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Branched fatty acid esters of hydroxy fatty acids are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Recently, we showed that 9-palmitic acid esters of hydroxypalmitic acid (9-PAHPA) and 9-oleic acid esters of hydroxypalmitic acid increased insulin sensitivity in mice when incorporated to a chow diet or to a high fat and high sucrose diet. However, preventive supplementation with 9-PAHPA and 9-oleic acid esters of hydroxypalmitic acid in high fat and high sucrose diet mice did not impair significant weight gain or the development of hyperglycemia. The aim of this work was therefore to study whether in two animal models of obesity, namely the classical diet-induced obesity (DIO) and the db/db mice, 9-PAHPA may have beneficial effects against obesity and liver and skeletal muscle metabolic dysfunction. In DIO mice, we observed that 9-PAHPA increased body weight and fat mass. In line with this observation, we found that 9-PAHPA supplementation decreased energy expenditure. In liver and in skeletal muscle, mitochondrial activities and oxidative stress parameters were not modified by 9-PAHPA supplementation. In db/db mice, 9-PAHPA had no effect on the dramatic weight gain and hyperglycemia. In addition, 9-PAHPA supplementation did not correct either the hepatomegaly and hepatic steatosis or the severe muscle atrophy recorded compared with db/+ animals. Likewise, supplementation with 9-PAHPA did not impact the different metabolic parameters analyzed, either in the liver or in the skeletal muscles. However, it decreased insulin resistance in DIO and db/db mice. In conclusion, our study indicated that a long-term intake of 9-PAHPA in DIO and db/db mice improved insulin sensitivity but had only few effects on obesity and associated metabolic disorders., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are a new family of endogenous lipids recently discovered. Several studies reported that some FAHFAs have antidiabetic and anti-inflammatory effects. The objective of this study was to explore the impact of two FAHFAs, 9-PAHPA or 9-OAHPA, on the metabolism of mice. C57Bl/6J male mice, 6 weeks old, were divided into 3 groups of 10 mice each. One group received a control diet and the two others groups received the control diet supplemented with 9-PAHPA or 9-OAHPA for 12 weeks. Mouse weight and body composition were monitored throughout the study. Some days before euthanasia, energy expenditure, glucose tolerance and insulin sensitivity were also determined. After sacrifice, blood and organs were collected for relevant molecular, biochemical and histological analyses. Although high intake of 9-PAHPA or 9-OAHPA increased basal metabolism, it had no direct effect on body weight. Interestingly, the 9-PAHPA or 9-OAHPA intake increased insulin sensitivity but without modifying glucose tolerance. Nevertheless, 9-PAHPA intake induced a loss of glucose-stimulated insulin secretion. Surprisingly, both studied FAHFAs induced hepatic steatosis and fibrosis in some mice, which were more marked with 9-PAHPA. Finally, a slight remodeling of white adipose tissue was also observed with 9-PAHPA intake. In conclusion, the long-term high intake of 9-PAHPA or 9-OAHPA increased basal metabolism and insulin sensitivity in healthy mice. However, this effect, highly likely beneficial in a diabetic state, was accompanied by manifest liver damage in certain mice that should deserve special attention in both healthy and pathological studies., Competing Interests: Conflict of interest The authors confirm that this article content has no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Metabolic syndrome components, including obesity, dyslipidemia and impaired glucose homeostasis, become a major public health issue. Muscles play a predominant role in insulin-mediated glucose uptake, and high fat diets may negatively affect muscle function and homeostasis. This work aimed to study the time-course of muscle lipid accumulation, oxidative stress and mitochondrial dysfunction and their association to impaired glucose homeostasis in rats fed an obesogenic diet. Male Wistar rats were fed with a standard or a high fat/high fructose (HFHFr) diet and sacrificed on 4, 8, 12, 16, 20 weeks. Rats fed the HFHFr diet developed mild overweight, increased liver and adipose tissue weights and glucose intolerance. The impaired glucose homeostasis increased gradually with the HFHFr diet to become significant on the 12th and 16th weeks of diet. In parallel, the muscle lipid composition showed an increase in the saturated fatty acids and the monounsaturated fatty acids with a marked decrease in the polyunsaturated fatty acids. The HFHFr diet also increased muscle contents of both diacylglycerols and Ceramides. Surprisingly, HFHFr diet did not induce major muscle mitochondrial dysfunction or oxidative stress. These results indicate that muscle lipid alterations, as well as impaired glucose homeostasis occur as early as the 8th week of HFHFr diet, increase to reach a plateau around the 12th-16th weeks of diet, and then attenuate towards the end of study. At these diet treatment durations, muscle mitochondrial activity and oxidative stress remained unchanged and do not seem to have a major role in the observed impaired glucose homeostasis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Whereas reactive oxygen species (ROS) can have opposite impacts on insulin signaling, they have mainly been associated with mitochondrial dysfunction in skeletal muscle. We analyzed the relationship between these three features in skeletal muscle of senescence accelerated mice (SAM) prone (P8), which are characterized by enhanced oxidative stress compared to SAM resistant (R1). Oxidative stress, ROS production, antioxidant system, mitochondrial content and functioning, as well as in vitro and in vivo insulin signaling were investigated in gastrocnemius and quadriceps muscles. In SAMP8 compared to SAMR1, muscle content in carbonylated proteins was two-fold (p < 0.01) and ROS production by xanthine oxidase 70% (p < 0.05) higher. Furthermore, insulin-induced Akt phosphorylation measured in vivo and ex vivo as well as muscle glucose uptake measured ex vivo were significantly higher (p < 0.05). Mitochondrial respiration evidenced uncoupling and higher respiration rates with substrates of complexes II and IV, in agreement with higher maximal activity of complexes II and IV (+ 18% and 62%, respectively, p < 0.05). By contrast, maximal activity of complex I was 22% lower (p < 0.05). All strain differences were corrected after 6 months of N-acetylcysteine (NAC) treatment, thus supporting the involvement of high ROS production in these differences. In conclusion in muscle of SAMP8 compared to SAMR1, high ROS production is associated to higher insulin sensitivity and glucose uptake but to lower mitochondrial complex I activity. These conflicting adaptations, with regards to the resulting imbalance between NADH production and use, were associated with intrinsic adjustments in the mitochondrial respiration chain (mitochondrial uncoupling, enhanced complexes II and IV activity). We propose that these bioenergetics adaptations may help at preserving muscle metabolic flexibility of SAMP8., (Copyright © 2017 Elsevier Inc. All rights reserved.)

