The attenuation of oxidative stress could be an important mechanism whereby the incidence of vascular complications in the MS (metabolic syndrome) may be diminished. The present study was undertaken to investigate the mechanism by which glycine, supplemented to the diet of SF (sucrose-fed) rats, modulates glutathione biosynthesis and protects against oxidative stress and altered endothelium-dependent relaxation in isolated aorta. Glycine reduced O2•- (superoxide anion radical) release in the presence of NADPH, and decreased protein carbonyl and lipid peroxidation. This effect of glycine could be because of the increased amount of glutathione synthetase, which may be responsible for increased glutathione (GSH) content in vascular tissue from SF rats. Moreover, glycine increased the amount of Cu,Zn-SOD (copper/zinc superoxide dismutase) and eNOS (endothelial NO synthase) in aorta from SF animals. Finally, it improved the relaxation response to ACh (acetylcholine) found impaired in aortic rings from SF rats. In the presence of NAC (N-acetylcysteine), a precursor of GSH, an improved ACh-mediated aortic relaxation of aortic rings from SF rats was observed, whereas BSO (buthionine sulfoximine), an inhibitor of glutathione biosynthesis, inhibited the relaxing effect of NAC in aortas from both control and SF rats. This experiment emphasizes the role of GSH in endothelial function in SF rats. The present data suggest that glycine rectifies vascular reactivity by increasing the biosynthesis of glutathione. Glutathione protects vascular tissue against oxidative stress, and enhances the availability of NO, which exerts its relaxing effect, thus contributing to the reduction of high BP (blood pressure) in the SF rats.

M. High-sucrose diet increases ROS generation, FFA accumulation, UCP2 level, and proton leak in liver mitochondria. Am J Physiol Endocrinol Metab 301: E1198 -E1207, 2011. First published September 13, 2011 doi:10.1152/ajpendo.00631.2010.-Obesity, a risk factor for insulin resistance, contributes to the development of type 2 diabetes and cardiovascular diseases. The relationship between increased levels of free fatty acids in the liver mitochondria, mitochondrial function, and ROS generation in rat model of obesity induced by a high-sucrose diet was not sufficiently established. We determined how the bioenergetic functions and ROS generation of the mitochondria respond to a hyperlipidemic environment. Mitochondria from sucrose-fed rats generated H2O2 at a higher rate than the control mitochondria. Adding fatty acid-free bovine serum albumin to mitochondria from sucrose-fed rats significantly reduced the rate of H2O2 generation. In contrast, adding exogenous oleic or linoleic acid exacerbated the rate of H2O2 generation in both sucrose-fed and control mitochondria, and the mitochondria from sucrose-fed rats were more sensitive than the control mitochondria. The increased rate of H2O2 generation in sucrose-fed mitochondria corresponded to decreased levels of reduced GSH and vitamin E and increased levels of Cu/Zn-SOD in the intermembrane space. There was no difference between the levels of lipid peroxidation and protein carbonylation in the two types of mitochondria. In addition to the normal activity of Mn-SOD, GPX and catalase detected an increased activity of complex II, and upregulation of UCP2 was observed in mitochondria from sucrose-fed rats, all of which may accelerate respiration rates and reduce generation of ROS. In turn, these effects may protect the mitochondria of sucrose-fed rats from oxidative stress and preserve their function and integrity. However, in whole liver these adaptive mechanisms of the mitochondria were inefficient at counteracting redox imbalances and inhibiting oxidative stress outside of the mitochondria. reactive oxygen species; free fatty acid; metabolic syndrome; mitochondrial function; oxidative stress; uncoupling protein 2 ABDOMINAL OBESITY AND HIGH LEVELS of circulating free fatty acids (FFAs) have been indicated as primary contributors to acquired insulin resistance and hypertension because they induce oxidative stress that affects insulin signaling and nitric oxide availability (30, 11). Insulin resistance leads to continuous lipolysis within adipocytes, releasing FFAs into the local circulation, where they are transported into the liver. In the liver, FFAs can be incorporated into triglycerides that accumulate and lead to nonalcoholic fatty liver disease, the primary hepatic complication of obesity (13, 57). Oxidative stress and mitochondrial dysfunction have been shown to play a critical role in the initiation and progression of fatty liver to the more serious condition of nonalcoholic steatohepatitis in obesity models (15,21,38). Several studies using an animal model of fa...

Metabolic syndrome (MS) is an obesity-associated collection of disorders, each of which contributes to cardiovascular risk. For patients with MS, it is difficult to follow a diet/exercise regime that would improve their symptoms. Therefore, the investigation of agents that may deal with its more serious aspects is an important medical field for research. Numerous experimental studies have confirmed the important role of medicinal plants or their active components in the prevention and treatment, and in lowering risk factors of MS. As oxidative stress and inflammation are involved in the association between obesity, insulin resistance (IR) and hypertension, antioxidant and anti-inflammatory plant components like polyphenols might be useful as a treatment for MS. The aqueous extract of Hibiscus Sabdariffa L (HSE), rich in several polyphenols, is commonly and effectively used in native medicines against hypertension, diabetes and liver disorders. HSE has also shown therapeutic promise in the prevention of MS in patients, probably due to its polyphenol content. Curcumins, derived from the spice turmeric, and resveratrol, polyphenols found in grapes and red wine respectively, in addition to their antioxidant and anti-inflammatory properties, inhibit preadipocyte proliferation, de novo lipogenesis and fat accumulation in liver. Thus, due to their efficacy in the regulation of multiple targets, polyphenols have received considerable interest as potential therapeutic agents for the prevention and treatment of MS. This review discusses the therapeutic use of HSE, as well as curcumin and resveratrol, in the context of obesity as an initiator of insulin resistance and hypertension, the two main features of MS, together with the underlying mechanisms of action.

