxiety-related behaviors were examined using elevated plus maze (EPM) and light/dark box tests. Thereafter, protein expression of astrocytic (GLAST and GLT-1) and neuronal (EAAC1) glutamate transporters were measured in the hippocampus by immunoblotting. Hypothyroid rats showed decreased anxiety-like behavior, as measured by longer time spent in the open arms of the EPM and in the light area of the light/dark box, compared to control rats. Hypothyroid rats had significantly higher GLAST and GLT-1 and lower EAAC1 protein levels in the hippocampus than did the euthyroid rats. Following exercise, anxiety levels decreased in the euthyroid group while protein expression of EAAC1 increased and returned to normal levels in the hypothyroid group. Our findings indicate that thyroid hormone deficiency was associated with alterations in protein expression of glutamate transporters in the hippocampus. Up-regulation of hippocampal GLAST and GLT-1 could be at least one of the mechanisms associated with the anxiolytic effects of congenital hypothyroidism.

Evaluation of left ventricular flow field changes after stress in patients with nonobstructive coronary artery disease using ultrasonic flow vector imaging.

Purpose: Vector flow mapping and treadmill exercise stress echocardiography were used to evaluate and explore changes in the left ventricular (LV) flow field of patients with nonobstructive coronary artery disease. Methods: Overall, 34 patients with nonobstructive (<50%) left anterior descending coronary artery stenosis (case group) and 36 patients with no coronary artery stenosis (control group) were included. Apical four-, three-, and two-chamber echocardiographic images were collected at rest and during early recovery from treadmill exercise. LV flow field, vortex area, and circulation (cir) changes were recorded in different phases: isovolumetric systole (S1), rapid ejection (S2), slow ejection (S3), isovolumetric diastole (D1), rapid filling (D2), slow filling (D3), and atrial systole (D4). Intra- and inter-group differences were compared before and after exercise loading. Results: The control and case groups demonstrated regular trends of eddy current formation and dissipation at rest and under stress. Compared with the control group, the case group had irregular streamline distributions. Abnormal vortices formed in the S1 and D3 apical segments and D1 left ventricular middle segment in the resting group. Compared with the control group, the resting group had decreased left ventricular S1 vortex areas and increased S3 vortex areas. The post-stress D1 and D3 vortex areas and D1 and D2 cir increased. Compared with at rest, after stress, the control group had decreased S1, S3, D2, and D3 vortex areas; increased S2, D1, D3, and D4 cir; and decreased D2 cir. After stress, the case group had decreased S3 and D2 vortex areas, increased D1 vortex areas, and increased S2, D1, D3, and D4 cir (P all < 0.001). Logistic regression and ROC curve analyses show that increased D1 vortex area after stress is an independent risk factor for stenosis in nonobstructive stenosis of coronary arteries (OR: 1.007, 95% CI: 1.005-1.010, P < 0.05). A D1 vortex area cutoff value of 82.26 had an AUC, sensitivity, and specificity of 0.67, 0.655, and 0.726, respectively. Conclusion: The resting left ventricular flow field changed in patients with nonobstructive left anterior descending coronary artery stenosis. Both groups had more disordered left ventricular blood flow after stress. The increased D1 vortex area after stress is an independent risk factor for mild coronary stenosis and may contribute to the assessment of nonobstructive coronary stenosis. VFM combined with treadmill stress is useful in evaluating left ventricular flow field changes in patients with nonobstructive coronary artery disease, which is valuable in the early evaluation of coronary heart disease.

Treadmill exercise pretreatment ameliorated structural synaptic plasticity impairments of medial prefrontal cortex in vascular dementia rat and improved recognition memory.