While myostatin gene deletion is a promising therapy to fight muscle loss during aging, this approach induces also skeletal muscle metabolic changes such as mitochondrial deficits, redox alteration and increased fatigability. In the present study, we evaluated the effects of aging on these features in aged wild-type (WT) and mstn knockout (KO) mice. Moreover, to determine whether an enriched-antioxidant diet may be useful to prevent age-related disorders, we orally administered to the two genotypes a melon concentrate rich in superoxide dismutase for 12 weeks. We reported that mitochondrial functional abnormalities persisted (decreased state 3 and 4 of respiration; p<0.05) in skeletal muscle from aged KO mice; however, differences with WT mice were attenuated at old age in line with reduced difference on running endurance between the two genotypes. Interestingly, we showed an increase in glutathione levels, associated with lower lipid peroxidation levels in KO muscle. Enriched antioxidant diet reduced the aging-related negative effects on maximal aerobic velocity and running limit time (p<0.05) in both groups, with systemic adaptations on body weight. The redox status and the hypertrophic phenotype appeared to be beneficial to KO mice, mitigating the effect of aging on the skeletal muscle metabolic remodeling., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Oxidative stress is involved in obesity. However, dietary antioxidants could prevent oxidative stress-induced damage. We have previously shown the preventive effects of a melon superoxide dismutase (SODB) on oxidative stress. However, the mechanism of action of SODB is still unknown. Here, we evaluated the effects of a 1-month curative supplementation with SODB on the liver of obese hamsters. Golden Syrian hamsters received either a standard diet or a cafeteria diet composed of high-fat, high-sugar, and high-salt supermarket products, for 15 weeks. This diet resulted in insulin resistance and in increased oxidative stress in the liver. However, inflammatory markers (IL-6, TNF-α, and NF-κB) were not enhanced and no liver steatosis was detected, although these are usually described in obesity-induced insulin resistance models. After the 1-month supplementation with SODB, body weight and insulin resistance induced by the cafeteria diet were reduced and hepatic oxidative stress was corrected. This could be due to the increased expression of the liver antioxidant defense proteins (manganese and copper/zinc superoxide dismutase, catalase, and glutathione peroxidase). Even though no inflammation was detected in the obese hamsters, inflammatory markers were decreased after SODB supplementation, probably through the reduction of oxidative stress. These findings suggest for the first time that SODB could exert its antioxidant properties by inducing the endogenous antioxidant defense. The mechanisms underlying this induction need to be further investigated., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Mitochondrial and NADPH oxidase systems and oxidative stress were investigated in 12 week high-fat high-sucrose (HFHS) diet-fed rats. A protective effect of wine polyphenol (PP) extract was also examined. In liver, maximal activities of CII and CII+III mitochondrial complexes were decreased but NADPH oxidase expression (p22(phox) and p47(phox)) and NADPH oxidase-dependent superoxide anion production were not modified, whereas oxidative stress (lipid and protein oxidation products and antioxidant systems) was increased with HFHS diet. In muscle, anion superoxide production was slightly increased while mitochondrial complex activities and lipid and protein oxidation products were not modified with HFHS diet. In heart, NADPH oxidase expression and superoxide anion production were increased, and maximal activity of mitochondrial respiratory chain complexes or oxidative stress parameters were not modified. Wine polyphenol extract had an inhibiting effect on liver oxidative stress and on heart NADPH oxidase expression and superoxide anion production, and on induction of hepatic steatosis with HFHS diet. Induction of mitochondrial dysfunction could be a primary event in the development of oxidative stress in liver, while in skeletal muscle and in heart the NADPH oxidase system seems to be mainly involved in oxidative stress. Wine polyphenol extract was shown to partially prevent oxidative stress in liver and heart tissues and to nearly completely prevent steatosis development in liver.

