Cardioprotective effects of tanshinone IIA pretreatment via kinin B2 receptor-Akt-GSK-3β dependent pathway in experimental diabetic cardiomyopathy

<p>Abstract</p> <p>Aims</p> <p>Diabetic cardiomyopathy, characterized by myocardial structural and functional changes, is a specific cardiomyopathy develops in patients with diabetes mellitus. The present study was to investigate the role of kinin B2 receptor-Akt-glycogen synthase kinase (GSK)-3β signalling pathway in mediating the protective effects of tanshinone IIA (TSN) on diabetic cardiomyopathy.</p> <p>Methods and results</p> <p>Streptozocin (STZ) induced diabetic rats (n = 60) were randomized to receive TSN, TSN plus HOE140 (a kinin B2 receptor antagonist), or saline. Healthy Sprague-Dawley (SD) rats (n = 20) were used as control. Left ventricular function, myocardial apoptosis, myocardial ultrastructure, Akt, GSK-3β and NF-κB phosphorylation, the expression of TNF-α, IL-6 and myeloperoxidase (MPO) were examined. Cardiac function was well preserved as evidenced by increased left ventricular ejection fraction (LVEF) and ± dp/dt (maximum speed of contraction/relaxation), along with decreased myocardial apoptotic death after TSN administration. TSN pretreatment alleviated mitochondria ultrastructure changes. TSN also enhanced Akt and GSK-3β phosphorylation and inhibited NF-κB phosphorylation, resulting in decreased TNF-α, IL-6 and MPO activities. Moreover, pretreatment with HOE140 abolished the beneficial effects of TSN: a decrease in LVEF and ± dp/dt, an inhibition of cardiomyocyte apoptosis, a destruction of cardiomyocyte mitochondria cristae, a reduction of Akt and GSK-3β phosphorylation, an enhancement of NF-κB phosphorylation and an increase of TNF-α, IL-6 and MPO production.</p> <p>Conclusion</p> <p>These data indicated that TSN is cardioprotective in the context of diabetic cardiomyopathy through kinin B2 receptor-Akt-GSK-3β dependent pathway.</p

The effect of intermittent hypoxic training on lung and heart tissues of healthy rats

Introduction: Recently, particular attention has been focused on the problem of the beneficial influence of intermittent hypoxia (IH) on the human organism. However, knowledge regarding the negative effects of intermittent hypoxic training (IHT) on cellular adaptive mechanisms remains limited. The aim of the present study was to investigate: 1) lung and heart ultrastructural changes under IHT; and 2) the adequateness of morphological and morphometric methods to determine the constructive and destructive displays of hypoxia. Material and methods: Adult male Wistar rats underwent IHT every day for 7&#8211;28 days. Lung and heart tissues were assessed by morphological and cellular morphometric methods. Results: We observed evident ultra structural changes of the lung air-blood barrier (LABB) by the 7&#8211;10th day of training. Structural damage of LABB was most considerable after 2 weeks of IHT exposure, its ultrastructure partially normalized by the end of the IHT 4-weeks course: there was diminishing of LABB hydration and disappearance of areas of its destruction. The structural changes in the heart blood-tissue barrier (HBTB) were considerably less marked compared with those in LABB during the 1st and 2nd weeks of training. Heart tissue structural changes increased by the end of the fourth week of IHT. Both tissue cells revealed no significant necrotic damage of mitochondria after IHT, while changes relating to the energy-directed restructuring of mitochondria were observed. We hypothesized that acute moderate hypoxia promotes a specific type of mitosis in lung and heart tissues. Conclusions: Ultrastructural changes in the rat lung and heart tissues depend on IHT duration. The phenomenon of micromitochondria within mitochondria is an additional adaptive mechanism for IH exposure.Introduction: Recently, particular attention has been focused on the problem of the beneficial influence of intermittent hypoxia (IH) on the human organism. However, knowledge regarding the negative effects of intermittent hypoxic training (IHT) on cellular adaptive mechanisms remains limited. The aim of the present study was to investigate: 1) lung and heart ultrastructural changes under IHT; and 2) the adequateness of morphological and morphometric methods to determine the constructive and destructive displays of hypoxia. Material and methods: Adult male Wistar rats underwent IHT every day for 7&#8211;28 days. Lung and heart tissues were assessed by morphological and cellular morphometric methods. Results: We observed evident ultra structural changes of the lung air-blood barrier (LABB) by the 7&#8211;10th day of training. Structural damage of LABB was most considerable after 2 weeks of IHT exposure, its ultrastructure partially normalized by the end of the IHT 4-weeks course: there was diminishing of LABB hydration and disappearance of areas of its destruction. The structural changes in the heart blood-tissue barrier (HBTB) were considerably less marked compared with those in LABB during the 1st and 2nd weeks of training. Heart tissue structural changes increased by the end of the fourth week of IHT. Both tissue cells revealed no significant necrotic damage of mitochondria after IHT, while changes relating to the energy-directed restructuring of mitochondria were observed. We hypothesized that acute moderate hypoxia promotes a specific type of mitosis in lung and heart tissues. Conclusions: Ultrastructural changes in the rat lung and heart tissues depend on IHT duration. The phenomenon of &#8220;micromitochondria within mitochondria&#8221; is an additional adaptive mechanism for IH exposure

