The Dose-Dependent Antioxidant Effects of Physical Exercise in the Hippocampus of Mice

Exercise increases both the consumption of oxygen and the production of reactive species in biological tissues, and this is counterbalanced by antioxidant adaptations to regular physical training. When the intensity of exercise fluctuates between mild and moderate, it improves the status of reduction–oxidation balance in the brain and induces neuroplasticity. However, intense exercise can oxidize the brain and impair neurological function. The effect of the frequency of exercise, which is an important factor in physical training, is still unknown. The effect of periodic exercise on biomarkers of oxidative stress in the hippocampus of mice was evaluated in this study. Mice were made to run on a treadmill for 8 weeks, two, three, or five times per week, and their hippocampi and quadriceps femoris muscles were then dissected. Biomarkers of oxidative damage were negatively correlated with the frequency of exercise and mitochondrial muscular activity, while the sulfhydryl contents were positively correlated with exercise frequency. A logistic analysis revealed a dose-dependent effect of exercise on these biomarkers. In summary, these results suggested that manipulating the frequency of physical exercise could induce antioxidant-related adaptations in the hippocampi of adult mice.     

Alterations in Skeletal Muscle Cell Homeostasis in a Mouse Model of Cigarette Smoke Exposure

Background

Skeletal muscle dysfunction is common in chronic obstructive pulmonary disease (COPD), a disease mainly caused by chronic cigarette use. An important proportion of patients with COPD have decreased muscle mass, suggesting that chronic cigarette smoke exposure may interfere with skeletal muscle cellular equilibrium. Therefore, the main objective of this study was to investigate the kinetic of the effects that cigarette smoke exposure has on skeletal muscle cell signaling involved in protein homeostasis and to assess the reversibility of these effects.

Methods

A mouse model of cigarette smoke exposure was used to assess skeletal muscle changes. BALB/c mice were exposed to cigarette smoke or room air for 8 weeks, 24 weeks or 24 weeks followed by 60 days of cessation. The gastrocnemius and soleus muscles were collected and the activation state of key mediators involved in protein synthesis and degradation was assessed.

Results

Gastrocnemius and soleus were smaller in mice exposed to cigarette smoke for 8 and 24 weeks compared to room air exposed animals. Pro-degradation proteins were induced at the mRNA level after 8 and 24 weeks. Twenty-four weeks of cigarette smoke exposure induced pro-degradation proteins and reduced Akt phosphorylation and glycogen synthase kinase-3β quantity. A 60-day smoking cessation period reversed the cell signaling alterations induced by cigarette smoke exposure.

Conclusions

Repeated cigarette smoke exposure induces reversible muscle signaling alterations that are dependent on the duration of the cigarette smoke exposure. These results highlights a beneficial aspect associated with smoking cessation.     

有氧运动改善AD模型APP/PS1双转基因小鼠中枢神经元线粒体融合分裂动态平衡

线粒体融合分裂平衡是线粒体动力学的需要。本研究观察12周规律有氧运动对APP/PS1双转基因小鼠中枢神经元线粒体融合分裂动态平衡的影响。本研究采用3月龄雄性APP/PS1小鼠（AD模型）随机分为AD安静组（AS）、AD运动组（AE）,同月龄雄性C57BL/6J小鼠做正常对照组（CS）。AE组进行12周规律跑台运动,5 d/周,60 min/d。前10 min运动速度12 m/min,后50 min运动速度15 m/min,跑台坡度为0°。八臂迷宫实验检测小鼠工作记忆错误频率和参考记忆错误频率;Western印迹检测小鼠皮层、海马组织中线粒体分裂蛋白Drp1和Fis1的含量,以及Drp1的活性（p-Drp1-Ser616）、线粒体融合蛋白Mfn1、Mfn2、Opa1的表达水平;透射电镜观察皮层、海马线粒体形态结构、健康线粒体比率及线粒体平均直径。本研究证实AS组较CS组工作记忆错误频率显著提高（P<0.05）,12周有氧运动显著降低工作记忆错误频率（P<0.05）。AS组小鼠皮层Fis1蛋白和海马脑区Drp1、Fis1蛋白表达水平及皮层、海马脑区Drp1蛋白的活性增加（P<0.05）。而皮层Mfn1和海马Mfn1、Mfn2蛋白表达水平显著降低（P<0.05）。12周有氧运动显著减低Fis1、Drp1蛋白表达及Drp1蛋白的活性,提高Mfn1、Mfn2蛋白表达水平（P<0.05）。AS组小鼠皮层、海马线粒体多呈现球形,部分线粒体膜结构消失,线粒体嵴结构紊乱。且AS组较CS组小鼠健康线粒体比率降低、直径缩短。12周规律有氧运动可明显改善线粒体形态和结构,提高健康线粒体比率及直径。本研究提示,12周规律有氧运动可有效抑制皮层、海马脑区线粒体分裂蛋白Drp1和 Fis1的表达,降低Drp1的活性（p-Drp1-Ser616）,上调线粒体融合蛋白Mfn1、Mfn2的蛋白表达水平,改善线粒体形态和结构以促进线粒体质量控制,是有氧运动改善AD模型空间学习记忆能力的分子机制之一。     