This study aimed to investigate structural synaptic plasticity in the medial prefrontal cortex of rats under treadmill exercise pretreatment or naive conditions in a vascular dementia model, followed by recognition memory performance in a novel object recognition task. In this study, 24 Sprague-Dawley rats were obtained and randomly assigned into 4 groups as follows: control group (Con group, n = 6), vascular dementia (VD group, n = 6), exercise and vascular dementia group (Exe + VD group, n = 6), and exercise group (Exe group, n = 6). Initially, 4 weeks of treadmill exercise intervention was administered to the rats in the Exe + VD and Exe groups. Then, to establish the vascular dementia model, the rats both in the VD and Exe + VD groups were subjected to bilateral common carotids arteries surgery. One week later, open-field task and novel recognition memory task were adopted to evaluate anxiety-like behavior and recognition memory in each group. Then, immunofluorescence and Golgi staining were used to evaluate neuronal number and spine density in the rat medial prefrontal cortex. Transmission electron microscopy was used to observe the synaptic ultrastructure. Finally, microdialysis coupled with high-performance liquid chromatography was used to assess the levels of 5-HT and dopamine in the medial prefrontal cortex. The behavior results showed that 4 weeks of treadmill exercise pretreatment significantly alleviated recognition memory impairment and anxiety-like behavior in VD rats (P < 0.01), while the rats in VD group exhibited impaired recognition memory and anxiety-like behavior when compared with the Con group (P < 0.001). Additionally, NeuN immunostaining results revealed a significant decrease of NeuN-marked neuron in the VD group compared to Con group (P < 0.01), but a significantly increase in this molecular marker was found in the Exe + VD group compared to the Con group (P < 0.01). Golgi staining results showed that the medial prefrontal cortex neurons in the VD group displayed fewer dendritic spines than those in the Con group (P < 0.01), and there were more spines on the dendrites of medial prefrontal cortex cells in Exe + VD rats than in VD rats (P < 0.01). Transmission electron microscopy further revealed that there was a significant reduction of synapses intensity in the medial prefrontal cortex of rats in the VD group when compared with the Con group(P < 0.01), but physical exercise was found to significantly increased synapses intensity in the VD model (P < 0.01). Lastly, the levels of dopamine and 5-HT in the medial prefrontal cortex of rats in the VD group was significantly lower compared to the Con group (P < 0.01), and treadmill exercise was shown to significantly increased the levels of dopamine and 5-HT in the VD rats (P < 0.05). Treadmill exercise pretreatment ameliorated structural synaptic plasticity impairments of medial prefrontal cortex in VD rat and improved recognition memory.

Long-term drinking of green tea combined with exercise improves hepatic steatosis and obesity in male mice induced by high-fat diet.

Dietary habits and exercise play an important role in the well-being of human health. Currently, how long of drinking tea combined with exercise could efficiently ameliorate hepatic steatosis and obesity still needs to be investigated. Here, short-term and long-term green tea drinking combined with exercise were studied to improve hepatic steatosis and obesity in high-fat diet-induced (HF) mice. Our results showed that Yunkang 10 green tea (GT) combined with exercise (Ex) exhibited synergistic prevention effects on ameliorating hepatic steatosis and obesity. Especially, 22-week intervention with GT or Ex improved all symptoms of obesity, which indicated that long-term intervention exhibited profound preventive effects than the short term. Moreover, the combined intervention of 22 weeks inhibited the activation of NF-κB pathway and the expression of proinflammatory cytokines, which suggests that tea combined exercise may improve liver steatosis mainly by inhibiting inflammation. The key molecules for regulating lipid and glucose metabolism SCD1 were obviously downregulated, and GLU2 and PPARγ were significantly upregulated by GT and exercise in the liver of high-fat diet-induced mice. This study demonstrated that long-term intervention with GT and exercise effectively relieved hepatic steatosis and obesity complications by ameliorating hepatic inflammation, reducing lipid synthesis, and accelerating glucose transport.

Association between arterial stiffness and autonomic dysfunction in participants underwent treadmill exercise testing: a cross-sectional analysis.

Data on the impact of arterial stiffness on autonomic function are limited. We sought to investigate whether heart rate recovery (HRR), a predictor of autonomic function, is impaired in patients with increased arterial stiffness. A total of 475 participants (mean age 55.8 ± 11.1 years, 34.3% women) who underwent a treadmill exercise test (TET) for the evaluation of chest pain were retrospectively analyzed. All patients underwent brachial-ankle pulse wave velocity (baPWV) measurement on the same day. HRR was defined as the difference in heart rate from maximal exercise to 1 min of recovery. Participants with the lowest HRR tertile were older and had more cardiovascular risk factors than those with the highest HRR tertile. Simple correlation analysis showed that baPWV was negatively correlated with HRR (r = - 0.327, P < 0.001). In multiple linear regression analysis, there was a significant association between baPWV and HRR, even after adjusting for potential confounders (ß = - 0.181, P < 0.001). In participants who underwent TET, baPWV was negatively correlated with HRR. The results of our study indicate a potential relationship between arterial stiffness and the autonomic nervous system.

Effects of Particulate Matter Inhalation during Exercise on Oxidative Stress and Mitochondrial Function in Mouse Skeletal Muscle.

Particulate matter (PM) has deleterious consequences not only on the respiratory system but also on essential human organs, such as the heart, blood vessels, kidneys, and liver. However, the effects of PM inhalation on skeletal muscles have yet to be sufficiently elucidated. Female C57BL/6 or mt-Keima transgenic mice were randomly assigned to one of the following four groups: control (CON), PM exposure alone (PM), treadmill exercise (EX), or PM exposure and exercise (PME). Mice in the three-treatment group were subjected to treadmill running (20 m/min, 90 min/day for 1 week) and/or exposure to PM (100 µg/m3). The PM was found to exacerbate oxidative stress and inflammation, both at rest and during exercise, as assessed by the levels of proinflammatory cytokines, manganese-superoxide dismutase activity, and the glutathione/oxidized glutathione ratio. Furthermore, we detected significant increases in the levels of in vivo mitophagy, particularly in the PM group. Compared with the EX group, a significant reduction in the level of mitochondrial DNA was recorded in the PME group. Moreover, PM resulted in a reduction in cytochrome c oxidase activity and an increase in hydrogen peroxide generation. However, exposure to PM had no significant effect on mitochondrial respiration. Collectively, our findings in this study indicate that PM has adverse effects concerning both oxidative stress and inflammatory responses in skeletal muscle and mitochondria, both at rest and during exercise.

Treadmill exercise can regulate the redox balance in the livers of APP/PS1 mice and reduce LPS accumulation in their brains through the gut-liver-kupffer cell axis.

A growing body of clinical data has shown that patients with Alzheimer's disease (AD) have symptoms such as liver dysfunction and microbial-gut-brain axis dysfunction in addition to brain pathology, presenting a systemic multisystemic pathogenesis. Considering the systemic benefits of exercise, here, we first observed the effects of long-term treadmill exercise on liver injuries in APP/PS1 transgenic AD mice and explored the potential mechanisms of the gut-liver-brain axis's role in mediating exercise's ability to reduce bacterial lipopolysaccharide (LPS) pathology in the brain. The results showed that the livers of the AD mice were in states of oxidative stress, while the mice after long-term treadmill exercise showed alleviation of their oxidative stress, their intestinal barriers were protected, and the ability of their Kupffer cells to hydrolyze LPS was improved, in addition to the accumulation of LPS in their brains being reduced. Notably, the livers of the AD mice were in immunosuppressed states, with lower pro-oxidative and antioxidative levels than the livers of the wild-type mice, while exercise increased both their oxidative and antioxidative levels. These results suggest that long-term exercise modulates hepatic redox homeostasis in AD mice, attenuates oxidative damage, and reduces the accumulation of LPS in the brain through the combined action of the intestine-liver-Kupffer cells.