Objective: Zinc (Zn) is an essential trace element that is a potent enhancer of protein metabolism due to its numerous roles in metabolic processes. Protein turnover decreases with age. We determined whether a Zn supplementation, which increases serum Zn concentration and Zn exchangeable pool mass, modifies whole-body protein turnover and albumin and fibrinogen synthesis rates in late-middle-aged men., Methods: Three groups of 16 healthy subjects 55-70 y of age participated in a randomized, doubled-blinded, placebo-controlled intervention. Each group received 0, 15, or 30 mg/d of supplemental Zn for 6 mo. At the end of the supplementation period, each subject received an intravenous infusion of L-[1-13C] leucine to quantify whole-body leucine fluxes and synthesis rates of albumin and fibrinogen., Results: In the placebo group, mean +/- SEM whole-body leucine fluxes to protein synthesis, to oxidation, and from protein degradation were 1.46 +/- 0.05, 0.40 +/- 0.01, and 1.73 +/- 0.06 micromol.kg(-1).min(-1), respectively. Zn supplementation did not significantly change whole-body leucine fluxes. In the placebo group, plasma concentration and fractional rate of protein synthesis were 45 +/- 1 g/L and 8.2 +/- 0.6%/d for albumin and 3.6 +/- 0.2 g/L and 16.7 +/- 1.3%/d for fibrinogen, respectively. Zn supplementation did not significantly change these parameters or the absolute rates of synthesis of these proteins., Conclusion: Increasing Zn supply does not modify whole-body protein metabolism and synthesis rates of albumin and fibrinogen in late-middle-aged men.