The Lung Inflammation and Skeletal Muscle Wasting Induced by Subchronic Cigarette Smoke Exposure Are Not Altered by a High-Fat Diet in Mice

Obesity and cigarette smoking independently constitute major preventable causes of morbidity and mortality and obesity is known to worsen lung inflammation in asthma. Paradoxically, higher body mass index (BMI) is associated with reduced mortality in smoking induced COPD whereas low BMI increases mortality risk. To date, no study has investigated the effect of a dietary-induced obesity and cigarette smoke exposure on the lung inflammation and loss of skeletal muscle mass in mice. Male BALB/c mice were exposed to 4 cigarettes/day, 6 days/week for 7 weeks, or sham handled. Mice consumed either standard laboratory chow (3.5 kcal/g, 12% fat) or a high fat diet (HFD, 4.3 kcal/g, 32% fat). Mice exposed to cigarette smoke for 7 weeks had significantly more inflammatory cells in the BALF (P<0.05) and the mRNA expression of pro-inflammatory cytokines and chemokines was significantly increased (P<0.05); HFD had no effect on these parameters. Sham- and smoke-exposed mice consuming the HFD were significantly heavier than chow fed animals (12 and 13%, respectively; P<0.05). Conversely, chow and HFD fed mice exposed to cigarette smoke weighed 16 and 15% less, respectively, compared to sham animals (P<0.05). The skeletal muscles (soleus, tibialis anterior and gastrocnemius) of cigarette smoke-exposed mice weighed significantly less than sham-exposed mice (P<0.05) and the HFD had no protective effect. For the first time we report that cigarette smoke exposure significantly decreased insulin-like growth factor-1 (IGF-1) mRNA expression in the gastrocnemius and tibialis anterior and IGF-1 protein in the gastrocnemius (P<0.05). We have also shown that cigarette smoke exposure reduced circulating IGF-1 levels. IL-6 mRNA expression was significantly elevated in all three skeletal muscles of chow fed smoke-exposed mice (P<0.05). In conclusion, these findings suggest that a down-regulation in local IGF-1 may be responsible for the loss of skeletal muscle mass following cigarette smoke exposure in mice.     

Can we optimise the exercise training prescription to maximise improvements in mitochondria function and content?

Background

While there is agreement that exercise is a powerful stimulus to increase both mitochondrial function and content, we do not know the optimal training stimulus to maximise improvements in mitochondrial biogenesis.

Scope of review

This review will focus predominantly on the effects of exercise on mitochondrial function and content, as there is a greater volume of published research on these adaptations and stronger conclusions can be made.

Major conclusions

The results of cross-sectional studies, as well as training studies involving rats and humans, suggest that training intensity may be an important determinant of improvements in mitochondrial function (as determined by mitochondrial respiration), but not mitochondrial content (as assessed by citrate synthase activity). In contrast, it appears that training volume, rather than training intensity, may be an important determinant of exercise-induced improvements in mitochondrial content. Exercise-induced mitochondrial adaptations are quickly reversed following a reduction or cessation of physical activity, highlighting that skeletal muscle is a remarkably plastic tissue. Due to the small number of studies, more research is required to verify the trends highlighted in this review, and further studies are required to investigate the effects of different types of training on the mitochondrial sub-populations and also mitochondrial adaptations in different fibre types. Further research is also required to better understand how genetic variants influence the large individual variability for exercise-induced changes in mitochondrial biogenesis.

