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Age is a prominent risk factor for cardiometabolic disease, often leading to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction exclusively resulting from physiological aging remain elusive. Previous research demonstrated age‐related functional alterations in baboons, analogous to humans. The goal of this study is to identify early cardiac molecular alterations preceding functional adaptations, shedding light on the regulation of age‐associated changes. Unbiased transcriptomics of left ventricle samples are performed from female baboons aged 7.5–22.1 years (human equivalent ≈30–88 years). Weighted‐gene correlation network and pathway enrichment analyses are performed, with histological validation. Modules of transcripts negatively correlated with age implicated declined metabolism‐oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty‐acid β‐oxidation. Transcripts positively correlated with age suggested a metabolic shift toward glucose‐dependent anabolic pathways, including hexosamine biosynthetic pathway (HBP). This shift is associated with increased glycosaminoglycan synthesis, modification, precursor synthesis via HBP, and extracellular matrix accumulation, verified histologically. Upregulated extracellular matrix‐induced signaling coincided with glycosaminoglycan accumulation, followed by cardiac hypertrophy‐related pathways. Overall, these findings revealed a transcriptional shift in metabolism favoring glycosaminoglycan accumulation through HBP before cardiac hypertrophy. Unveiling this metabolic shift provides potential targets for age‐related cardiac diseases, offering novel insights into early age‐related mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: Diabetes mellitus (DM) impairs wound healing. The aim was to determine whether DM influences mitochondrial respiration in wounded skin (WS) and non‐wounded skin (NWS), in a pre‐clinical wound healing model of streptozotocin (STZ)‐induced diabetes. Methods: Six weeks after diabetes induction, two wounds were created in the back of C57BL/J6 mice. Using high‐resolution respirometry (HRR), oxygen flux was measured, in WS and NWS, using two substrate‐uncoupler‐inhibitor titration protocols, at baseline (day 0), day 3 and 10 post‐wounding, in STZ‐DM and non‐diabetic (NDM) mice. Flux control ratios for the oxidative phosphorylation (OXPHOS) capacity were calculated. Results: A significant increase in mitochondrial respiration was observed in STZ‐DM skin compared to control skin at baseline. The OXPHOS capacity was decreased in WS under diabetes at day 3 post‐wounding (inflammation phase). However, at day 10 post‐wounding (remodeling phase), the OXPHOS capacity was higher in WS from STZ‐DM compared to NDM mice, and compared to NWS from STZ‐DM mice. A significant relative contribution of pyruvate, malate and glutamate (PMG) oxidation to the OXPHOS capacity was observed in WS compared to NWS from STZ‐DM mice, at day 10, while the relative contribution of fatty acid oxidation to the OXPHOS capacity was higher in NWS. The OXPHOS capacity is altered in WS from STZ‐DM compared to NDM mice across the healing process, and so is the substrate contribution in WS and NWS from STZ‐DM mice, at each time point. Conclusion: HRR may be a sensitive tool to evaluate the underlying mechanisms of tissue repair during wound healing. [ABSTRACT FROM AUTHOR]

Background: The consumption of high‐caloric diets strongly contributes to the development of non‐communicable diseases (NCDs), including cardiovascular disease, the leading cause of mortality worldwide. Exercise (along with diet intervention) is one of the primary non‐pharmacological approaches to promote a healthier lifestyle and counteract the rampant prevalence of NCDs. The present study evaluated the effects of exercise cessation after a short period training on the cardiac metabolic and mitochondrial function of female rats. Methods: Seven‐week‐old female Sprague–Dawley rats were fed a control or a high‐fat, high‐sugar (HFHS) diet and, after 7 weeks, the animals were kept on a sedentary lifestyle or submitted to endurance exercise for 3 weeks (6 days per week, 20–60 min/day). The cardiac samples were analysed 8 weeks after exercise cessation. Results: The consumption of the HFHS diet triggered impaired glucose tolerance, whereas the HFHS diet and physical exercise resulted in different responses in plasma adiponectin and leptin levels. Cardiac mitochondrial respiration efficiency was decreased by the HFHS diet consumption, which led to reduced ATP and increased NAD(P)H mitochondrial levels, which remained prevented by exercise 8 weeks after cessation. Exercise training‐induced cardiac adaptations in redox balance, namely increased relative expression of Nrf2 and downstream antioxidant enzymes persist after an eight‐week exercise cessation period. Conclusions: Endurance exercise modulated cardiac redox balance and mitochondrial efficiency in female rats fed a HFHS diet. These findings suggest that exercise may elicit cardiac adaptations crucial for its role as a non‐pharmacological intervention for individuals at risk of developing NCDs. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is an incurable neurodegenerative movement disorder. PD affects 2% of the population above 65 years old; however, with the growing number of senior citizens, PD prevalence is predicted to increase in the following years. Pathologically, PD is characterized by dopaminergic cell neurodegeneration in the substantia nigra, resulting in decreased dopamine levels in the nigrostriatal pathway, triggering motor symptoms. Although the pathological mechanisms leading to PD are still unclear, large evidence indicates that oxidative stress plays an important role, not only because it increases with age which is the most significant risk factor for PD development, but also as a result of alterations in several processes, particularly mitochondria dysfunction. The modulation of oxidative stress, especially using dietary mitochondriotropic antioxidants, represents a promising approach to prevent or treat PD. Although most mitochondria‐targeted antioxidants with beneficial effects in PD‐associated models have failed to show any therapeutic benefit in clinical trials, several questions remain to be clarified. Hereby, we review the role played by oxidative stress in PD pathogenesis, emphasizing mitochondria as reactive oxygen species (ROS) producers and as targets for oxidative stress‐related dysfunctional mechanisms. In addition, we also describe the importance of using dietary‐based mitochondria‐targeted antioxidants as a valuable strategy to counteract the deleterious effects of ROS in pre‐clinical and/or clinical trials of PD, pointing out their significance to slow, and possibly halt, the progression of PD. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease that affects motor neurons. This disease is associated with oxidative stress especially in mutant superoxide dismutase 1 (mutSOD1) patients. However, less is known for the most prevalent sporadic ALS form, due to a lack of disease models. Here, we studied oxidative stress profiles in lymphoblasts from ALS patients with mutSOD1 or unknown (undSOD1) mutations. Methods: mutSOD1 and undSOD1 lymphoblasts, as well as sex/age‐matched controls (3/group) were obtained from Coriell and divided into 46 years‐old‐men (C1), 46 years‐old‐women (C2) or 26/27 years‐old‐men (C3) cohorts. Growth curves were performed, and several parameters associated with redox homeostasis were evaluated, including SOD activity and expression, general oxidative stress levels, lipid peroxidation, response to oxidative stimulus, glutathione redox cycle, catalase expression, and activity, and Nrf2 transcripts. Pooled (all cohorts) and paired (intra‐cohort) statistical analyses were performed, followed by clustering and principal component analyses (PCA). Results: Although a high heterogeneity among lymphoblast redox profiles was found between cohorts, clustering analysis based on 7 parameters with high chi‐square ranking (total SOD activity, oxidative stress levels, catalase transcripts, SOD1 protein levels, metabolic response to mM concentrations of tert‐butyl hydroperoxide, glutathione reductase activity, and Nrf2 transcript levels) provided a perfect cluster segregation between samples from healthy controls and ALS (undSOD1 and mutSOD1), also visualized in the PCA. Conclusions: Our results show distinct redox signatures in lymphoblasts from mutSOD1, undSOD1 and healthy controls that can be used as therapeutic targets for ALS drug development. [ABSTRACT FROM AUTHOR]

Cell culture conditions highly influence cell metabolism in vitro. This is relevant for preclinical assays, for which fibroblasts are an interesting cell model, with applications in regenerative medicine, diagnostics and therapeutic development for personalized medicine, and the validation of ingredients for cosmetics. Given these cells' short lifespan in culture, we aimed to identify the best cell culture conditions and promising markers to study mitochondrial health and stress in normal human dermal fibroblasts (NHDF). We tested the effect of reducing glucose concentration in the cell medium from high glucose (HGm) to a more physiological level [low glucose medium (LGm)], or its complete removal and replacement by galactose [medium that forces oxidative phosphorylation (OXPHOSm)], always in the presence of glutamine and pyruvate. We have demonstrated that only with OXPHOSm was it possible to observe the selective inhibition of mitochondrial adenosine triphosphate (ATP) production. This reliance on mitochondrial ATP was accompanied by changes in oxygen consumption rate and extracellular acidification rate, oxidation of citric acid cycle substrates, fatty acids, lactate, and other substrates, increased mitochondrial network extension and polarization, the increased protein content of voltage‐dependent anion channel (VDAC) and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha and changes in several key transcripts related to energy metabolism. LGm did not promote significant metabolic changes in NHDF, although mitochondrial network extension and VDAC protein content were increased compared to HGm‐cultured cells. Our results indicate that short‐term adaptation to OXPHOSm is ideal for studying mitochondrial health and stress in NHDF. [ABSTRACT FROM AUTHOR]

Summary: The main purpose of this paper is to study fuel cell performance using an interdigitated flow field with intermediate channel blocks on the cathode side. Application of an intermediate block in the middle of the interdigitated flow channel is a very new idea aimed at increasing the performance of polymer membrane fuel cells, which in practice result in novel arrangements of interdigitated flow channels. A middle block is desirable because the change in flow channel is minimal, the cost of fabricating bipolar plates does not increase, and it leads to an increase in the transfer rate of reactants into the gas diffusion layer due to enhanced over‐rib flow pattern and direction. In this work, a three‐dimensional, isothermal, and two‐phase model is used to simulate the performance of such fuel cells. The polarization curves, the distribution of reactants on the cathode side, the distribution of liquid water, and the induced transverse flow were analyzed for three type of interdigitated flow fields along with parallel flow fields at reference conditions. The results showed that interdigitated flow fields with middle blocks lead to an increase in reactant transfer to the catalyst layer, an increase in reaction rate, and better removal of the resulting liquid water within the fuel cell. In the reference condition, in terms of maximum power density, the type I interdigitated flow field (without intermediate block) increased the net power by 8.2% compared to the parallel flow field, and the type II and III interdigitated flow fields also increased the power by 12.58% and 9.03%, respectively. At high current density, the type II interdigital flow field had the best performance in terms of enhancing the transfer of reactants to the catalyst layer and the expulsion of liquid water from that layer. [ABSTRACT FROM AUTHOR]

While FOIE GRAS' focus was on training early-stage researchers based on different NAFLD-centred projects, mtFOIE GRAS's objective was to promote inter-sectorial staff exchange between the different institutions involved, also revolving around NAFLD projects. Nonalcoholic fatty liver disease (NAFLD) has risen rapidly in parallel with the recent surge in hypertension and metabolic comorbidities, including obesity, type 2 diabetes mellitus (T2DM), hyperlipidaemia and metabolic syndrome.1 With significant population urbanization over the past 30 years, the mass consumption of highly processed ready-made food, rich in fructose, saturated fat and cholesterol, accompanied by environmental determinants (including air pollution and endocrine-disrupting chemicals2-4), is increasing in most European countries. NAFLD encompasses a full range of hepatic disorders from simple steatosis (nonalcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH), which can lead to cryptogenic cirrhosis and hepatocellular carcinoma (HCC). [Extracted from the article]

According to the 'multiple‐hit' hypothesis, several factors can act simultaneously in nonalcoholic fatty liver disease (NAFLD) progression. Increased nitro‐oxidative (nitroso‐oxidative) stress may be considered one of the main contributors involved in the development and risk of NAFLD progression to nonalcoholic steatohepatitis (NASH) characterized by inflammation and fibrosis. Moreover, it has been repeatedly postulated that mitochondrial abnormalities are closely related to the development and progression of liver steatosis and NAFLD pathogenesis. However, it is difficult to determine with certainty whether mitochondrial dysfunction or oxidative stress are primary events or a simple consequence of NAFLD development. On the one hand, increasing lipid accumulation in hepatocytes could cause a wide range of effects from mild to severe mitochondrial damage with a negative impact on cell fate. This can start the cascade of events, including an increase of cellular reactive nitrogen species (RNS) and reactive oxygen species (ROS) production that promotes disease progression from simple steatosis to more severe NAFLD stages. On the other hand, progressing mitochondrial bioenergetic catastrophe and oxidative stress manifestation could be considered accompanying events in the vast spectrum of abnormalities observed during the transition from NAFL to NASH and cirrhosis. This review updates our current understanding of NAFLD pathogenesis and clarifies whether mitochondrial dysfunction and ROS/RNS are culprits or bystanders of NAFLD progression. [ABSTRACT FROM AUTHOR]

Embryonic and foetal development are critical periods of development in which several environmental cues determine health and disease in adulthood. Maternal conditions and an unfavourable intrauterine environment impact foetal development and may programme the offspring for increased predisposition to metabolic diseases and other chronic pathologic conditions throughout adult life. Previously, non‐communicable chronic diseases were only associated with genetics and lifestyle. Now the origins of non‐communicable chronic diseases are associated with early‐life adaptations that produce long‐term dysfunction. Early‐life environment sets the long‐term health and disease risk and can span through multiple generations. Recent research in developmental programming aims at identifying the molecular mechanisms responsible for developmental programming outcomes that impact cellular physiology and trigger adulthood disease. The identification of new therapeutic targets can improve offspring's health management and prevent or overcome adverse consequences of foetal programming. This review summarizes recent biomedical discoveries in the Developmental Origins of Health and Disease (DOHaD) hypothesis and highlight possible developmental programming mechanisms, including prenatal structural defects, metabolic (mitochondrial dysfunction, oxidative stress, protein modification), epigenetic and glucocorticoid signalling‐related mechanisms suggesting molecular clues for the causes and consequences of programming of increased susceptibility of offspring to metabolic disease after birth. Identifying mechanisms involved in DOHaD can contribute to early interventions in pregnancy or early childhood, to re‐set the metabolic homeostasis and break the chain of subsequent events that could lead to the development of disease. [ABSTRACT FROM AUTHOR]

Background: Changes in the nutritional environment in utero induced by maternal obesity (MO) lead to foetal metabolic dysfunction predisposing offspring to later‐life metabolic diseases. Since mitochondria play a crucial role in hepatic metabolism and function, we hypothesized that MO prior to conception and throughout pregnancy programmes foetal sheep liver mitochondrial phenotype. Material and methods: Ewes ate an obesogenic diet (150% requirements; MO), or 100% requirements (CTR), from 60 days prior to conception. Foetal livers were removed at 0.9 gestation. We measured foetal liver mitochondrial DNA copy number, activity of superoxide dismutase, cathepsins B and D and selected protein content, total phospholipids and cardiolipin and activity of mitochondrial respiratory chain complexes. Results: A significant decrease in activities of mitochondrial complexes I, II‐III and IV, but not aconitase, was observed in MO. In the antioxidant machinery, there was a significant increase in activity of total superoxide dismutase (SOD) and SOD2 in MO. However, no differences were found regarding autophagy‐related protein content (p62, beclin‐I, LC3‐I, LC3‐II and Lamp2A) and cathepsin B and D activities. A 21.5% decrease in total mitochondrial phospholipid was observed in MO. Conclusions: The data indicate that MO impairs foetal hepatic mitochondrial oxidative capacity and affects total mitochondrial phospholipid content. In addition, MO affects the regulation of foetal liver redox pathways, indicating metabolic adaptations to the higher foetal lipid environment. Consequences of in utero programming of foetal hepatic metabolism may persist and compromise mitochondrial bioenergetics in later life, and increase susceptibility to metabolic diseases. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is currently the most prevalent cause of chronic liver disease and constitutes a major risk for the development of end-stage liver disease. 2012; 2 (3): 31 - 37. 5 Rosenberg M, Ferguson R. Maintaining relevance: an evaluation of health message sponsorship at Australian community sport and arts events. [Extracted from the article]

Purpose: The positional analysis of hepatic glycogen enrichment from deuterated water (2H2O) by 2H NMR has been applied previously to resolve the contributions of glucose and fructose to glycogen synthesis in rodents fed a high sucrose diet. To further validate this method, this analysis was applied to mice fed with synthetic diets whose carbohydrate components consisted solely of either glucose or fructose. Methods: Eight glucose‐fed and 12 fructose‐fed mice were given 2H2O followed by ad libitum feeding overnight. Mice were then euthanized, hepatic glycogen was isolated and derivatized to monoacetone glucose, and 2H‐enrichment of positions 2, 5, and 6S were measured by 2H NMR. From these data, the fraction of overnight glycogen appearance from the direct pathway and/or glycogen cycling and indirect pathway were estimated. Indirect pathway fractions were resolved into Krebs cycle and triose‐phosphate sources—the latter including contributions from fructose metabolism. Results: After overnight feeding, the fraction of overnight glycogen appearance derived from direct pathway and/or glycogen cycling in glucose‐fed‐mice was 63 ± 1%. For the indirect pathway, Krebs cycle and triose‐phosphate sources contributed 22 ± 1% and 15 ± 1%, respectively. For fructose‐fed‐mice, glycogen appearance was dominated by triose‐phosphate sources (60 ± 2%) with lesser contributions from Krebs cycle (14 ± 1%) and direct and/or glycogen cycling (26 ± 2%). Conclusions: 2H NMR analysis of hepatic glycogen 2H enrichment from 2H2O provides realistic profiles of dietary glucose and fructose contributions to hepatic glycogen synthesis in mice fed with diets containing 1 or the other sugar as the sole carbohydrate source. [ABSTRACT FROM AUTHOR]

Abstract: Background: Expression of TRAP1, a member of the HSP90 chaperone family, has been implicated in tumour protective effects, based on its differential mitochondrial localization and function. Design: This work was designed to provide new insights into the pathways involved in TRAP1‐provided cytoprotection on NSCLC. For this, TRAP1‐depleted A549 human NSCLC cells and MRC‐5 normal lung fibroblasts were produced using a siRNA approach and main cellular quality control mechanisms were investigated. Results: TRAP1‐depleted A549 cells displayed decreased cell viability likely due to impaired mitochondrial function including decreased ATP/AMP ratio, oxygen consumption and membrane potential, as well as increased apoptotic indicators. Furthermore, the negative impact of TRAP1 depletion on mitochondrial function was not observed in normal MRC‐5 lung cells, which might be due to the differential intracellular localization of the chaperone in tumour versus normal cells. Additionally, A549 TRAP1‐depleted cells showed increased autophagic flux. Functionally, autophagy inhibition resulted in decreased cell viability in both TRAP1‐expressing and TRAP1‐depleted tumour cells with minor effects on MRC‐5 cells. Conversely, autophagy stimulation decreased cell viability of both A549 and MRC‐5 TRAP1‐expressing cells while in A549 TRAP1‐depleted cells, increased autophagy augmented viability. Conclusions: Our results show that even though TRAP1 depletion affects both normal MRC‐5 and tumour A549 cell proliferation, inhibition of autophagy per se led to a decrease in tumour cell mass, while having a reduced effect on the normal cell line. The strategy of targeting TRAP1 in NSCLC shows future potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Background Patients with diabetes are at a high risk of developing both micro- and macrovascular disease. Hyperglycaemia seems to be the main factor in the pathogenesis of diabetic cardiomyopathy, often based on increased oxidative stress. Carvedilol, a β-adrenergic blocker, has intrinsic antioxidant properties and was previously described to be effective in the protection of cardiac mitochondria against oxidative stress. The objective of this study was to evaluate the effect of carvedilol on hyperglycaemia-induced oxidative damage and mitochondrial abnormalities in cardiac and skeletal muscle in streptozotocin-treated rats. Materials and methods Body mass, blood glucose, the level of protein carbonylation, caspase-9- and caspase-3-like activities, mitochondrial proteins, the status of antioxidant defence system and stress-related proteins were evaluated in streptozotocin vs streptozotocin + carvedilol (1 mg/kg/day)-treated rats. Results The results showed that carvedilol decreased blood glucose in streptozotocin-treated animals. Content of catalase in the heart and SOD2, SOD1 and catalase in skeletal muscle were increased by carvedilol treatment in streptozotocin-treated animals. At this particular time point, streptozotocin-induced hyperglycaemia did not cause caspase activation or increase in protein carbonylation status. The data showed that carvedilol increased the level of antioxidant enzymes, what may contribute to preserve cell redox balance during hyperglycaemia. We also showed here for the first time that carvedilol effects on streptozotocin-treated rats are tissue dependent, with a more predominant effect on skeletal muscle. Conclusions Based on data showing modulation of the antioxidant network in the heart, carvedilol may be beneficial in diabetic patients without advanced disease complications, delaying their progression. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is the fourth most common cancer in men and the sixth leading cause of death in Algeria. To examine the relationship between lifestyle factors, including diet, and family history and PC risk, a case-control study was performed in an eastern Algerian population, comprising 90 patients with histologically confirmed PC and 190 controls. Data collection was carried out through a structured questionnaire and statistical analysis was performed to evaluate the different variables. The data showed that consumption of lamb and beef meat and high intake of animal fat and dairy products increased PC risk. Seven to thirteen vegetables servings per week and fourteen or more servings decreased PC risk by 62% and 96%, respectively. Seven to fourteen fruit servings per week decrease PC risk by 98%. Green tea consumption reduced the risk of PC but the results were statistically borderline. Increased risk was observed for individuals with family history of PC in first and in second degree. A positive strong association was also found for alcohol and smoking intake and a dose-response relationship existed for quantity and history of smoking. This study suggests that dietary habits, lifestyle factors, and family history have influence on the development of PC in Algerian population. [ABSTRACT FROM AUTHOR]

Background Bisphenol A (BPA) is one of the most widely produced chemicals worldwide and is often used in the production of food and beverage containers. As a result of BPA contact with food, drink and toiletries, its ingestion and absorption by humans has been growing. The industrialization and modern lifestyles brought a constant exposure to several health-disturbing compounds and ushered a new era of chronic diseases. The endocrine disruptor potential of BPA is well known, but the research around its epigenotoxic effects raised further concerns whether chronic exposure to BPA can contribute to chronic human illness, including cancer in hormone-sensitive organs. Materials and methods Focusing on computerized databases, we reviewed original and review articles which elucidate and link some of the information already available about BPA and related epigenetic alterations. Results A number of studies indicate that short-term administration of low or high-doses of BPA may be associated with an increased risk of epigenetic modifications, increasing the risk for carcinogenesis. However, it is clear that more studies considering real daily exposures are essential to define a real tolerable daily intake and to tighten\xA0up\xA0manufactory regulations. Conclusion In this review, we highlight some evidences suggesting a relationship between BPA exposure, genotoxic activity and epigenetic modifications, which may prime for carcinogenesis. [ABSTRACT FROM AUTHOR]

Background Cancer cells are widely recognized for being able to adapt their metabolism towards converting available nutrients into biomass to increase proliferation rates. Materials and methods We will review a series of nuclear magnetic resonance ( NMR)-based stable isotope tracer methodologies for probing cancer metabolism. Results The monitoring of such adaptations is of the utmost importance to unravel cancer metabolism and tumour growth. Several major metabolic targets have been recognized as promising foci and have been addressed by multiple studies in recent years. In this work are presented strategies to quantify glycolysis, pentose phosphate pathway, Krebs cycle turnover and de novo lipogenesis by NMR isotopomer analysis. Conclusions Being able to adequately define the interplay between metabolic pathways allows the monitoring of their prevalence in tissues and such information is critical for an accurate knowledge of the metabolic distinctive nature of tumours towards devising more efficient antitumorigenic strategies. Discussed methodologies are currently available in the literature, but to date, no single review has compiled all their possible uses, particularly in an interdependent perspective. [ABSTRACT FROM AUTHOR]

The complexes [(η5-C5H4-CO-R)Mo(CO)2(η3-C3H5)] [R = OH ( 1), Phe-OMe ( 2)] have been examined as guests for the cyclodextrin (CD) hosts β-CD and heptakis(2,3,6-tri- O-methyl)-β-CD (TRIMEB), and the resultant inclusion compounds have been characterised in the solid state by elemental and thermogravimetric analyses, powder X-ray diffraction, 13C{1H} cross-polarisation (CP) magic angle spinning (MAS) NMR spectroscopy and FTIR spectroscopy. Single-crystal X-ray analysis of 1 shows that the unit cell contains centrosymmetric supramolecular dimers comprising two dicarbonyl complexes linked through hydrogen-bonding interactions involving the carboxylic acid groups. In screening tests for antiproliferative effects, the CD adducts containing 1 displayed enhanced antitumour activity against mouse melanoma (when compared with nonincluded 1), while showing minimal activity towards human adenocarcinoma and nontumour rat myoblast cell lines. TRIMEB encapsulation resulted in a predominant toxic effect on tumour cells versus the non-neoplastic myoblast cells. [ABSTRACT FROM AUTHOR]

Background Several strategies have been developed to counteract liver injury as a consequence of nonsteroid anti-inflammatory drugs toxicity. Here, we aimed to determine whether physical exercise results in liver mitochondrial protection against in vitro diclofenac toxicity. Material and methods Male adult Sprague-Dawley rats were divided into sedentary, 12-week endurance training ( ET) and voluntary activity ( VPA). In vitro liver mitochondrial function as assessed by oxygen consumption, transmembrane electric potential (ΔΨ) and susceptibility to the mitochondrial permeability transition pore ( MPTP) was evaluated in the absence and presence of diclofenac. Mitochondrial oxidative stress markers [Mn SOD, aconitase, - SH and MDA, SIRT3, p66shc(Ser36)/p66shc ratio] and apoptotic signalling (caspases 3, 8 and 9, Bax, Bcl-2 and CypD) were assessed. Content of OXPHOS components and qualitative liver morphological evaluation were assessed. Results Despite no effects of ET and VPA on basal liver mitochondrial oxygen consumption or ΔΨ endpoints, exercised animals showed lower susceptibility to MPTP. Diclofenac-induced decrease in ΔΨ, increased state 4 respiration and susceptibility to MPTP opening were all prevented by exercise. Under untreated conditions, VPA group showed higher aconitase activity, while ET decreased MDA and increased Bax content. VPA decreased p66shc(Ser36), complex III and V OXPHOS subunits. Both ET and VPA increased complex IV OXPHOS subunit, and SIRT3 and Bcl-2 content and decreased caspase 9 activity. Unexpectedly, ET and VPA decreased ANT. Conclusions Both chronic physical exercise models augmented the resistance to in vitro diclofenac-induced mitochondrial alterations, including increased MPTP susceptibility, possibly by modulating oxidative stress and MPTP regulators. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is an anticancer anthracycline that presents a dose-dependent and cumulative cardiotoxicity as one of the most serious side effects. Several hypotheses have been advanced to explain DOX cardiac side effects, which culminate in the development of life-threatening cardiomyopathy. One of the most studied mechanisms involves the activation of DOX molecule into a more reactive semiquinone by mitochondrial Complex I, resulting in increased oxidative stress. The present review describes and critically discusses what is known about some of the potential mechanisms of DOX-induced cardiotoxicity including mitochondrial oxidative damage and loss of cardiomyocytes. We also discuss alterations of mitochondrial metabolism and the unique characteristics of DOX delayed toxicity, which can also interfere on how the cardiac muscle handles a 'second-hit stress.' We also present pharmaceutical and nonpharmaceutical approaches that may decrease DOX cardiac alterations in animal models and humans and discuss the limitations of each strategy. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease, encompassing hepatic steatosis, nonalcoholic steatohepatitis ( NASH), fibrosis and cirrhosis, is a significant health problem associated with modern lifestyle, based on caloric overconsumption and physical inactivity. Although the mechanisms associated with progression from the 'benign' steatosis to NASH are still elusive, mitochondrial dysfunction seems to play an important role in this degenerative process. Degeneration of mitochondrial function during NASH has been associated with impaired β-oxidation, oxidative phosphorylation and increased reactive oxygen species production, contributing to hepatocyte death and inflammatory response. Despite the fact that several therapeutic approaches can be used in the context of NASH, including insulin-sensitizing agents, anti-obesity drugs, lipid-lowering drugs or mitochondrial-targeted drugs, dietary and physical activity are still the most effective strategies. In fact, active lifestyles decrease insulin resistance and body weight and result in decreased histological signs of liver injury. In fatty liver, physical activity prevents the disease progression through mitochondrial adaptations, namely by increasing cytochrome c content, enzyme activities and fatty acid oxidation, which are lost after some days of physical inactivity. However, less is known about the effect of physical activity on NASH-associated mitochondrial dysfunction. After a brief characterization of NASH and its association with liver mitochondrial (dys)function, the present review addresses the impact of physical (in)activity on NASH and, particularly, the possible contribution of active lifestyles to the modulation of liver mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

The Syrian hamster Harderian gland exhibits sexually dimorphic porphyrin biosynthesis, wherein the female glands display an extraordinarily high concentration of porphyrins. Damage derived from this production of porphyrins, mediated by reactive oxygen species, causes the glands to develop autophagic processes, which culminate in detachment-derived cell death; these cells normally play a central role in the secretory activity of the gland. The main aim of this study was to analyze how a change in the redox state impacts autophagy. Female Syrian hamsters were treated daily with melatonin (25 μg, subcutaneously) at ZT 10 for 1-2 months (N-acetyl-5-methoxytryptamine), an endogenous antioxidant that ameliorates the deleterious effects of free radicals via a variety of mechanisms. The length of treatment affected the redox balance, the autophagy machinery, and the activation of p53 and NF-κB. One-month treatment displaces redox balance to the antioxidant side, promotes autophagy through a p53-mediated mechanism, and increases cell detachment. Meanwhile, 2-month treatment restores redox balance to the oxidant side, activates NF-κB reducing autophagy to basal levels, increases number of type II cells, and reduces number of detached cells. Our results conclude that the redox state can modulate autophagy through redox-sensitive transcriptions factors. Additionally, these findings support a hypothesis that ascribes differences in the autophagic-lysosomal pathway to epithelial cell types, thereby restricting detachment-induced autophagic cell death to epithelial cell type I. [ABSTRACT FROM AUTHOR]

Menopause is a consequence of the normal aging process in women. This fact implies that the physiological and biochemical alterations resulting from menopause often blur with those from the aging process. It is thought that menopause in women presents a higher risk for cardiovascular disease although the precise mechanism is still under discussion. The postmenopause lipid profile is clearly altered, which can present a risk factor for cardiovascular disease. Due to the role of mitochondria in fatty acid oxidation, alterations of the lipid profile in the menopausal women will also influence mitochondrial fatty acid oxidation fluxes in several organs. In this paper, we propose that alterations of mitochondrial bioenergetics in the heart, consequence from normal aging and/or from the menopausal process, result in decreased fatty acid oxidation and accumulation of fatty acid intermediates in the cardiomyocyte cytosol, resulting in lipotoxicity and increasing the cardiovascular risk in the menopausal women. [ABSTRACT FROM AUTHOR]

Incident solar radiation has changed in the last 50 years, as an initial dimming trend from 1960 to approximately 1990 was followed by an ongoing brightening period, with concomitant changes in the partitioning between direct and diffuse fractions. Such radiation changes are expected to affect the global water cycle. In this study, we use the Community Land Model ( CLM) to perform global offline simulations for the period 1948-2004 and study the effects of solar forcing changes on trends in evapotranspiration and runoff. The modeled components of the hydrologic cycle respond strongly to the imposed radiation changes in several regions, especially in the tropics. Exceptions are regions with soil moisture-limited evapotranspiration regime, such as the U.S. Great Plains. In Europe and the Eastern US, the imposed 7 W m−2 solar dimming for 1960-1990 leads to an evapotranspiration reduction of 1.5 W m−2 or approximately 5% of the mean and an enhancement of runoff by equal percentage. In these regions, the imposed 6 W m−2 solar brightening leads to a 3 W m−2 increase of evapotranspiration in 1990-2004, and a runoff reduction of between 7 and 10% of the mean. Additional simulations investigating the impact of higher diffuse radiation fraction during 1960-1990 suggest mostly an increase of evapotranspiration in the tropics of 2.5 W m−2 (3% of mean) due to increased photosynthesis from shaded leaves, but with smaller opposite effects elsewhere because of lower ground evaporation. The runoff trend resulting from the imposed radiation/aerosols effect is of the same sign and approximate relative magnitude (but larger absolute magnitude) as those calculated, in various studies, for other potential drivers of runoff change such as climate, CO2, or land use. These results thus strengthen the claim that radiation effects on runoff are not to be neglected. Understanding the impacts of radiation on the water cycle will affect projections of river flow and freshwater availability for human consumption. [ABSTRACT FROM AUTHOR]

In conditions of ischemia/reperfusion (I/R), the relative use of all available substrates by the heart has a significant effect on the recovery of the organ. This substrate preference in perfused hearts is influenced by ischemia. We followed the metabolic fate of [U-13C]glucose and [3-13C]lactate in hearts preserved in Celsior (Cs) and histidine buffer solution (HBS) for 4 or 6 h and subsequently perfused with a Krebs-Henseleit solution (KH) containing [U-13C]glucose and [3-13C]lactate. We also assessed gender-specific metabolic modulation in our I/R experimental conditions. Hearts from male and female Wistar rats (6-8 weeks) were subjected to moderate (0-240 min) or prolonged (240-360 min) cold ischemia whilst immersed in Cs and HBS, and perfused for 30 min with KH containing [U-13C]glucose and [3-13C]lactate. After perfusion, hearts were freeze-clamped and metabolites were extracted for 13C NMR isotopomer analysis. In control conditions, there were no differences with regard to lactate origin in hearts from males and females. After 6 h of preservation in Cs, lactate origin was mostly from [U-13C]glucose in hearts from males and from [3-13C]lactate in hearts from females. During the 6 h of organ preservation in HBS, the lactate pool showed a strong contribution from unenriched sources in male hearts and from [U-13C]glucose in female hearts. The glutamate C2/C4 ratio was stable or increased in hearts from females after I/R, and the alanine index increased in hearts from both males and females. Octanoate was, as predicted, the preferential substrate during perfusion. Glucose and lactate suffer a distinct metabolic fate in our I/R conditions, which is related to the cardioplegic solution used during organ storage, and the gender. Hearts from females appear to be less sensitive to I/R injury, and heart preservation in HBS proved to be effective in enhancing anaplerosis during perfusion, especially in hearts from females. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (4): 319–329 Background Hyperglycaemia-resulting in mitochondrial bioenergetics’ complications is associated with skeletal muscle dysfunction. The aim of this work was to analyse the effect of long-term severe hyperglycaemia on gastrocnemius mitochondrial bioenergetics, with special relevance on the susceptibility to mitochondrial permeability transition pore (MPTP) opening. Methods Sixteen adult (6- to 8-week-old) male Wistar rats were randomly divided into two groups ( n = 8/group): control and diabetic. A single dose (50 mg kg−1) of streptozotocin (STZ) was administrated i.p. to induce hyperglycaemia. In vitro mitochondrial oxygen consumption rates, membrane potential (Δψ) fluctuations, MPTP induction as followed by osmotic swelling and extramitochondrial calcium movements and caspase 9-like activity were evaluated 18 weeks after STZ treatment. Results STZ treatment induced an increase in state 4 and a decrease in the respiratory control ratio with complex I substrates ( P < 0·05), whereas no differences were observed using complex II substrates. In both conditions, no significant differences were observed when measuring maximal Δψ, although STZ treatment increased Δψ during ADP-induced depolarization when succinate was used. The most critical result was that muscle mitochondria isolated from STZ-treated rats showed a decrease susceptibility to MPTP induction by calcium, as followed by two different experimental protocols. Interestingly, the protection was accompanied by a decrease in muscle caspase 9-like activity. Conclusions These data demonstrate that 18 weeks of STZ treatment lead to a decrease in gastrocnemius mitochondrial respiratory control ratio and to decreased calcium-dependent mitochondrial MPTP. Results from this and other works suggest that mitochondrial effects of hyperglycaemia are time and organ specific. [ABSTRACT FROM AUTHOR]

Abstract: To address the possibility that mitochondria are involved in the age-related loss of testicular function, we characterized mitochondrial bioenergetics in rat testis. A peak of mitochondrial functionality was detected in adult animals, with a decrease in both young and older animals. In the latter group a decrease in mitochondrial function was matched with an increase in proton leak and expression and activity of uncoupling protein 2 (UCP2), suggesting that proton leak may be involved in managing age-dependent mitochondrial dysfunction. [Copyright &y& Elsevier]

Nonsteroidal anti-inflammatory drugs have been associated with hepatotoxicity in susceptible patients. One such example is nimesulide, a preferential cyclooxygenase 2-inhibitor, widely used for the treatment of inflammation and pain. It was suggested that nimesulide could exert its hepatotoxicity by altering hepatic mitochondrial function, which was demonstrated in vitro. The objective of this study was to verify whether liver mitochondria isolated from rats treated with doses of nimesulide well above therapeutic levels possessed decreased calcium tolerance and oxidative phosphorylation, which indicates in vivo nimesulide mitochondrial toxicity. Male and female rats received nimesulide or its vehicle twice daily, for 5 days, and were killed on the seventh day for the isolation of liver mitochondria. Mitochondrial respiration, transmembrane electric potential, and calcium tolerance were characterized in all experimental groups. Nimesulide had no effect on liver mitochondrial function. Indexes of mitochondrial integrity, calcium loading capacity, and oxidative phosphorylation efficiency were unchanged between liver mitochondria from treated and control animals. In the animals tested, no evidence of degraded mitochondrial function due to nimesulide administration could be found. The results corroborate the notion that despite recognized in vitro mitochondrial toxicity, nimesulide does not cause detectable mitochondrial dysfunction in Wistar rats, even when administered in much higher concentrations than those known to have anti-inflammatory effects. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:53-61, 2007; Published online in Wiley InterScience (). DOI 10.1002/jbt.20159 [ABSTRACT FROM AUTHOR]

Abstract: Mitochondria from Zucker fatty (ZF) rats (a model for fatty liver disease) showed a delay in the repolarization after a phosphorylative cycle and a decrease on state 3 respiration, suggesting alterations at the phosphorylative system level. The ATPase activity showed no differences between control and ZF rats, implying alterations in other components of the phosphorylative system. A pronounced depletion in the content of the adenine nucleotide translocator (ANT) was observed by Western blotting, while no alterations were found in the mitochondrial voltage-dependent anion channel content. These data suggest that hepatic accumulation of fat impairs mitochondrial function, reflecting the loss of oxidative phosphorylation capacity caused by a decrease in the ANT content. [Copyright &y& Elsevier]

Background: Renal disease associated with diabetes mellitus is a major problem among diabetic patients. The role of mitochondria in the pathogenesis of diabetes has received a large amount of attention in the last years, but many aspects of this subject are still poorly understood. In the present study, we studied the susceptibility of the mitochondrial permeability transition (MPT) on kidney mitochondria from the Goto-Kakizaki (GK) rat, an animal model featuring physiological and pathological alterations characteristic of type 2 diabetes.Methods: Kidney mitochondria were isolated by differential centrifugations; mitochondrial electric transmembrane potential and calcium loading capacity were evaluated with a TPP+-selective electrode and with a calcium-sensitive fluorescent probe. Coenzyme Q9, Q10 and vitamin E were evaluated by high-performance liquid chromatography (HPLC).Results: Kidney mitochondria from the diabetic animals had an increased susceptibility to the induction of the MPT by calcium. We observed a loss of calcium-loading capacity and a higher calcium-induced mitochondrial depolarization. Vitamin E and coenzyme Q9 were also increased in kidney mitochondria from GK rats.Conclusions: The results show an enhanced MPT activation in kidney mitochondria from GK rats, which lead us to suggest that this condition may be one major alteration triggered by chronic diabetes in kidney cells, ultimately leading to cell dysfunction. [ABSTRACT FROM AUTHOR]

Cardiac dysfunction is associated with diabetes. It was previously shown that heart mitochondria from diabetic rats have a reduced calcium accumulation capacity. The objective of this work was to determine whether the reduction in calcium accumulation by cardiac mitochondria from diabetic rats is related to an enhanced susceptibility to induction of the mitochondrial permeability transition. Streptozotocin-induced diabetic rats were used as a model to study the alterations caused by diabetes in the permeability transition, 21 days after streptozotocin administration. Heart mitochondria were isolated to evaluate respiratory parameters and susceptibility to the calcium-dependent permeability transition. Our results show that streptozotocin diabetes facilitates the mitochondrial permeability transition in cardiac mitochondria, resulting in decreased mitochondrial calcium accumulation. We also observed that heart mitochondria from diabetic rats had depressed oxygen consumption during the phosphorylative state. The reduced mitochondrial calcium uptake observed in heart mitochondria from diabetic rats is related to an enhanced susceptibility to the permeability transition rather than to damage to the calcium uptake machinery. [Copyright &y& Elsevier]

Background: Hepatic ischemia/reperfusion (I/R) injury is characterized by features such as cholestasis. Mitochondria become susceptible to damage during ischemia and after reperfusion. The aim of this study was to determine if silymarin and tauroursodeoxycholic acid (TUDC), would prevent impairment of liver mitochondrial function following I/R injury. Methods: Livers of male Wistar rats were subjected to 45 min of hepatic ischemia. During the 90 min of reperfusion, livers were perfused with either vehicle, silymarin, or TUDC. Changes in membrane potential, mitochondrial respiration as well as susceptibility to mitochondrial permeability transition (MPT) induction were evaluated and endogenous adenine nucleotides were measured. Results: In rats subjected to I/R, compared with the control group, a severe impairment of mitochondrial bioenergetics was observed. State 3 respiration was decreased and state 4 enhanced, associated with lower membrane potential developed following succinate energization. An increased susceptibility to MPT induction by calcium/phosphate was also observed. The effects of I/R injury were ameliorated in the presence of silymarin but not TUDC. Similarly, ATP levels following I/R were lower, in comparison with the control group and the silymarin treatment but not TUDC. Conclusion: Thus, silymarin, but not TUDC, prevents the most significant changes that occur in mitochondria during I/R, and probably, the associated cell dysfunction, through their central role in cellular bioenergetics. [Copyright &y& Elsevier]

Heart disease is the leading cause of mortality in developed countries, and novel regenerative procedures are warranted. Direct cardiac conversion (DCC) of adult fibroblasts can create induced cardiomyocytes (iCMs) for gene and cell‐based heart therapy, and in addition to holding great promise, still lacks effectiveness as metabolic and age‐associated barriers remain elusive. Here, by employing MGT (Mef2c, Gata4, Tbx5) transduction of mouse embryonic fibroblasts (MEFs) and adult (dermal and cardiac) fibroblasts from animals of different ages, we provide evidence that the direct reprogramming of fibroblasts into iCMs decreases with age. Analyses of histone posttranslational modifications and ChIP‐qPCR revealed age‐dependent alterations in the epigenetic landscape of DCC. Moreover, DCC is accompanied by profound mitochondrial metabolic adaptations, including a lower abundance of anabolic metabolites, network remodeling, and reliance on mitochondrial respiration. In vitro metabolic modulation and dietary manipulation in vivo improve DCC efficiency and are accompanied by significant alterations in histone marks and mitochondrial homeostasis. Importantly, adult‐derived iCMs exhibit increased accumulation of oxidative stress in the mitochondria and activation of mitophagy or dietary lipids; they improve DCC and revert mitochondrial oxidative damage. Our study provides evidence that metaboloepigenetics plays a direct role in cell fate transitions driving DCC, highlighting the potential use of metabolic modulation to improve cardiac regenerative strategies. [ABSTRACT FROM AUTHOR]

The article reports on an article titled, "The cholecystokinin-1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice," by H.H. Wang et al., published in a previous issue of the "European Journal of Clinical Investigation." The article obtained the highest consideration by the Council of the European Society of Clinical Investigation (ESCI) Committee and was selected as the winner of the 2017 ESCI Award for the Best Basic Research Article.

The author discusses the animal model study on female pigs to understand the cardio-protective effect of receptor-interacting proteins kinases 1 (RIPK1) Necrostatin on acute myocardial infarction. Topics include surgical coronary occlusion, cardiac catheterization and echocardiography, and the role of RIPK1 on tissues injury.

A letter to the editor is presented in response to the article, related to development and treatment of inflammatory vascular disease (IVD), published in previous issues of the journal.