Objectives: This work aims at studying the effect of daily versus twice weekly long-term Fe supplementation on Fe absorption and status in Fe-deficient women., Design and Methods: The study design is a randomized controlled open study carried out in the Internal Medicine Department, CHU de Clermont-Ferrand, France. Twenty-four young women participated in this study and were randomized into two groups: Group 1 received 50 mg Fe daily, and group 2 received 50 mg Fe twice weekly for 3 months. On day 10 (D10) and on day 90 (D90) of Fe supplementation, blood samples were obtained, and women received orally about 5 mg of 57Fe, and blood was sampled at different times over 24 h. The 57Fe absorption was evaluated by calculating the areas under the curves (AUC). Fe and oxidative stress status were also assessed., Results: 57Fe absorption was similar in both groups on D10 but was greatly decreased in Group 1 and remained high in Group 2 on D90. Fe status was more improved in Group 1 than in Group 2. Oxidative stress status remained statistically unchanged., Conclusions: Our study shows that daily Fe supplementation is able to correct an Fe deficiency much more than twice weekly Fe supplementation in young women.

Objective: We compared the effects of different kinds of bread fermentation on mineral bioavailability., Methods: Wistar rats were fed one of the following experimental diets for 21 d: control, reconstituted whole wheat flour (white flour plus bran), yeast bread, and sourdough bread. The apparent mineral absorption and intestinal fermentation were measured in each animal., Results: Phytate contents in yeast and sourdough bread were lower than in reconstituted whole wheat flour (-52% and -71%, respectively). Total cecal pool of short-chain fatty acids, in particular the butyrate pool, was significantly increased by the ingestion of unrefined products. Calcium homeostasis was not modified by these nutritional conditions, whereas magnesium absorption was significantly greater in rats fed the control and sourdough diets than in those consuming whole wheat flour and yeast bread. Magnesium kidney excretion was slightly stimulated by sourdough bread. Compared with the control diet, iron balance was significantly reduced by reconstituted whole wheat flour diet. Yeast bread making counteracted the deleterious effects of whole wheat on iron absorption, whereas sourdough bread making enhanced iron absorption. Further, liver and plasma iron and transferrin saturation levels were lower in rats adapted to the flour diet than in other groups. Zinc absorption was strongly depressed in the presence of unprocessed reconstituted whole wheat flour in the diet, but yeast fermentation afforded a zinc assimilation comparable to the control diet, whereas the sourdough bread led to maximal zinc absorption. Copper absorption increased significantly when rats were fed the sourdough bread, whereas unprocessed whole flour depressed copper absorption (-41% versus control diet)., Conclusion: Mineral bioavailability from reconstituted whole wheat flour can be improved by bread making. Although yeast fermentation minimizes the unfavorable effects of phytic acid, sourdough bread is a better source of available minerals, especially magnesium, iron, and zinc.

The in vivo measurement of highly reactive free radicals, such as the z.rad OH radical, is very difficult. New specific markers, which are based on the ability of z.rad OH to attack the benzene rings of aromatic molecules, are currently under investigation. The produced hydroxylated compounds can be measured directly. In vivo, radical metabolism of salicylic acid produces two main hydroxylated derivatives (2,3- and 2,5-dihydroxybenzoic acids). The latter acid can be also produced by enzymatic pathways through the cytochrome P-450 system, while the former acid is reported to be solely formed by direct hydroxyl radical attack. Therefore, measurement of 2, 3-DHBA, following oral administration of the drug acetyl salicylate, could be proposed for assessment of oxidative stress in vivo. In this paper, a sensitive method for the identification and quantification of hydroxylation products from the reaction of z. rad OH with salicylate in vivo is presented. It employs a high performance liquid chromatography and electrochemical detection system. A detection limit of < 1 pmol for the hydroxylation products has been achieved with linear response over at least five orders of magnitude. Using this technique, we measured plasma levels of 2,3- and 2,5-DHBA dihydroxylated derivatives and salicylic acid and determined the ratios following administration of 1 g acetyl salicylate in 20 healthy subjects.