General significance

The importance of mitochondria for both athletic performance and health underlines the importance of better understanding the factors that regulate exercise-induced changes in mitochondrial biogenesis. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.     

Effect of cigarette smoke on lipid peroxidation,antioxidant enzymes and NMDA receptor subunits 2A and 2B concentration in rat hippocampus

The effect of cigarette smoke on lipid peroxidation and antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase and on the concentration of N-methyl-d-aspartate receptor (NMDAR) subunits 2A and 2B in the hippocampus of Sprague-Dawley rats exposed to cigarette smoke for 2h/day for a period of 4 weeks was determined. It was observed that NMDAR 2A and 2B concentrations in the hippocampus were enhanced in the case of animals exposed to cigarette smoke, whereas lipid peroxidation and antioxidant enzyme activities did not show any change as compared to control animals. The results of our study suggest that cigarette smoke induces NMDAR 2A and 2B expression in the hippocampus, and that this is not due to an increased lipid peroxidation, because cigarette smoke has no effect on lipid peroxidation and antioxidant enzyme activities in the hippocampus.     

Il1-β Involvement in Cognitive Impairment after Sepsis

Sepsis is defined as the host's reaction to infection and characterised by a systemic inflammatory response with important clinical implications. Central nervous system dysfunction secondary to sepsis is associated with local generation of pro- and anti-inflammatory cytokines, impaired cerebral microcirculation, an imbalance of neurotransmitters, apoptosis and cognitive impairment. It's known that the IL-1β is one of the first cytokines to be altered. Thus, the objective of this study was to evaluate the role of IL-1β in cognitive parameters in brain tissue through the use of an IL-1β (IL-1ra) receptor antagonist up to 10 days and to assess blood–brain barrier permeability, cytokine levels, oxidative parameters and energetic metabolism up to 24 h, after sepsis induction. To this aim, we used sham-operated Wistar rats or submitted to the cecal ligation and perforation (CLP) procedure. Immediately after, the animals received one dose of 10 μg of IL-1ra. After 24 h, the rats were killed and were evaluated for biochemical parameters in the pre-frontal cortex, hippocampus and striatum. After 10 days, the animals were submitted to the habituation to the open field and step-down inhibitory avoidance task. We observed that the use of IL-1ra reverted the increase of blood–brain barrier permeability in the pre-frontal cortex, hippocampus and striatum; the increase of IL-1β, IL1-6 and TNF-α levels in the pre-frontal cortex and striatum; the decrease of complex I activity in the pre-frontal, hippocampus and striatum; the increase of oxidative parameters in pre-frontal cortex, hippocampus and striatum; and cognitive impairment. In conclusion, the results observed in this study reinforce the role of acute brain inflammatory response, in particular, the IL1β response, in the cognitive impairment associated with sepsis.     

Endogenous enzymes (NOX and ECSOD) regulate smoke-induced oxidative stress

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and the incidence is increasing as the population ages. Cigarette smoking is the primary risk factor; however, only a minority of smokers develop the disease. Inhalation of cigarette smoke introduces an abundance of free radicals into the lungs, causing oxidative stress and inflammation. We hypothesized that after the initial burst of oxidative stress associated with cigarette smoke exposure, a sustained source of endogenous free radical production is modulated by the antioxidant enzyme extracellular superoxide dismutase (ECSOD) and the superoxide-generating complex NADPH oxidase (NOX). Primary mouse macrophages exposed to cigarette smoke extract exhibited increased oxidative stress as indicated by fluorogenic dyes and isoprostane concentration, which was suppressed in the presence of both a superoxide dismutase mimetic and a NOX inhibitor. Similarly, primary macrophages isolated from ECSOD-overexpressing mice or NOX-deficient mice showed reduced oxidative stress in response to cigarette smoke treatment. In addition, both reduced glutathione and cytokines (MIP2 and IFNγ) were increased in bronchoalveolar lavage fluid of wild-type mice exposed to cigarette smoke but not in ECSOD-overexpressing or NOX-deficient mice. These data suggest that the mechanisms underlying the host defense against cigarette smoke-induced oxidative damage and subsequent development of COPD may include endogenous oxidases and antioxidant enzymes.     

Regulation of hypothalamic NPY by diet and smoking

Appetite is regulated by a number of hypothalamic neuropeptides including neuropeptide Y (NPY), a powerful feeding stimulator that responds to feeding status, and drugs such as nicotine and cannabis. There is debate regarding the extent of the influence of obesity on hypothalamic NPY. We measured hypothalamic NPY in male Sprague-Dawley rats after short or long term exposure to cafeteria-style high fat diet (32% energy as fat) or laboratory chow (12% fat). Caloric intake and body weight were increased in the high fat diet group, and brown fat and white fat masses were significantly increased after 2 weeks. Hypothalamic NPY concentration was only significantly decreased after long term consumption of the high fat diet. Nicotine decreases food intake and body weight, with conflicting effects on hypothalamic NPY reported. Body weight, plasma hormones and brain NPY were investigated in male Balb/c mice exposed to cigarette smoke for 4 days, 4 and 12 weeks. Food intake was significantly decreased by smoke exposure (2.32+/-0.03g/24h versus 2.71+/-0.04g/24h in control mice (non-smoke exposed) at 12 weeks). Relative to control mice, smoke exposure led to greater weight loss, while pair-feeding the equivalent amount of chow caused an intermediate weight loss. Chronic smoke exposure, but not pair-feeding, was associated with decreased hypothalamic NPY concentration, suggesting an inhibitory effect of cigarette smoking on brain NPY levels. Thus, consumption of a high fat diet and smoke exposure reprogram hypothalamic NPY. Reduced NPY may contribute to the anorexic effect of smoke exposure.     

Etiological role of cigarette smoking in rheumatoid arthritis: Nasal exposure to cigarette smoke condensate extracts augments the development of collagen-induced arthritis in mice

Cigarette smoking is a major environmental risk factor for rheumatoid arthritis (RA). However, the experimental bases supporting the etiological role of cigarette smoking in RA have not been fully provided. We have reported that cigarette smoke condensate (CSC), by means of subcutaneous injection into DBA/1J mice with collagen and complete Freund’s adjuvant or intraperitoneal injection one day before immunization, augmented the development of arthritis in the mouse model of collagen type II-induced arthritis (CIA). However, these experimental procedures may not be appropriate for cigarette smoking. In this study, we nasally exposed mice to mainstream CSC and found that CSC augmented the induction and development of arthritis and antibody level against collagen. Histological examination confirmed the augmenting effect of CSC. These findings provide experimental bases supporting the etiological role of cigarette smoking in RA.     

Intense Exercise Induces Mitochondrial Dysfunction in Mice Brain

There are conflicts between the effects of free radical over-production induced by exercise on neurotrophins and brain oxidative metabolism. The objective of this study was to investigate the effects of intense physical training on brain-derived neurotrophic factor (BDNF) levels, COX activity, and lipoperoxidation levels in mice brain cortex. Twenty-seven adult male CF1 mice were assigned to three groups: control untrained, intermittent treadmill exercise (3 × 15 min/day) and continuous treadmill exercise (45 min/day). Training significantly (P < 0.05) increased citrate synthase activity when compared to untrained control. Blood lactate levels classified the exercise as high intensity. The intermittent training significantly (P < 0.05) reduced in 6.5% the brain cortex COX activity when compared to the control group. BDNF levels significantly (P < 0.05) decreased in both exercise groups. Besides, continuous and intermittent exercise groups significantly (P < 0.05) increased thiobarbituric acid reactive species levels in the brain cortex. In summary, intense exercise promoted brain mitochondrial dysfunction due to decreased BDNF levels in the frontal cortex of mice.     

Effect of vitamin E and selenium on antioxidant enzymes in brain,kidney and liver of cigarette smoke-exposed mice

The present study was conducted to evaluate the protective effects of vitamin E and selenium (Se) application on alteration of antioxidant enzyme activities against cigarette smoking induced oxidative damage in brains, kidneys and liver of mice. Male mice (balb/c) were exposed to cigarette smoke and treated with Se and/or vitamin E. Glutathione transferase (GST), glutathione peroxidase (GPX), glutathione reductase (GRX), superoxide dismutase (SOD) and catalase (CAT) enzyme activities in mice brain, kidney and liver were measured spectrophotometrically. GST, GPX, GRX, SOD and CAT enzyme activities in the brains of smoke-exposed mice were found lower than the enzymes activities of control mice and Se-and vitamin E-treated mice at the end of the three and five months. Opposite to brain, enzyme activities in kidneys and livers of smoke-exposed mice were found higher than the enzymes activities of control mice and Se-and vitamin E-treated mice at the end of the three and five months. Activities of GST, GPX, GRX SOD and CAT in the livers, kidneys and brains of smoke-exposed mice were found statistically different (p < 0.01) compared to control mice and Se-and vitamin E-treated mice. Combined application of vitamin E and Se had an additive protective effect against changing enzymes activities in smoke-exposed mice livers, kidneys and brains at the end of the both application periods. These results suggest that cigarette smoke exposure enhances the oxidative stress, thereby disturbing the tissue antioxidant defense system and combined application of vitamin E and Se protects the brain, kidney and liver from oxidative damage through their antioxidant potential.     