Metabolic diseases such as obesity, metabolic syndrome, and type II diabetes are often characterized by increased reactive oxygen species (ROS) generation in mitochondrial respiratory complexes, associated with fat accumulation in cardiomyocytes, skeletal muscle, and hepatocytes. Several rodents studies showed that lipid accumulation in cardiac myocytes produces lipotoxicity that causes apoptosis and leads to heart failure, a dynamic pathological process. Meanwhile, several tissues including cardiac tissue develop an adaptive mechanism against oxidative stress and lipotoxicity by overexpressing uncoupling proteins (UCPs), specific mitochondrial membrane proteins. In heart from rodent and human with obesity, UCP2 and UCP3 may protect cardiomyocytes from death and from a state progressing to heart failure by downregulating programmed cell death. UCP activation may affect cytochrome c and proapoptotic protein release from mitochondria by reducing ROS generation and apoptotic cell death. Therefore the aim of this review is to discuss recent findings regarding the role that UCPs play in cardiomyocyte survival by protecting against ROS generation and maintaining bioenergetic metabolism homeostasis to promote heart protection.

Cytochrome c release from mitochondria has been described to be related to reactive oxygen species (ROS) generation. With ROS generation being increased in fatty liver from sucrose-fed (SF) rats, we hypothesized that cytochrome c release might be positively associated with H2O2 generation from SF mitochondria. Surprisingly, cytochrome c release from mitochondria of SF liver was found to be significantly lower compared with control (C) mitochondria oxidizing pyruvate/malate or succinate. Exposure of mitochondria to exogenous superoxide radical generated by the xanthine/xanthine oxidase system elicits a dose-response cytochrome c release in both control and SF mitochondria, but cytochrome c release remains lower in SF mitochondria compared with C mitochondria. Furthermore, the addition of ebselen, PEG-catalase, or catalase, a H2O2 scavenger, significantly reduces cytochrome c release from C and SF mitochondria. Our results suggest that both intra- and extramitochondrial H2O2 are involved in cytochrome c release, but the persisting difference between C and SF levels can be attributed to the differences in cardiolipin compositions. Indeed, the ratio of palmitic acid-rich cardiolipin species was found to be increased in lipid membrane from SF mitochondria compared with C mitochondria, whereas that of linoleic acid-rich cardiolipin species was found decreased. In addition, the content of tafazzin, a protein responsible for cardiolipin remodeling, was decreased in SF mitochondria. Therefore, we conclude that the changes observed in the composition of cardiolipin molecular species in SF mitochondria may be involved in cytochrome c interaction with mitochondrial inner membrane lipid and in its reduced release from SF mitochondria.

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In metabolic diseases such as obesity, metabolic syndrome and type II diabetes, the over-expression of uncoupling proteins (UCPs) in a response to increased reactive oxygen species (ROS) generation by mitochondrial respiratory complexes, and to the excess of free fatty acid (FFA) supply from adipose tissue, may protect cells from oxidative stress, lipotoxicity and in turn from death. UCPs by reducing superoxide anion and H2O2 generation trigger several signals to cell for their adaptation to the lipotoxic microenvironment. In mitochondria, a decrease of cytochrome c (cyt c) and proapoptotic protein release promotes cell survival and proliferation. The altered lipid metabolism also affects cardiolipin susceptibility to the peroxidation, a process involved in the dissociation of cyt c from mitochondrial inner membrane and its release, a key step of apoptosis. Therefore, UCPs by attenuating ROS generation and lipotoxicity may downregulate programmed cell death, a well-known physiological process controlling cell proliferation contributing to uncontrolled cell proliferation and tumorigenesis. In addition, tumor cells over-expressed UCPs, by inhibiting ROS generation acquire resistance to death during pharmacological treatment with oxidative stress drug inducers. Therefore, the aim of this review is to discuss recent findings regarding the role that UCPs play in cell survival by protecting against ROS generation and maintaining bioenergetic metabolism homeostasis to promote cell proliferation.

The mechanistic link between obesity and renal failure has been proposed to involve mitochondria reactive oxygen species generation and lipotoxicity. These pathological conditions make mitochondria of particular interest in the regulation of cell function and death by both apoptosis and autophagy. Therefore, this work was undertaken to investigate mitochondria function, autophagy, and apoptosis protein markers in the kidney from a rat model of intra-abdominal obesity and renal damage induced by a high-sucrose diet. Mitochondria from sucrose-fed (SF) kidneys in the presence of pyruvate-malate generated H2O2 at a higher rate than from control (79.81 ± 4.98 vs. 65.84 ± 1.95 pmol·min−1·mg protein−1). With succinate, the release of H2O2 was significantly higher compared with pyruvate-malate, and it remained higher in SF than in control mitochondria (146.4 ± 8.8 vs. 106.1 ± 5.9 pmol·min−1·mg protein−1). However, cytochrome c release from SF kidney mitochondria was lower than from control. In addition, cardiolipin, a mitochondria-specific phospholipid, was found increased in SF mitochondria due to the enhanced amount of both cardiolipin synthase and tafazzin. Cardiolipin was also found enriched with saturated and monounsaturated fatty acids, which are less susceptible to peroxidative stress involved in cytochrome c release. Furthermore, beclin-1 and light chain 3-B, as autophagy protein markers, and caspase-9, as apoptosis protein marker, were found decreased in SF kidneys. These results suggest that the decline of autophagy protein markers and the lack of apoptosis process could be a pathological mechanism of cell dysfunction leading to the progression of renal disease in SF rats.