Phytic acid (PA) and fructooligosaccharides (FOS) such as inulin are two food components that are able to modify mineral absorption negatively or positively. The influence of PA and FOS on the cecal and apparent mineral absorption as well as on the mineral status (plasma, hepatic, and bone) were investigated in four groups of rats fed one of the experimental diets: a fiber-free (FF) diet, a FF diet containing 7 g/kg PA (FF + PA), a diet containing 100 g/kg inulin (FOS), or a FOS diet containing 7 g/kg PA (FOS + PA). The cecal enlargement together with the acidification of cecal pH in rats adapted to FOS diets led to an improved Ca and Mg cecal absorption. Mineral apparent absorption was significantly enhanced by FOS ingestion (Ca, +20%; Mg, +50%; Fe, +23%; Cu, +45%), whereas PA decreased this factor only for trace elements (Fe, -48%; Zn, -62%; Cu, -31%). These inhibitory effects of a FF + PA diet have repercussions on blood (Mg, -15%; Fe, -12%; transferrin saturation -31%), liver (Mg, -18%; Fe, -42%; Zn, -25%), and bone (Zn, -25%) variables. However, the introduction of FOS into a PA diet counteracted these observed deleterious effects by stimulating bacterial hydrolysis of PA (+60% in rats adapted to FOS + PA compared to those fed the FF + PA diet) and by improving cecal absorption of minerals.

Free radicals are likely involved in the aging process and there is a growing body of evidence that free radical damage to cellular function is associated with a number of age-related diseases such as atherosclerosis, cancer, and neurologic disorders. The present study was designed to evaluate in a healthy population the evolution with age of 8-epiPGF2alpha plasma levels, a recently proposed marker of in vivo lipid peroxidation. Moreover we investigated this marker of oxidative stress in patients with Alzheimer's disease (AD), an age-related neurodegenerative disorder in the development of which free radicals have been involved. Our results show that in the healthy population studied, despite decreased antioxidant defenses with increasing age as monitored by antioxidant capacity measurement, plasma 8-epiPGF2alpha levels were not correlated with age. Moreover, we have demonstrated that AD patients presented no modification of plasma 8-epiPGF2alpha level and no major alteration of the antioxidant status. In conclusion, the measurement of plasma 8-epiPGF2alpha did not allow us to detect alterations in oxidative stress with aging or in AD.

The thymine oxidative lesion-5-hydroxymethyluracil (HMUra)-was measured in urine collected from cancer patients. These patients all received chemotherapy using Adriamycin. Adriamycin (ADR) intercalates DNA coils and interferes with normal cell metabolism through diverse biochemical mechanisms that may explain its different actions. The anticancer action of ADR could derive from its interaction with topoisomerase II, resulting in DNA nicking followed by DNA fragmentation and apoptosis. Side effects of ADR-mainly its cardiotoxicity-may derive from the fact that ADR generates superoxide and hydroxyl radicals in two ways: redox-cycling and a Haber-Weiss type reaction due to Fe-ADR complexes. The oxygen free radicals, particularly .OH, are thought to be produced by ADR directly in genomic material and attack all its components. 5-Hydroxymethyluracil is a thymine lesion provoked by these attacks, and it has been proposed as a marker of DNA alterations. In this article, we report the results of a study involving 14 cancer patients treated with ADR. We found that urine HMUra is significantly increased by the anticancer therapy (HMUra (nmol/24 h): 74.4 9.46 vs. 96.3 8.74; p < .01), this increase reveals a higher risk of mutagenesis. Our study is the first to show an in vivo alteration of DNA by ADR. Results also show that thiobarbituric acid reactants increase significantly, and that the vitamin levels for retinol and alpha-tocopherol, which are antioxidant vitamins, are lower at the end of chemotherapy. We suggest to supplement these patients with vitamins A and E, and selenium to reduce the side effects of ADR.