Chronic cigarette smoke causes oxidative damage and apoptosis to retinal pigmented epithelial cells in mice

The purpose of this study was to determine whether mice exposed to chronic cigarette smoke develop features of early age-related macular degeneration (AMD). Two month old C57Bl6 mice were exposed to either filtered air or cigarette smoke in a smoking chamber for 5 h/day, 5 days/week for 6 months. Eyes were fixed in 2.5% glutaraldehyde/2% paraformaldehyde and examined for ultrastructural changes by transmission electron microscopy. The contralateral eye was fixed in 2% paraformaldehyde and examined for oxidative injury to the retinal pigmented epithelium (RPE) by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG) immunolabeling and apoptosis by TUNEL labeling. Mice exposed to cigarette smoke had immunolabeling for 8-OHdG in 85+/-3.7% of RPE cells counted compared to 9.5+/-3.9% in controls (p<0.00001). Bruch membrane was thicker in mice exposed to smoke (1086+/-332 nm) than those raised in air (543+/-132 nm; p = 0.0069). The two most pronounced ultrastructural changes (severity grading scale from 0-3) seen were a loss of basal infoldings (mean difference in grade = 1.98; p<0.0001), and an increase in intracellular vacuoles (mean difference in grade = 1.7; p<0.0001). Ultrastructural changes to Bruch membrane in cigarette-smoke exposed mice were smaller in magnitude but consistently demonstrated significantly higher grade injury in cigarette-exposed mice, including basal laminar deposits (mean difference in grade = 0.54; p<0.0001), increased outer collagenous layer deposits (mean difference in grade = 0.59; p = 0.002), and increased basal laminar deposit continuity (mean difference in grade = 0.4; p<0.0001). TUNEL assay showed a higher percentage of apoptotic RPE from mice exposed to cigarette smoke (average 8.0+/-1.1%) than room air (average 0+/-0%; p = 0.043). Mice exposed to chronic cigarette smoke develop evidence of oxidative damage with ultrastructural degeneration to the RPE and Bruch membrane, and RPE cell apoptosis. This model could be useful for studying the mechanism of smoke induced changes during early AMD.     

Cigarette smoke increases progesterone receptor and homeobox A10 expression in human endometrium and endometrial cells: a potential role in the decreased prevalence of endometrial pathology in smokers

Cigarette smoking has long been tied to a multitude of poor health outcomes; however, in reproductive biology, smoking has shown several unintuitive findings. Smoking is associated with significantly decreased rates of endometriosis and endometrial cancer. Here, we show that treatment with cigarette smoke extract leads to increased mRNA and protein expression of homeobox A10 (HOXA10) and progesterone receptor (PGR) as well as more rapid decidualization of endometrial stromal cells in vitro. In vivo, mice exposed to cigarette smoke similarly showed increased expression of HOXA10 and PGR in the endometrium. Both HOXA10 and PGR drive endometrial differentiation and are suppressed in endometrial tumors and in endometriosis. The increased expression found upon exposure to cigarette smoke may provide a protective effect, mediating the decreased incidence of endometrial disease among smokers. This mechanism contrasts with the accepted paradigm that the effects of smoking on the uterus are secondary to ovarian alterations rather than direct effects on endometrium as demonstrated here.     