Effect of Buyanghuangwu recipe on exhausted mice skeletal muscle mitochondrial ultrastructure and function

目的  通过建立小鼠游泳运动疲劳模型，探讨补阳还五汤（BYHWT）对运动性疲劳小鼠骨骼肌线粒体超微结构及蛋白AMPK表达的影响。方法  实验选用健康雄性清洁级SD小鼠48只，随机均分为对照组和补阳还五汤低、中、高剂量组，每组12只。常规饲料喂养外，BYHWT低、中、高剂量组分别给予12.5ｇ/kg、25.0ｇ/kg、50.0ｇ/kg的BYHWT灌胃，对照组给予等量生理盐水，连续给药7天，采用负重游泳实验建立小鼠力竭模型。用透射电镜观察骨骼肌细胞线粒体超微结构，Real-time PCR法测定骨骼肌AMPK蛋白表达。结果  运动性疲劳小鼠骨骼肌线粒体数量明显减少，线粒体空泡样变，嵴断裂显著，核染色质浓缩边集、核缩小、核膜增厚，而补阳还五汤药物干预后，骨骼肌线粒体形态趋于正常；模型组大鼠骨骼肌组织AMPK蛋白表达水平较正常对照组、补阳还五汤组明显降低，差异有显著性（P＜0.05），而正常对照组和补阳还五汤组间差异无显著性（P＞0.05）。结论  补阳还五汤具有一定的抗运动性疲劳作用，其机制可能与其减少线粒体损伤，增强线粒体功能，增加骨骼肌AMPK蛋白表达有关。Objective: Discusses the influence that Buyanghuangwu recipe for exercise-induced fatigue mice skeletal muscle mitochondrial ultrastructure and the influence of AMPK protein expression, by establishing mice swimming exercise fatigue model. Methods: 48 SD mice of healthy male at clean level were chose to do experiments, randomly divided into control group and BYHWR low, medium and high group, each group of 12. Regular feed, BYHWR low, medium and high group were given 12.5g/kg, 25.0g/kg, 50.0g/kg for BYHWR to fill the stomach, the control group given amount of normal saline, administered continuously for 7d, weight loading swimming experiment is adopted to establish the mice model of exhaustion. Skeletal muscle cells are observed by transmission electron microscope mitochondria ultrastructure, Real-time PCR method skeletal muscle AMPK protein expression. Results: The number of mitochondria in skeletal muscle of exercise-induced fatigue mice decreased significantly, mitochondrial vacuole degeneration, rupture of mitochondria were obvious, nucleus chromatin concentrated edge set, nucleus contracted and nuclear membrane thickened. After intervention of BYHWR, skeletal muscle The expression of AMPK protein in the skeletal muscle of the model group was significantly lower than that of the normal control group and the group of BYHWR group (P&lt;0.05). The expression of AMPK protein in the normal control group and BYHWR group was no significant difference between the two groups (P&gt;0.05). Conclusion: BYHWR group has certain resistance exercise fatigue, and its mechanisms potentially increase AMPK protein expression in skeletal muscle, reduce mitochondrial damage, and strengthen the function of mitochondria

