A necessary role of DNMT3A in endurance exercise by suppressing ALDH1L1-mediated oxidative stress
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ABSTRACT:
SUBMITTER: Dr. Sona Kang
PROVIDER: S-SCDT-EMBOJ-2020-106491 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Oxidative stress (OS) associated with an intense exercise may have a negative influence on equine health. The aim of this study was to determine the effects of endurance races on oxidative and antioxidative status of horses by evaluating changes in reactive oxygen metabolites (d-ROMs), malondialdehyde (MDA), biological antioxidant potential (BAP) and oxidative stress index (OSI) values. The study was carried out on 53 race starts (28 individual horses) competing at different endurance races according to distance (40 and 80 km) and difficulty (easy and demanding). Blood samples were taken before and after the race. RESULTS:Compared to levels of OS serum biomarkers before the race, an increase in values of d-ROMs (P?<? 0.01), MDA (P?<? 0.01), and BAP (P?<? 0.001), and a decrease in OSI (P?<? 0.001) have been noted after the race. Contrary to other measured biomarkers, BAP did not show significant individual effects of horses. Horses competing at shorter races have shown a significant change in d-ROMs (P?=?0.002), BAP (P?<? 0.001) and OSI (P?=?0.004), whereas those competing at longer races in MDA (P?=?0.002), BAP (P?<? 0.001) and OSI (P?<? 0.001) post-race values. Endurance racing induced changes in values of d-ROMs, BAP and OSI during both easy and demanding races. CONCLUSIONS:Changes in all measured OS biomarkers indicate that prolonged aerobic exercise during endurance race could contribute to the imbalance between oxidants and antioxidants in horses, mainly characterised by a pronounced antioxidant response. Biological antioxidant potential was found to be the most reliable biomarker of OS in endurance horses in the present study.
| S-EPMC6035461 | biostudies-literature
Project description:ObjectivesLong-term, irregular endurance exercise may result in disturbance to the angiogenesis of heart muscles and blood supply. The aim of the present study is to evaluate the effects of mid- and long-term endurance exercise on the process of angiogenesis.Materials and methodsEighteen male Wister rats of 220±10 g, were randomly assigned to three groups of 6 rats including: Control, Mid, and Long Group. After the training sessions, the rats were weighed and sacrificed.ResultsIn comparison to the Control Group, the both groups, indicated remarkable increase in the weight of heart and significantly higher serum LDH and CK activity (P<0.01). In addition, after the training sessions, weakened antioxidant heart system (TAC, total thiol groups, and GPX activity) and increased oxidative stress markers (MDA and NO) were remarkably observed in Mid Group and particularly in those in the Long Group in comparison to the Control Group (P<0.05). Finally, significant increase in VEGF-B, MEF-2C and MMP-2 gene expression was found for both experimental groups, associated with the up-regulation of ANGPT-1 and HDAC4 in the Mid Group (P<0.05). While the longer exercise period induced significantly upper VEGF-B, MEF-2C, and MMP-2 and significantly lower ANGPT-1 and HDAC4 in the Long Group (P<0.05).ConclusionIn this study, higher oxidative status and upper angiogenic gene expression with higher VEGF-B, MEF-2c, and MMP-2 and lower ANGPT-1 and HDAC4 were traced as effects of long-term endurance exercise. These results point to the dis-regulation of blood supply in the presence of angiogenesis resulting from long-term exercise.
| S-EPMC6118080 | biostudies-literature
Project description:Low-osmolality carbohydrate-electrolyte solution (LCS) ingestion can replace losses from exercise-induced dehydration, but the benefits of LCS ingestion strategy after exhaustive endurance exercise (EEE) remain unknown. The present study evaluated the effects of LCS ingestion on dehydration, oxidative stress, renal function, and aerobic capacity after EEE. In our study with its double-blind, crossover, counterbalanced design, 12 healthy male participants were asked to consume LCS (150 mL four times per hour) or placebo (water) 1 h before and 1 h after EEE. All participants completed a graded exercise test to exhaustion on a treadmill for the determination of maximal oxygen consumption (VO2max), applied to further intensity calibration, and then completed the EEE test. The average heart rate, maximal heart rate, running time to exhaustion, and peak oxygen uptake (VO2peak) were recorded during the exercise period. The participants' body weight was recorded at different time points before and after the EEE to calculate the dehydration rate. Blood samples were drawn at baseline and before, immediately after, 1 h after, and 2 h after EEE to determine indicators of oxidative stress and renal function. The results indicated that the dehydration rates in participants with LCS ingestion at 15 min, 30 min, and 45 min after EEE were significantly lower than in participants with placebo ingestion (-1.86 ± 0.47% vs. -2.24 ± 0.72%; -1.78 ± 0.50% vs. -2.13 ± 0.74%; -1.54 ± 0.51% vs. -1.94 ± 0.72%, respectively; p < 0.05). In addition, the concentration of catalase in participants with LCS ingestion immediately after EEE was significantly higher than in participants with placebo ingestion (2046.21 ± 381.98 nmol/min/mL vs. 1820.37 ± 417.35 nmol/min/mL; p < 0.05). Moreover, the concentration of protein carbonyl in participants with LCS ingestion immediately after EEE was slightly lower than in participants with placebo ingestion (2.72 ± 0.31 nmol carbonyl/mg protein vs. 2.89 ± 0.43 nmol carbonyl/mg protein; p = 0.06). No differences were noted for other variables. Our findings conclude that LCS ingestion can effectively avoid fluid loss and oxidative stress after EEE. However, LCS ingestion had no benefits for renal function or aerobic capacity.
| S-EPMC7222420 | biostudies-literature
Project description:Ultra-endurance (UE) race has been associated with brain metabolic changes, but it is still unknown which regions are vulnerable. This study investigated whether high-volume training in rodents, even under moderate intensity, can induce cerebellar oxidative and inflammatory status. Forty-five adult rats were divided into six groups according to a training period, followed or not by an exhaustion test (ET) that simulated UE: control (C), control + ET (C-ET), moderate-volume (MV) training and MV-ET, high-volume training (HV) and HV-ET. The training period was 30 (MV) and 90 (HV) min/day, 5 times/week for 3 months as a continuous running on a treadmill at a maximum velocity of 12 m/min. After 24 h, the ET was performed at 50% maximum velocities up to the animals refused to run, and then serum lactate levels were evaluated. Serum and cerebellar homogenates were obtained 24 h after ET. Serum creatine kinase (CK), lactate dehydrogenase (LDH), and corticosterone levels were assessed. Lipid peroxidation (LP), nitric oxide (NO), Interleukin 1? (IL-1?), and GFAP proteins, reduced and oxidized glutathione (GSH and GSSG) levels, superoxide dismutase (SOD) and catalase (CAT) activities were quantified in the cerebellum. Serum lactate concentrations were lower in MV-ET (?20%) and HV-ET (?40%) compared to the C-ET group. CK and corticosterone levels were increased more than ? twofold by HV training compared to control. ET increased CK levels in MV-ET vs. MV group (P = 0.026). HV induced higher LP levels (?40%), but an additive effect of ET was only seen in the MV-ET group (P = 0.02). SOD activity was higher in all trained groups vs. C and C-ET (P < 0.05). CAT activity, however, was intensified only in the MV group (P < 0.02). The 50 kDa GFAP levels were enhanced in C-ET and MV-ET vs. respective controls, while 42 kDa (?40%) and 39 kDa (?26%) isoform levels were reduced. In the HV-ET group, the 50 KDa isoform amount was reduced ?40-60% compared to the other groups and the 39 KDa isoform, increased sevenfold. LDH levels, GSH/GSSG ratio, and NO production were not modified. ET elevated IL-1? levels in the CT and MV groups. Data shows that cerebellar resilience to oxidative damage may be maintained under moderate-volume training, but it is reduced by UE running. High-volume training per se provoked systemic metabolic changes, cerebellar lipid peroxidation, and unbalanced enzymatic antioxidant resource. UE after high-volume training modified the GFAP isoform profile suggesting impaired astrocyte reactivity in the cerebellum.
| S-EPMC7492828 | biostudies-literature
Project description:OBJECTIVE:Ribosomal protein S6 Kinase-1 (S6K1) has been linked to resistance exercise-mediated improvements in glycemia. We hypothesized that S6K1 may also play a role in regulating glycemic control in response to endurance exercise training. METHODS:S6k1-knockout (S6K1KO) and WT mice on a 60 cal% high-fat diet were trained for 4 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls. RESULTS:WT mice showed improved glucose tolerance after training. In contrast, S6K1KO mice displayed equally high glucose tolerance already in the sedentary state with no further improvement after training. Similarly, training decreased mitochondrial ROS production in skeletal muscle of WT mice, whereas ROS levels were already low in the sedentary S6K1KO mice with no further decrease after training. Nevertheless, trained S6K1KO mice displayed an increased running capacity compared to trained WT mice, as well as substantially reduced triglyceride contents in liver and skeletal muscle. The improvements in glucose handling and running endurance in S6K1KO mice were associated with markedly increased ketogenesis and a higher respiratory exchange ratio. CONCLUSIONS:In high-fat fed mice, loss of S6K1 mimics endurance exercise training by reducing mitochondrial ROS production and upregulating oxidative utilization of ketone bodies. Pharmacological targeting of S6K1 may improve the outcome of exercise-based interventions in obesity and diabetes.
| S-EPMC5681242 | biostudies-literature
Project description:Androgen-deprivation therapy has been identified to induce oxidative stress in prostate cancer (PCa), leading to reactivation of androgen receptor (AR) signaling in a hormone-refractory manner. Thus, antioxidant therapies have gained attention as adjuvants for castration-resistant PCa. Here, we report for the first time that human endostatin (ES) prevents androgen-independent growth phenotype in PCa cells through its molecular targeting of AR and glucocorticoid receptor (GR) and downstream pro-oxidant signaling. This reversal after ES treatment significantly decreased PCa cell proliferation through down-regulation of GR and up-regulation of manganese superoxide dismutase and reduced glutathione levels. Proteome and biochemical analyses of ES-treated PCa cells further indicated a significant up-regulation of enzymes in the major reactive oxygen species (ROS) scavenging machinery, including catalase, glutathione synthetase, glutathione reductase, NADPH-cytochrome P450 reductase, biliverdin reductase, and thioredoxin reductase, resulting in a concomitant reduction of intracellular ROS. ES further augmented the antioxidant system through up-regulation of glucose influx, the pentose phosphate pathway, and NAD salvaging pathways. This shift in cancer cell redox homeostasis by ES significantly decreased the effect of protumorigenic oxidative machinery on androgen-independent PCa growth, suggesting that ES can suppress GR-induced resistant phenotype upon AR antagonism and that the dual targeting action of ES on AR and GR can be further translated to PCa therapy.-Lee, J. H., Kang, M., Wang, H., Naik, G., Mobley, J. A., Sonpavde, G., Garvey, W. T., Darley-Usmar, V. M., Ponnazhagan, S. Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress.
| S-EPMC5349799 | biostudies-literature
Project description:Doxorubicin (DOX) is a highly potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. DOX-induced cardiotoxicity involves increased oxidative stress and activated endoplasmic reticulum-mediated apoptosis. Alginate oligosaccharide (AOS) is a non-immunogenic, non-toxic and biodegradable polymer, with anti-oxidative, anti-inflammatory and anti-endoplasmic reticulum stress properties. The present study examined whether AOS pretreatment could protect against acute DOX cardiotoxicity, and the underlying mechanisms focused on oxidative stress and endoplasmic reticulum-mediated apoptosis. We found that AOS pretreatment markedly increased the survival rate of mice insulted with DOX, improved DOX-induced cardiac dysfunction and attenuated DOX-induced myocardial apoptosis. AOS pretreatment mitigated DOX-induced cardiac oxidative stress, as shown by the decreased expressions of gp91 (phox) and 4-hydroxynonenal (4-HNE). Moreover, AOS pretreatment significantly decreased the expression of Caspase-12, C/EBP homologous protein (CHOP) (markers for endoplasmic reticulum-mediated apoptosis) and Bax (a downstream molecule of CHOP), while up-regulating the expression of anti-apoptotic protein Bcl-2. Taken together, these findings identify AOS as a potent compound that prevents acute DOX cardiotoxicity, at least in part, by suppression of oxidative stress and endoplasmic reticulum-mediated apoptosis.
| S-EPMC5192468 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive lethal disorder caused by the lack of dystrophin, which determines myofibers mechanical instability, oxidative stress, inflammation, and susceptibility to contraction-induced injuries. Unfortunately, at present, there is no efficient therapy for DMD. Beyond several promising gene- and stem cells-based strategies under investigation, physical activity may represent a valid noninvasive therapeutic approach to slow down the progression of the pathology. However, ethical issues, the limited number of studies in humans and the lack of consistency of the investigated training interventions generate loss of consensus regarding their efficacy, leaving exercise prescription still questionable. By an accurate analysis of data about the effects of different protocol of exercise on muscles of mdx mice, the most widely-used pre-clinical model for DMD research, we found that low intensity exercise, especially in the form of low speed treadmill running, likely represents the most suitable exercise modality associated to beneficial effects on mdx muscle. This protocol of training reduces muscle oxidative stress, inflammation, and fibrosis process, and enhances muscle functionality, muscle regeneration, and hypertrophy. These conclusions can guide the design of appropriate studies on human, thereby providing new insights to translational therapeutic application of exercise to DMD patients.
| S-EPMC8066278 | biostudies-literature
Project description:ObjectiveIn this investigation, we addressed the contribution of the core circadian clock factor, BMAL1, in skeletal muscle to both acute transcriptional responses to exercise and transcriptional remodeling in response to exercise training. Additionally, we adopted a systems biology approach to investigate how loss of skeletal muscle BMAL1 altered peripheral tissue homeostasis as well as exercise training adaptations in iWAT, liver, heart, and lung of male mice.MethodsCombining inducible skeletal muscle specific BMAL1 knockout mice, physiological testing and standardized exercise protocols, we performed a multi-omic analysis (transcriptomics, chromatin accessibility and metabolomics) to explore loss of muscle BMAL1 on muscle and peripheral tissue responses to exercise.ResultsMuscle-specific BMAL1 knockout mice demonstrated a blunted transcriptional response to acute exercise, characterized by the lack of upregulation of well-established exercise responsive transcription factors including Nr4a3 and Ppargc1a. Six weeks of exercise training in muscle-specific BMAL1 knockout mice induced significantly greater and divergent transcriptomic and metabolomic changes in muscle. Surprisingly, liver, lung, inguinal white adipose and heart showed divergent exercise training transcriptomes with less than 5% of 'exercise-training' responsive genes shared for each tissue between genotypes.ConclusionsOur investigation has uncovered the critical role that BMAL1 plays in skeletal muscle as a key regulator of gene expression programs for both acute exercise and training adaptations. In addition, our work has uncovered the significant impact that altered exercise response in muscle and its likely impact on the system plays in the peripheral tissue adaptations to exercise training. Our work also demonstrates that if the muscle adaptations diverge to a more maladaptive state this is linked to increased gene expression signatures of inflammation across many tissues. Understanding the molecular targets and pathways contributing to health vs. maladaptive exercise adaptations will be critical for the next stage of therapeutic design for exercise mimetics.
| S-EPMC11294728 | biostudies-literature
Project description:Stat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3Y705 contributes to its nucleic translocation, while phospho-Stat3S727 leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. In comparison to well-characterized signaling pathways interplaying with Stat3Y705, little is known about Stat3S727. In this work, we studied the influence of Stat3 deficiency on the viability of cells exposed to H2O2 or hypoxia using siRNA and CRISPR/Cas9 genome-editing. We found dysregulation of mitochondrial activity, which was associated with excessive ROS formation and reduced mitochondrial membrane potential, and observed a synergistic effect for oxidative stress-mediated apoptosis in Stat3-KD cells or cells carrying Stat3Y705F, but not Stat3S727D, suggesting the importance of functional mitochondrial Stat3 in this context. We also found that ROS-mediated activation of ASK1/p38MAPK was involved and adding antioxidants, p38MAPK inhibitor, or genetic repression of ASK1 could easily rescue the cellular damage. Our finding reveals a new role of mitochondrial Stat3 in preventing ASK1/p38MAPK-mediated apoptosis, wich further support the notion that selective inhibition mitochondrial Stat3 could provide a primsing target for chemotherapy.
| S-EPMC5684365 | biostudies-literature