Menthol Attenuates Respiratory Irritation and Elevates Blood Cotinine in Cigarette Smoke Exposed Mice

Addition of menthol to cigarettes may be associated with increased initiation of smoking. The potential mechanisms underlying this association are not known. Menthol, likely due to its effects on cold-sensing peripheral sensory neurons, is known to inhibit the sensation of irritation elicited by respiratory irritants. However, it remains unclear whether menthol modulates cigarette smoke irritancy and nicotine absorption during initial exposures to cigarettes, thereby facilitating smoking initiation. Using plethysmography in a C57Bl/6J mouse model, we examined the effects of L-menthol, the menthol isomer added to cigarettes, on the respiratory sensory irritation response to primary smoke irritants (acrolein and cyclohexanone) and smoke of Kentucky reference 2R4 cigarettes. We also studied L-menthol’s effect on blood levels of the nicotine metabolite, cotinine, immediately after exposure to cigarette smoke. L-menthol suppressed the irritation response to acrolein with an apparent IC₅₀ of 4 ppm. Suppression was observed even at acrolein levels well above those necessary to produce a maximal response. Cigarette smoke, at exposure levels of 10 mg/m³ or higher, caused an immediate and marked sensory irritation response in mice. This response was significantly suppressed by L-menthol even at smoke concentrations as high as 300 mg/m³. Counterirritation by L-menthol was abolished by treatment with a selective inhibitor of Transient Receptor Potential Melastatin 8 (TRPM8), the neuronal cold/menthol receptor. Inclusion of menthol in the cigarette smoke resulted in roughly a 1.5-fold increase in plasma cotinine levels over those observed in mice exposed to smoke without added menthol. These findings document that, L-menthol, through TRPM8, is a strong suppressor of respiratory irritation responses, even during highly noxious exposures to cigarette smoke or smoke irritants, and increases blood cotinine. Therefore, L-menthol, as a cigarette additive, may promote smoking initiation and nicotine addiction.     

Exercise training increases mitochondrial biogenesis in the brain

Increased muscle mitochondria are largely responsible for the increased resistance to fatigue and health benefits ascribed to exercise training. However, very little attention has been given to the likely benefits of increased brain mitochondria in this regard. We examined the effects of exercise training on markers of both brain and muscle mitochondrial biogenesis in relation to endurance capacity assessed by a treadmill run to fatigue (RTF) in mice. Male ICR mice were assigned to exercise (EX) or sedentary (SED) conditions (n = 16-19/group). EX mice performed 8 wk of treadmill running for 1 h/day, 6 days/wk at 25 m/min and a 5% incline. Twenty-four hours after the last training bout a subgroup of mice (n = 9-11/group) were euthanized, and brain (brain stem, cerebellum, cortex, frontal lobe, hippocampus, hypothalamus, and midbrain) and muscle (soleus) tissues were isolated for analysis of mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α), Silent Information Regulator T1 (SIRT1), citrate synthase (CS), and mitochondrial DNA (mtDNA) using RT-PCR. A different subgroup of EX and SED mice (n = 7-8/group) performed a treadmill RTF test. Exercise training increased PGC-1α, SIRT1, and CS mRNA and mtDNA in most brain regions in addition to the soleus (P < 0.05). Mean treadmill RTF increased from 74.0 ± 9.6 min to 126.5 ± 16.1 min following training (P < 0.05). These findings suggest that exercise training increases brain mitochondrial biogenesis, which may have important implications, not only with regard to fatigue, but also with respect to various central nervous system diseases and age-related dementia that are often characterized by mitochondrial dysfunction.     

Cardiac-Specific Overexpression of Metallothionein Rescues against Cigarette Smoking Exposure-Induced Myocardial Contractile and Mitochondrial Damage

Objectives

Second hand cigarette smoke is an independent risk factor for cardiovascular disease. Although a tie between smoking and cardiovascular disease is well established, the underlying mechanisms still remains elusive due to the lack of adequate animal models. This study was designed to use a mouse model of exposure to cigarette smoke, a surrogate of environmental tobacco smoke, to evaluate the impact of cardiac overexpression of heavy metal scavenger metallothionein on myocardial geometry, contractile and intracellular Ca²⁺ properties and apoptosis following side-stream smoke exposure.

Methods

Adult male wild-type FVB and metallothionein transgenic mice were placed in a chamber exposed to cigarette smoke for 1 hour daily for 40 days. Echocardiographic, cardiomyocyte contractile and intracellular Ca²⁺ properties, fibrosis, apoptosis and mitochondrial damage were examined.

Results

Our data revealed that smoke exposure enlarged ventricular end systolic and diastolic diameters, reduced myocardial and cardiomyocyte contractile function, disrupted intracellular Ca²⁺ homeostasis, facilitated fibrosis, apoptosis and mitochondrial damage (cytochrome C release and aconitase activity), the effects of which were attenuated or mitigated by metallothionein. In addition, side-stream smoke expose enhanced phosphorylation of Akt and GSK3β without affecting pan protein expression in the heart, the effect of which was abolished or ameliorated by metallothionein. Cigarette smoke extract interrupted cardiomyocyte contractile function and intracellular Ca²⁺ properties, the effect of which was mitigated by wortmannin and NAC.

Conclusions

These data suggest that side-stream smoke exposure led to myocardial dysfunction, intracellular Ca²⁺ mishandling, apoptosis, fibrosis and mitochondrial damage, indicating the therapeutic potential of antioxidant against in second smoking-induced cardiac defects possibly via mitochondrial damage and apoptosis.     

Late-Onset Running Biphasically Improves Redox Balance,Energy- and Methylglyoxal-Related Status,as well as SIRT1 Expression in Mouse Hippocampus

Despite the active research in this field, molecular mechanisms underlying exercise-induced beneficial effects on brain physiology and functions are still matter of debate, especially with regard to biological processes activated by regular exercise affecting the onset and progression of hippocampal aging in individuals unfamiliar with habitual physical activity. Since such responses seem to be mediated by changes in antioxidative, antiglycative and metabolic status, a possible exercise-induced coordinated response involving redox, methylglyoxal- and sirtuin-related molecular networks may be hypothesized. In this study, hippocampi of CD1 mice undergoing the transition from mature to middle age were analyzed for redox-related profile, oxidative and methylglyoxal-dependent damage patterns, energy metabolism, sirtuin1 and glyoxalase1 expression after a 2- or 4-mo treadmill running program. Our findings suggested that the 4-mo regular running lowered the chance of dicarbonyl and oxidative stress, activated mitochondrial catabolism and preserved sirtuin1-related neuroprotection. Surprisingly, the same cellular pathways were negatively affected by the first 2 months of exercise, thus showing an interesting biphasic response. In conclusion, the duration of exercise caused a profound shift in the response to regular running within the rodent hippocampus in a time-dependent fashion. This research revealed important details of the interaction between exercise and mammal hippocampus during the transition from mature to middle age, and this might help to develop non-pharmacological approaches aimed at retarding brain senescence, even in individuals unfamiliar with habitual exercise.     

Cigarette smoke exposure induces ROS-mediated autophagy by regulating sestrin,AMPK, and mTOR level in mice

Many pathological conditions linked to cigarette smoking are caused by the production of reactive oxygen species (ROS). The present study was conducted to analyze the effect of ROS on the lungs of Swiss mice exposed to cigarette smoking, focusing on autophagy-mediated mechanisms, and investigate the involvement of SESN2, AMPK, and mTOR signaling. Mice were exposed to cigarette smoke (CS) for 7, 15, 30, 45, and 60 days; the control group was not exposed to CS. Only mice exposed to CS for 45 days were selected for subsequent N-acetylcysteine (NAC) supplementation and smoke cessation analyses. Exposure to CS increased the production of ROS and induced molecular changes in the autophagy pathway, including an increase in phosphorylated AMPK and ULK1, reduction in phosphorylated mTOR, and increases in SESN2, ATG12, and LC3B levels. NAC supplementation reduced ROS levels and reversed all molecular changes observed upon CS treatment, suggesting the involvement of oxidative stress in inducing autophagy upon CS exposure. When exposure to CS was stopped, there were decreases in the levels of oxidative stress, AMPK and ULK1 phosphorylation, and autophagy-initiating molecules and increase in mTOR phosphorylation. In conclusion, these results suggest the involvement of ROS, SESN2, AMPK, and mTOR in the CS-induced autophagic process in the lung.     

Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle

Skeletal muscle exhibits superb plasticity in response to changes in functional demands. Chronic increases of skeletal muscle contractile activity, such as endurance exercise, lead to a variety of physiological and biochemical adaptations in skeletal muscle, including mitochondrial biogenesis, angiogenesis, and fiber type transformation. These adaptive changes are the basis for the improvement of physical performance and other health benefits. This review focuses on recent findings in genetically engineered animal models designed to elucidate the mechanisms and functions of various signal transduction pathways and gene expression programs in exercise-induced skeletal muscle adaptations.