Numerous experimental and clinical studies have reported a role of radical forms of oxygen in the etiology of the manifestations of reperfusion of the ischemic myocardium. However, clinical results remain controversial. The aim of this study was to ascertain the existence of reperfusion-related radical stress after thrombolysis with a marker that is easy to use and reliable. Thirty patients hospitalized for acute myocardial infarction were involved in the study. Of these, 18 had been subjected to intravenous thrombolysis (Group I) and 12 had not (Group II). They were compared to two control groups who had no history of myocardial infarction. Of these, 16 were patients with coronary heart disease hospitalized for stable angina (Group III) and 17 were patients free of any known cardiovascular disease (Group IV). Radical activity was assessed in plasma samples taken from a peripheral vein over a 10-day period of hospitalization by measuring (1) malondialdehydes (MDA) concentrations using fluorometry techniques or HPLC, (2) the antioxidant activity of glutathione peroxidase (GPx) and (3) the concentration of various antiradical compounds (beta-carotene, vitamins A and E, uric acid). All patients in Group I had a patent artery on coronary angiography and showed a significant increase in plasma MDA when compared to those who had not been subjected to thrombolysis (3.15 +/- 0.62 and 2.70 +/- 0.40 mole/l of plasma, respectively). Furthermore, GPx plasma activity was also significantly increased following thrombolysis. By contrast, there was no significant alteration in the antiradical compounds measured. These data suggest that MDA measurements (an early measurement 1-2 days and a late measurement 5-7 days after reperfusion) by fluorometry is a good marker of radical stress during reperfusion in man. The assessment of this marker in patients might represent a simple and reliable test of reperfusion efficacy following thrombolysis, and it might enable one to test the effect of various antioxidant therapies associated with thrombolytic treatment.

The aim of the present study was to assess whether an 8-wk oral selenium supplementation (standard food enriched with 2500 micrograms Se/kg) in rats might prevent the cardiotoxicity of adriamycin (ADR) treatment. ADR was administered at a dose of 2.5 mg/kg body wt intraperitoneally twice weekly for 3 wk. One week after the end of ADR treatment, rats (n = 10 per group) were killed and their hearts were perfused on a Langendorff mode and subjected to a 30-min period of low-flow ischemia (residual flow = 0.1 ml/min) followed by reperfusion (15 min). The results were as follows: 1) selenium supplementation significantly increased the activity of cardiac mitochondrial glutathione peroxidase (GPx) in ADR-treated rats (control: 206 +/- 17.4 IU/g protein; Se: 277 +/- 24.5 IU/g protein, p < 0.05); 2) selenium supplementation reduced myocardial malondialdehyde content in ADR-treated rats (control: 1220 +/- 49.1 nmol/g protein; Se: 1010 +/- 75.9 nmol/g protein; p < 0.05); and 3) ADR treatment significantly increased the degree of reperfusion-induced structural alterations to sarcomeres compared to untreated hearts. Again, this phenomenon was abolished by selenium supplementation. In conclusion, this study demonstrates that selenium supplementation is able to limit ADR cardiotoxicity in isolated rat hearts submitted to a sequence of ischemia/reperfusion.

Adriamycin (doxorubicin) is an antineoplastic drug used to treat various cancers; however, its chronic use is accompanied by cardiotoxicity. Previous results suggested that free radical formation may contribute to Adriamycin toxicity. Adriamycin-induced cardiotoxicity was examined in rats maintained on either standard or selenium-supplemented diets. Adriamycin was administered intraperitoneally; the cumulative dose was 15 mg/kg body weight. Selenium status, glutathione peroxidase activities, vitamin E, and MDA contents were determined on red blood cell (RBC) and cardiac homogenates. RBC selenium levels and selenium glutathione peroxidase activity were significantly increased in selenium-supplemented animals compared with control or placebo groups. However, Adriamycin-treated rats showed a significant decrease in RBC selenium and selenium glutathione peroxidase compared with the placebo group. Moreover, treatment with Adriamycin increased RBC MDA content, which was attenuated by the selenium supplementation. In parallel, RBC vitamin E decreased markedly in the Adriamycin-treated group and was totally restored by selenium supplementation. Cardiac biochemical analyses confirmed the blood results. Thus, a free radical mechanism does contribute to Adriamycin cardiotoxicity, and shows the importance of balancing selenium levels in Adriamycin-treated subjects to limit Adriamycin's action. A decrease in Adriamycin cardiotoxicity with no concomitant decrease in its antineoplastic activity would considerably improve the therapeutic benefit of the drug.