Метаболическая активность митохондрий корней гороха в условиях моделированной микрогравитации

Наведено дані досліджень впливу кліностатування на метаболічну активність мітохондрій, ізольованих із коренів 5-добових проростків гороху (Pisum sativum L). Встановлено збільшення швидкості окиснення в стані 3 малату+глутамату та екзогенного НАДН, а також значення коефіцієнта дихального контролю одночасно зі зниженням відношення АДФ/О порівняно з контролем. Висловлено припущення, що такі зміни характеру дихання є наслідком адаптації метаболічної системи мітохондрій до умов кліностатування.The effect of clinorotation on the respiration of mitochondria isolated from roots of pea 5-day-old seedlings has been examined. An increase in the rate of oxidation of malate and NADH in state 3 is detected. A respiratory control ratio is also increased simultaneously with a decrease in the efficiency of oxidative phosphorylation. Such character of mitochondrial respiration under simulated microgravity is supposed to be a consequence of the adaptation to these conditions

Manipulation of Mitochondria Dynamics Reveals Separate Roles for Form and Function in Mitochondria Distribution

Mitochondria shape is controlled by membrane fusion and fission mediated by mitofusins, Opa1, and Drp1, whereas mitochondrial motility relies on microtubule motors. These processes govern mitochondria subcellular distribution, whose defects are emphasized in neurons because of their polarized structure. We have studied how perturbation of the fusion/fission balance affects mitochondria distribution in Drosophila axons. Knockdown of Marf or Opa1 resulted in progressive loss of distal mitochondria and in a distinct oxidative phosphorylation and membrane potential deficit. Downregulation of Drp1 rescued the lethality and bioenergetic defect caused by neuronal Marf RNAi, but induced only a modest restoration of axonal mitochondria distribution. Surprisingly, Drp1 knockdown rescued fragmentation and fully restored aberrant distribution of axonal mitochondria produced by Opa1 RNAi; however, Drp1 knockdown did not improve viability or mitochondria function. Our data show that proper morphology is critical for proper axonal mitochondria distribution independent of bioenergetic efficiency. The health of neurons largely depends on mitochondria function, but does not depend on shape or distribution. Trevisan et al. separate the independent contribution of form and function in determining the distribution of mitochondria in axons. They show that morphology is crucial for proper axonal mitochondria distribution, independent of their bioenergetic efficiency. However, the health of neurons depends on mitochondria function, but does not depend on shape or distributio

SENNA PLANT INDUCES DISRUPTION ON THE MITOCHONDRIA OF HYMENOLEPIS DIMINUTA

Objective: The present study aims at observing the effects of three species of Senna plants, viz. Senna alata, S. alexandrina and S. occidentalis on the ultrastructure of the mitochondria of the tapeworm, Hymenolepis diminuta.Methods: Worms were treated with leaf extracts of the three plant species with a standard dose concentration of 40 mg/ml and keeping one group of parasites in phosphate buffer saline (PBS) as a control. The parasites from control and treated medium were simultaneously removed after the loss of motility and fixed in 3% gluteraldehyde. They were processed for ultramicrograph observations of the worm's mitochondria with special reference to shape and cytoplasm through transmission electron microscopy (TEM).Results: The study showed loss of architecture in the outer mitochondrial membrane. The inner membrane became distorted with inconspicuous cristae and matrix became lucent in all plant treated worms compared to control. Amongst the three plants, S. alexandrina showed overall distortion in the shape leading to bloating of mitochondria.Conclusion: The observations depict pronounced alterations in the structure of mitochondria, thus signifying depletion of energy synthesis in the parasite. Senna plant could, therefore, be a potent anthelmintic alternative

Amyloid Β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer's Disease-Related Models.

Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria-ER contact sites (MERCS) are altered in Alzheimer's disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER-mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD