Maternal training during lactation modifies breast milk fatty acid composition and male offspring glucose homeostasis in rat.

The perinatal exposome can modify offspring metabolism and health later in life. Within this concept, maternal exercise during gestation has been reported modifying offspring glucose sensing and homeostasis, while the impact of such exercise during lactation is little-known. We thus aimed at evaluating short- and long-term effects of it on offspring pancreatic function, assuming a link with changes in breast milk composition. Fifteen-week-old primiparous female Wistar rats exercised during lactation at a constant submaximal intensity (TR) or remained sedentary (CT). Male offspring were studied at weaning and at 7 months of age for growth, pancreas weight, glycemia and insulin responses. Milk protein content was determined by the bicinchoninic acid assay (BCA colorimetric method), and lipid content and fatty acid composition by gas chromatography. Mature milk from TR rats contained significantly less saturated (-7 %) and more monounsaturated (+18 %) and polyunsaturated (PUFA +12 %) fatty acids compared to CT rats, with no difference in total lipid and protein concentrations. In offspring from TR vs CT mothers, fasting glycemia was lower, pancreas weight was higher with a lower insulin content (-37 %) at weaning. Such outcomes were correlated with milk PUFA levels and indices of desaturase or elongase activities. These effects were no longer present at 7 months, whereas a more efficient muscle insulin sensitivity was observed. Maternal training during lactation led to a specific milk phenotype that was associated with a short-term impact on glucose homeostasis and pancreatic function of the male offspring.

Concomitant exposure to benzo[a]pyrene and triclosan at environmentally relevant concentrations induces metabolic syndrome with multigenerational consequences in Silurana (Xenopus) tropicalis.

Numerous studies suggest that amphibians are highly sensitive to endocrine disruptors (ED) but their precise role in population decline remains unknown. This study shows that frogs exposed to a mixture of ED throughout their life cycle, at environmentally relevant concentrations, developed an unexpected metabolic syndrome. Female Silurana (Xenopus) tropicalis exposed to a mixture of benzo[a]pyrene and triclosan (50 ng·L-1 each) from the tadpole stage developed liver steatosis and transcriptomic signature associated with glucose intolerance syndrome, and pancreatic insulin hyper secretion typical of pre-diabetes. These metabolic disorders were associated with delayed metamorphosis and developmental mortality in their progeny, both of which have been linked to reduced adult recruitment and reproductive success. Indeed, F1 females were smaller and lighter and presented reduced reproductive capacities, demonstrating a reduced fitness of ED-exposed Xenopus. Our results confirm that amphibians are highly sensitive to ED even at concentrations considered to be safe for other animals. This study demonstrates that ED might be considered as direct contributing factors to amphibian population decline, due to their disruption of energetic metabolism.

Maternal exercise before and during gestation modifies liver and muscle mitochondria in rat offspring.

It is now well established that the intrauterine environment is of major importance for offspring health during later life. Endurance training during pregnancy is associated with positive metabolic adjustments and beneficial effects on the balance between pro-oxidants and antioxidants (redox state) in the offspring. Our hypothesis was that these changes could rely on mitochondrial adaptations in the offspring due to modifications of the fetal environment induced by maternal endurance training. Therefore, we compared the liver and skeletal muscle mitochondrial function and the redox status of young rats whose mothers underwent moderate endurance training (treadmill running) before and during gestation (T) with those of young rats from untrained mothers (C). Our results show a significant reduction in the spontaneous H2O2 release by liver and muscle mitochondria in the T versus C offspring (P<0.05). These changes were accompanied by alterations in oxygen consumption. Moreover, the percentage of short-chain fatty acids increased significantly in liver mitochondria from T offspring. This may lead to improvements in the fluidity and the flexibility of the membrane. In plasma, glutathione peroxidase activity and protein oxidation were significantly higher in T offspring than in C offspring (P<0.05). Such changes in plasma could represent an adaptive signal transmitted from mothers to their offspring. We thus demonstrated for the first time, to our knowledge, that it is possible to act on bioenergetic function including alterations of mitochondrial function in offspring by modifying maternal physical activity before and during pregnancy. These changes could be crucial for the future health of the offspring.

Mitochondrial NADH redox potential impacts the reactive oxygen species production of reverse Electron transfer through complex I.

There is substantial evidence that Reactive Oxygen Species (ROS) play a major part in cell functioning. Although their harmfulness through oxidative stress is well documented, their role in signaling and sensing as an oxidative signal still needs to be investigated. In most cells, the mitochondrial Electron Transport Chain (ETC) is the primary source of ROS. The production of ROS by reverse electron transfer through complex I has been demonstrated both in an experimental context but also in many pathophysiological situations. Therefore, understanding the mechanisms that regulate this ROS production is of great interest to control its harmful effects. We used nigericin, Pi and valinomycin as tools to modulate the pH gradient (∆pH) and the membrane potential (∆Ψ) of the protonmotive force (∆p) in liver and muscle mitochondria to accurately determine how these parameters control the ROS production. We show that a high ∆Ψ is the "sine qua none" condition for ROS production from the reverse electron transfer (RET) through the complex I. However, a high ∆Ψ is not the only condition governing ROS production. Indeed, using tools that modulate the mitochondrial NADH level, we also demonstrate that ROS production is directly related to the mitochondrial redox potential when the membrane potential is almost stable.

Stress exposure alters brain mRNA expression of the genes involved in insulin signalling, an effect modified by a high fat/high fructose diet and cinnamon supplement.

In occidental societies, high fat and high sugar diets often coincide with episodes of stress. The association is likely to modify brain energy control. Brain insulin signalling is rarely studied in stressed individuals consuming high fat diets. Furthermore the effects of cinnamon supplement are not known in these conditions. Therefore, we exposed rats, over a 12-week period, to a control (C) or a high fat/high fructose (HF/HFr) diet that induces peripheral insulin resistance. A cinnamon supplement (C+CN and HF/HFr +CN) was added or not. After diet exposure, one group of rats was exposed to a 30-min restraint followed by a 10-min open-field test, their combination featuring a moderate stressor, the other rats staying unstressed in their home cages. The insulin signalling in hippocampus and frontal cortex was studied through the mRNA expression of the following genes: insulin receptor (Ir), insulin receptor substrate (Irs1), glucose transporters (Glut1 and Glut3), glycogen synthase (Gys1) and their modulators, Akt1 and Pten. In C rats, stress enhanced the expression of Ir, Irs1, Glut1, Gys1 and Akt1 mRNA. In C+CN rats, stress induced an increase in Pten but a decrease in Gys1 mRNA expression. In HF/HFr rats, stress was associated with an increase in Pten mRNA expression. In HF/HFr+CN rats, stress increased Pten mRNA expression but also decreased Gys1 mRNA expression. This suggests that a single moderate stress favours energy refilling mechanisms, an effect blunted by a previous HF/HFr diet and cinnamon supplement.

Unexpected metabolic disorders induced by endocrine disruptors in Xenopus tropicalis provide new lead for understanding amphibian decline.

Despite numerous studies suggesting that amphibians are highly sensitive to endocrine disruptors (EDs), both their role in the decline of populations and the underlying mechanisms remain unclear. This study showed that frogs exposed throughout their life cycle to ED concentrations low enough to be considered safe for drinking water, developed a prediabetes phenotype and, more commonly, a metabolic syndrome. Female Xenopus tropicalis exposed from tadpole stage to benzo(a)pyrene or triclosan at concentrations of 50 ng⋅L-1 displayed glucose intolerance syndrome, liver steatosis, liver mitochondrial dysfunction, liver transcriptomic signature, and pancreatic insulin hypersecretion, all typical of a prediabetes state. This metabolic syndrome led to progeny whose metamorphosis was delayed and occurred while the individuals were both smaller and lighter, all factors that have been linked to reduced adult recruitment and likelihood of reproduction. We found that F1 animals did indeed have reduced reproductive success, demonstrating a lower fitness in ED-exposed Xenopus Moreover, after 1 year of depuration, Xenopus that had been exposed to benzo(a)pyrene still displayed hepatic disorders and a marked insulin secretory defect resulting in glucose intolerance. Our results demonstrate that amphibians are highly sensitive to EDs at concentrations well below the thresholds reported to induce stress in other vertebrates. This study introduces EDs as a possible key contributing factor to amphibian population decline through metabolism disruption. Overall, our results show that EDs cause metabolic disorders, which is in agreement with epidemiological studies suggesting that environmental EDs might be one of the principal causes of metabolic disease in humans.

Maternal exercise modifies body composition and energy substrates handling in male offspring fed a high-fat/high-sucrose diet.

KEY POINTS: Maternal training during gestation enhances offspring body composition and energy substrates handling in early adulthood. Offspring nutrition also plays a role as some beneficial effects of maternal training during gestation disappear after consumption of a high-fat diet. ABSTRACT: Maternal exercise during gestation has been reported to modify offspring metabolism and health. Whether these effects are exacerbated when offspring are receiving a high-fat diet remains unclear. Our purpose was to evaluate the effect of maternal exercise before and during gestation on the offspring fed a high-fat/high-sucrose diet (HF) by assessing its body composition, pancreatic function and energy substrates handling by two major glucose-utilizing tissues: liver and muscle. Fifteen-week-old nulliparous female Wistar rats exercised 4 weeks before as well as during gestation at a constant submaximal intensity (TR) or remained sedentary (CT). At weaning, pups from each group were fed either a standard diet (TRCD or CTCD) or a high-fat/high-sucrose diet (TRHF or CTHF) for 10 weeks. Offspring from TR dams gained less weight compared to those from CT dams. Selected fat depots were larger with the HF diet compared to control diet (CD) but significantly smaller in TRHF compared to CTHF. Surprisingly, the insulin secretion index was higher in islets from HF offspring compared to CD. TR offspring showed a higher muscle insulin sensitivity estimated by the ratio of phosphorylated protein kinase B to total protein kinase B compared with CT offspring (+48%, P < 0.05). With CD, permeabilized isolated muscle fibres from TR rats displayed a lower apparent affinity constant (Km ) for pyruvate and palmitoyl coenzyme A as substrates compared to the CT group (-46% and -58%, respectively, P < 0.05). These results suggest that maternal exercise has positive effects on young adult offspring body composition and on muscle carbohydrate and lipid metabolism depending on the nutritional status.

Middle Iron-Enriched Fructose Diet on Gestational Diabetes Risk and on Oxidative Stress in Offspring Rats.

Gestational diabetes mellitus (GDM) is associated with increased insulin resistance and a heightened level of oxidative stress (OS). Additionally, high iron consumption could also increase insulin resistance and OS, which could aggravate GDM risk. The aim of this study is to evaluate a high fructose diet (F) as an alternative experimental model of GDM on rats. We also have evaluated the worst effect of a fructose iron-enriched diet (FI) on glucose tolerance and OS status during pregnancy. Anthropometric parameters, plasma glucose levels, insulin, and lipid profile were assessed after delivery in rats fed an F diet. The effects observed in mothers (hyperglycemia, and hyperlipidemia) and on pups (macrosomia and hypoglycemia) are similar to those observed in women with GDM. Therefore, the fructose diet could be proposed as an experimental model of GDM. In this way, we can compare the effect of an iron-enriched diet on the metabolic and redox status of mother rats and their pups. The mothers' glycemic was similar in the F and FI groups, whereas the glycemic was significantly different in the newborn. In rat pups born to mothers fed on an FI diet, the activities of the antioxidant enzyme glutathione peroxidase (GPx) and glutathione-S-transferase in livers and GPx in brains were altered and the gender analysis showed significant differences. Thus, alterations in the glycemic and redox status in newborns suggest that fetuses are more sensitive than their mothers to the effect of an iron-enriched diet in the case of GDM pregnancy. This study proposed a novel experimental model for GDM and provided insights on the effect of a moderate iron intake in adding to the risk of glucose disorder and oxidative damage on newborns.

A relevant exposure to a food matrix contaminated environmentally by polychlorinated biphenyls induces liver and brain disruption in rats.

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants present in dietary fats. Most studies evaluating PCB effects have been conducted with a single compound or a mixture of PCBs given as a single acute dose. The purpose of this study was to evaluate in vivo PCB toxicity in a realistic model of exposure: a low daily dose of PCBs (twice the tolerable daily intake (TDI)), chronically administered (8 weeks) to rats in contaminated goat milk. Liver and brain PCB toxicities were investigated by evaluating oxidative stress status and mitochondrial function. PCB toxicity in the liver was also estimated by transaminase enzymatic activity. This study shows that even at low doses, chronic PCB exposure resulted in a statistically significant reduction of mitochondrial function in liver and brain. In the liver, oxygen consumption in the condition of adenosine triphosphate (ATP) production (state 3) decreased by 22-29% (p < 0.01), according to the respiratory substrates. In the brain, respiratory chain complexes II and III were reduced by 24% and 39%, respectively (p < 0.005). The exposed rats presented higher lipid peroxidation status (+20%, p < 0.05) and transaminase activity (+30%, p < 0.05) in the blood. Thus, our study showed that exposure of rats to a daily realistic dose of PCBs (twice the TDI in a food complex mixture of environmental origin) resulted in multiple disruptions in the liver and brain.

Short-term and long-term effects of submaximal maternal exercise on offspring glucose homeostasis and pancreatic function.

Only a few studies have explored the effects of maternal exercise during gestation on adult offspring metabolism. We set out to test whether maternal controlled submaximal exercise maintained troughout all gestational periods induces persistant metabolic changes in the offspring. We used a model of 15-wk-old nulliparous female Wistar rats that exercised (trained group) before and during gestation at a submaximal intensity or remained sedentary (control group). At weaning, male offspring from trained dams showed reduced basal glycemia (119.7 ± 2.4 vs. 130.5 ± 4.1 mg/dl, P < 0.05), pancreas relative weight (3.96 ± 0.18 vs. 4.54 ± 0.14 g/kg body wt, P < 0.05), and islet mean area (22,822 ± 4,036 vs. 44,669 ± 6,761 µm(2), P < 0.05) compared with pups from control dams. Additionally, they had better insulin secretory capacity when stimulated by 2.8 mM glucose + 20 mM arginine compared with offspring from control dams (+96%, P < 0.05). At 7 mo of age, offspring from trained mothers displayed altered glucose tolerance (AUC = 15,285 ± 527 vs. 11,898 ± 988 mg·dl(-1)·120 min, P < 0.05) and decreased muscle insulin sensitivity estimated by the phosphorylated PKB/total PKB ratio (-32%, P < 0.05) and tended to have a reduced islet insulin secretory capacity compared with rats from control dams. These results suggest that submaximal maternal exercise modifies short-term male offspring pancreatic function and appears to have rather negative long-term consequences on sedentary adult offspring glucose handling.

Cinnamon intake alleviates the combined effects of dietary-induced insulin resistance and acute stress on brain mitochondria.

Insulin resistance (IR), which is a leading cause of the metabolic syndrome, results in early brain function alterations which may alter brain mitochondrial functioning. Previously, we demonstrated that rats fed a control diet and submitted to an acute restraint stress exhibited a delayed mitochondrial permeability transition pore (mPTP) opening. In this study, we evaluated the combined effects of dietary and emotional stressors as found in western way of life. We studied, in rats submitted or not to an acute stress, the effects of diet-induced IR on brain mitochondria, using a high fat/high fructose diet (HF(2)), as an IR inducer, with addition or not of cinnamon as an insulin sensitizer. We measured Ca(2+) retention capacity, respiration, ROS production, enzymatic activities and cell signaling activation. Under stress, HF(2) diet dramatically decreased the amount of Ca(2+) required to open the mPTP (13%) suggesting an adverse effect on mitochondrial survival. Cinnamon added to the diet corrected this negative effect and resulted in a partial recovery (30%). The effects related to cinnamon addition to the diet could be due to its antioxidant properties or to the observed modulation of PI3K-AKT-GSK3ß and MAPK-P38 pathways or to a combination of both. These data suggest a protective effect of cinnamon on brain mitochondria against the negative impact of an HF(2) diet. Cinnamon could be beneficial to counteract deleterious dietary effects in stressed conditions.

Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury.

Inhibiting the opening of mitochondrial permeability transition pore (mPTP), thereby maintaining the mitochondrial membrane potential and calcium homeostasis, could reduce the induction of cell death. Although recombinant human erythropoietin (rhEpo) and carbamylated erythropoietin (Cepo) were shown to prevent apoptosis after traumatic brain injury (TBI), their impact on mPTP is yet unknown. Thirty minutes after diffuse TBI (impact-acceleration model), rats were intravenously administered a saline solution (TBI-saline), 5000 UI/kg rhEpo (TBI-rhEpo) or 50 µg/kg Cepo (TBI-Cepo). A fourth group received no TBI insult (sham-operated) (n = 11 rats per group). Post-traumatic brain edema was measured using magnetic resonance imaging. A first series of experiments was conducted 2 h after TBI (or equivalent) to investigate the mitochondrial function with the determination of thresholds for mPTP opening and ultrastructural mitochondrial changes. In addition, the intramitochondrial calcium content [Caim] was measured. In a second series of experiments, brain cell apoptosis was assessed at 24 h post-injury. TBI-rhEpo and TBI-Cepo groups had a reduced brain edema compared with TBI-saline. They had higher threshold for mPTP opening with succinate as substrate: 120 (120-150) (median, interquartiles) and 100 (100-120) versus 80 (60-90) nmol calcium/mg protein in TBI-saline, respectively (p < 0.05). Similar findings were shown with glutamate-malate as substrate. TBI-rhEpo and Cepo groups had less morphological mitochondrial disruption in astrocytes. The elevation in [Caim] after TBI was not changed by rhEpo and Cepo treatment. Finally, rhEpo and Cepo reduced caspase-3 expression at 24 h post-injury. These results indicate that rhEpo and Cepo could modulate mitochondrial dysfunction after TBI. The mechanisms involved are discussed.

Acute stress delays brain mitochondrial permeability transition pore opening.

Since emotional stress elicits brain activation, mitochondria should be a key component of stressed brain response. However, few studies have focused on mitochondria functioning in these conditions. In this work, we aimed to determine the effects of an acute restraint stress on rat brain mitochondrial functions, with a focus on permeability transition pore (PTP) functioning. Rats were divided into two groups, submitted or not to an acute 30-min restraint stress (Stress, S-group, vs. Control, C-group). Brain was removed immediately after stress. Mitochondrial respiration and enzymatic activities (complex I, complex II, hexokinase) were measured. Changes in PTP opening were assessed by the Ca(2+) retention capacity. Cell signaling pathways relevant to the coupling between mitochondria and cell function (adenosine monophosphate-activated protein kinase, phosphatidylinositol 3-kinase, glycogen synthase kinase 3 beta, MAPK, and cGMP/NO) were measured. The effect of glucocorticoids was also assessed in vitro. Stress delayed (43%) the opening of PTP and resulted in a mild inhibition of complex I respiratory chain. This inhibition was associated with significant stress-induced changes in adenosine monophosphate-activated protein kinase signaling pathway without changes in brain cGMP level. In contrast, glucocorticoids did not modify PTP opening. These data suggest a rapid adaptive mechanism of brain mitochondria in stressed conditions, with a special focus on PTP regulation. In a rat model of acute restraint stress, we observed substantial changes in brain mitochondria functioning. Stress significantly (i) delays (43%) the opening of permeability transition pore (PTP) by the calcium (Ca(2+) ), its main inductor and (ii) results in an inhibition of complex I in electron transport chain associated with change in AMPK signaling pathway. These data suggest an adaptive mechanism of brain mitochondria in stressed condition, with a special focus on PTP regulation.

Impact of manganese on primary hippocampal neurons from rodents.

Manganese-enhanced magnetic resonance imaging (MEMRI) is a powerful tool for in vivo tract tracing or functional imaging of the central nervous system. However Mn(2+) may be toxic at high levels. In this study, we addressed the impact of Mn(2+) on mouse hippocampal neurons (HN) and neuron-like N2a cells in culture, using several approaches. Both HN and N2a cells not exposed to exogenous MnCl2 were shown by synchrotron X-ray fluorescence to contain 5 mg/g Mn. Concentrations of Mn(2+) leading to 50% lethality (LC50) after 24 h of incubation were much higher for N2a cells (863 mM) than for HN (90 mM). The distribution of Mn(2+) in both cell types exposed to Mn(2+) concentrations below LC50 was perinuclear whereas that in cells exposed to concentrations above LC50 was more diffuse, suggesting an overloading of cell storage/detoxification capacity. In addition, Mn(2+) had a cell-type and dose-dependent impact on the total amount of intracellular P, Ca, Fe and Zn measured by synchrotron X-ray fluorescence. For HN neurons, immunofluorescence studies revealed that concentrations of Mn(2+) below LC50 shortened neuritic length and decreased mitochondria velocity after 24 h of incubation. Similar concentrations of Mn(2+) also facilitated the opening of the mitochondrial permeability transition pore in isolated mitochondria from rat brains. The sensitivity of primary HN to Mn(2+) demonstrated here supports their use as a relevant model to study Mn(2+) -induced neurotoxicity.

Effect of a high-fat--high-fructose diet, stress and cinnamon on central expression of genes related to immune system, hypothalamic-pituitary-adrenocortical axis function and cerebral plasticity in rats.

The intake of a high-fat/high-fructose (HF/HFr) diet is described to be deleterious to cognitive performances, possibly via the induction of inflammatory factors. An excess of glucocorticoids is also known to exert negative effects on cerebral plasticity. In the present study, we assessed the effects of an unbalanced diet on circulating and central markers of inflammation and glucocorticoid activity, as well as their reversal by dietary cinnamon (CN) supplementation. A group of male Wistar rats were subjected to an immune challenge with acute lipopolysaccharide under a HF/HFr or a standard diet. Another group of Wistar rats were fed either a HF/HFr or a control diet for 12 weeks, with or without CN supplementation, and with or without restraint stress (Str) application before being killed. We evaluated the effects of such regimens on inflammation parameters in the periphery and brain and on the expression of actors of brain plasticity. To assess hypothalamic-pituitary-adrenocortical axis activity, we measured the plasma concentrations of corticosterone and the expression of central corticotrophin-releasing hormone, mineralocorticoid receptor, glucocorticoid receptor and 11ß-hydroxysteroid dehydrogenase. We found that the HF/HFr diet induced the expression of cytokines in the brain, but only after an immune challenge. Furthermore, we observed the negative effects of Str on the plasma concentrations of corticosterone and neuroplasticity markers in rats fed the control diet but not in those fed the HF/HFr diet. Additionally, we found that CN supplementation exerted beneficial effects under the control diet, but that its effects were blunted or even reversed under the HF/HFr diet. CN supplementation could be beneficial under a standard diet. [corrected].

Metyrapone effects on systemic and cerebral energy metabolism.

Metyrapone is a cytochrome P(450) inhibitor that protects against ischemia- and excitotoxicity-induced brain damages in rodents. This study examines whether metyrapone would act on energy metabolism in a manner congruent with its neuroprotective effect. In a first investigation, the rats instrumented with telemetric devices measuring abdominal temperature, received i.p. injection of either metyrapone or saline. One hour after injection, their blood and hippocampus were sampled. Hippocampus metabolite concentrations were measured using (1)H high-resolution magic angle spinning-magnetic resonance spectroscopy ((1)H HRMAS-MRS). The hippocampus levels in phosphorylated mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) were measured by Western Blot analysis and those of c-fos and HSP70-2 mRNA were quantified by RT-PCR. In a second investigation, the rats received the same treatment and were sacrificed 1h after. The functioning of mitochondria was immediately studied on their whole brain. Metyrapone provoked a slight hypothermia which was correlated to the increase in blood glucose concentration. Metyrapone also increased blood lactate concentrations without modifying hippocampus lactate content. In the hippocampus, metyrapone decreased γ-aminobutyric acid (GABA) and glutamate levels but increased glutamine and N-acetyl-aspartate contents (NAA). Phosphorylated mTOR and AMPK and the c-fos and HSP70-2 mRNA levels were similar between treatment groups. Metyrapone did not modify blood corticosterone levels. Mitochondrial oxygen consumption was similar in both groups whatever the substrate used. These metabolic modifications, which take place without modifying blood glucocorticoid levels, are consistent with the neuroprotective properties of metyrapone as demonstrated in animal models.

Prerequisites for ubiquinone analogs to prevent mitochondrial permeability transition-induced cell death.

The permeability transition pore (PTP) is a mitochondrial inner membrane channel involved in cell death. The inhibition of PTP opening has been proved to be an effective strategy to prevent cell death induced by oxidative stress. Several ubiquinone analogs are known to powerfully inhibit PTP opening with an effect depending on the studied cell line. Here, we have studied the effects of ubiquinone 0 (Ub(0)), ubiquinone 5 (Ub(5)) and ubiquinone 10 (Ub(10)) on PTP regulation, H(2)O(2) production and cell viability in U937 cells. We found that Ub(0) induced both PTP opening and H(2)O(2) production. Ub(5) did not regulate PTP opening yet induced H(2)O(2) production. Ub(10) potently inhibited PTP opening yet induced H(2)O(2) production. Both Ub(0) and Ub(5) induced cell death, whereas Ub(10) was not toxic. Moreover, Ub(10) prevented tert-butyl hydroperoxide-induced PTP opening and subsequent cell death. We conclude that PTP-inhibitor ubiquinone analogs are able to prevent PTP opening-induced cell death only if they are not toxic per se, which is the case when they have no or low pro-oxidant activity.

Cinnamon increases liver glycogen in an animal model of insulin resistance.

The objective of this study was to determine the effects of cinnamon on glycogen synthesis, related gene expression, and protein levels in the muscle and liver using an animal model of insulin resistance, the high-fat/high-fructose (HF/HFr) diet-fed rat. Four groups of 22 male Wistar rats were fed for 12 weeks with (1) HF/HFr diet to induce insulin resistance, (2) HF/HFr diet containing 20 g cinnamon per kilogram of diet, (3) control diet, and (4) control diet containing 20 g cinnamon per kilogram of diet. In the liver, cinnamon added to the HF/HFr diet led to highly significant increases of liver glycogen. There were no significant changes in animals consuming the control diet plus cinnamon. In the liver, cinnamon also counteracted the decreases of the gene expressions due to the consumption of the HF/HFr diet for the insulin receptor, insulin receptor substrates 1 and 2, glucose transporters 1 and 2, and glycogen synthase 1. In muscle, the decreased expressions of these genes by the HF/HFr diet and glucose transporter 4 were also reversed by cinnamon. In addition, the overexpression of glycogen synthase 3ß messenger RNA levels and protein observed in the muscle of HF/HFr fed rats was decreased in animals consuming cinnamon. These data demonstrate that, in insulin-resistant rats, cinnamon improves insulin sensitivity and enhances liver glycogen via regulating insulin signaling and glycogen synthesis. Changes due to cinnamon in control animals with normal insulin sensitivity were not significant.

New evidence of a mitochondrial genetic background paradox: impact of the J haplogroup on the A3243G mutation.

BACKGROUND: The A3243G mutation in the tRNALeu gene (UUR), is one of the most common pathogenic mitochondrial DNA (mtDNA) mutations in France, and is associated with highly variable and heterogeneous disease phenotypes. To define the relationships between the A3243G mutation and mtDNA backgrounds, we determined the haplogroup affiliation of 142 unrelated French patients - diagnosed as carriers of the A3243G mutation - by control-region sequencing and RFLP survey of their mtDNAs. RESULTS: The analysis revealed 111 different haplotypes encompassing all European haplogroups, indicating that the 3243 site might be a mutational hot spot. However, contrary to previous findings, we observed a statistically significant underepresentation of the A3243G mutation on haplogroup J in patients (p = 0.01, OR = 0.26, C.I. 95%: 0.08-0.83), suggesting that might be due to a strong negative selection at the embryo or germ line stages. CONCLUSION: Thus, our study supports the existence of mutational hotspot on mtDNA and a "haplogroup J paradox," a haplogroup that may increase the expression of mtDNA pathogenic mutations, but also be beneficial in certain environmental contexts.