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Antioxidant and anti-inflammatory properties of gamma- oryzanol attenuates insulin resistance by increasing GLUT- 4 expression in skeletal muscle of obese animals
Abstract
Background
Skeletal muscle is the most important organ for whole-body glucose homeostasis. However, it has been suggested that obesity-related inflammation could be involved in insulin resistance and diabetes mellitus type 2 (DM2) development due several mechanisms, among them, the reduced expression of the glucose transporter type 4 (GLUT-4). Gamma-oryzanol (γOz) is a compound present in the whole grain of rice that presents anti-inflammatory and antioxidant activities. The aim of this study was to verify if the effect antioxidant and anti-inflammatory of yOz attenuate insulin resistance in skeletal muscle of obese rats by increasing GLUT- 4 expression.
Methods
Male Wistar rats (±187g) were initially randomly distributed into 2 experimental groups (control, n = 6, and high sugar-fat diet (HSF), n = 12) for 20 weeks. At week 20th of this study, once obesity and insulin resistance were detected in the HSF group, animals were divided to begin the treatment with γOz or continue receiving HSF for 10 more weeks. At the end it was analyzed nutritional, metabolic, inflammatory and oxidative stress parameters and GLUT-4 protein expression.
Results
The treatment improved insulin resistance, reduced inflammation, increased antioxidant response and GLUT-4 expression.
Conclusion
It is possible to conclude that the antioxidant and anti-inflammatory activity of yOz attenuates insulin resistance by increasing GLUT-4 expression in skeletal muscle of obese animals.
... Furthermore, increased plasma-free fatty acids can stimulate adiponectin secretion. Aerobic training, by increasing lipolysis [39,40] and crocin (one of saffron's components) by inhibiting pancreatic lipase, which indirectly leads to malabsorption of fat, could lead to an increase in plasma-free fatty acids and stimulate adiponectin secretion [41]. In addition, decreasing insulin resistance might be another reason for increasing adiponectin. ...
Background: This study aimed to investigate the effects of 8-week aerobic training (AT) and saffron supplementation on inflammation and metabolism in middle-aged obese women with type 2 diabetes mellitus (T2DM). Methods: Thirty-two obese women with T2DM were randomly divided into four groups (n = 8 in all groups): saffron + training (ST), placebo + training (PT), saffron supplementation (SS), and placebo (P). The ST and PT groups performed eight weeks of aerobic training (AT) (three sessions/week at 60–75% HRmax). A daily dose of 400 mg saffron powder was consumed by the ST and SS groups for 8 weeks. Blood samples were taken after 12 h of fasting, 48 h before the first AT session, 48 h and two weeks after the last AT session. Results: AT, saffron supplementation, and their combination affected body mass index (BMI), homeostatic model assessment for insulin resistance (HOMA-IR), and serum levels of insulin, adiponectin, interleukin-6 (IL-6), high-density lipoprotein cholesterol (HDL-C), cholesterol, and triglyceride (TG) (p < 0.05). However, body weight, body fat percentage, and serum levels of glucose, resistin, tumor necrosis factor-alpha (TNF-α), irisin, and low-density lipoprotein cholesterol (LDL-C) showed significant changes in the ST group only (p < 0.05). In addition, a significant difference was seen between all factors in post-training and follow-up in the ST group (p < 0.05). Conclusions: Saffron supplementation at a dose of 400 mg/day, when combined with AT, could improve inflammation, metabolism, glycemic status, and lipid profile in T2DM patients, and these changes are sustainable at up to 2 weeks of detraining.
... By binding to PPARδ and ERRγ directly, γ-oryzanol could upregulate mitochondrial biogenesis and alleviate inflammation, reducing the occurrence of muscle weakness of the aged mice [121]. Moreover, γ-oryzanol supplementation is demonstrated to promote GLUT4 translocation, alleviating insulin resistance in obese mice [122]. In addition, the antioxidant function of γ-oryzanol in muscle could be enhanced under an exercise condition [123], suggesting the physical exercise combined with γ-oryzanol supplementation might be a beneficial strategy to prevent muscle dysregulation. ...
Skeletal muscle plays a primary role in metabolic health and physical performance. Conversely, skeletal muscle dysfunctions such as muscular dystrophy, atrophy and aging-related sarcopenia could lead to frailty, decreased independence and increased risk of hospitalization. Dietary intervention has become an effective approach to improving muscle health and function. Evidence shows that whole grains possess multiple health benefits compared with refined grains. Importantly, there is growing evidence demonstrating that bioactive substances derived from whole grains such as polyphenols, γ-oryzanol, β-sitosterol, betaine, octacosanol, alkylresorcinols and β-glucan could contribute to enhancing myogenesis, muscle mass and metabolic function. In this review, we discuss the potential role of whole-grain-derived bioactive components in the regulation of muscle function, emphasizing the underlying mechanisms by which these compounds regulate muscle biology. This work will contribute toward increasing awareness of nutraceutical supplementation of whole grain functional ingredients for the prevention and treatment of muscle dysfunctions.
... On the other hand, the HSF plus γOz group that received the compound along with the HSF diet presented, at the end of the experiment, insulin resistance attenuation, lower plasma insulin and triglycerides levels, and lower hepatic values of IL-6 and TNF-α. These results confirm the positive effect of gamma oryzanol on obesity-related disorders and the reduction in inflammation [11,20,29]. ...
Nonalcoholic fatty liver disease (NAFLD) is the main cause of liver disease. The physiopathological processes involved in the disease are metabolic syndrome (MetS) components (central obesity, dyslipidemia, insulin resistance/type 2 diabetes, hypertension), genetic, and dietary factors, including unsaturated fats and sweetened beverages, which are able to lead to inflammation and oxidative stress, conditions associated with progression and severity of NAFLD. Gamma-oryzanol (γOz) is a nutraceutical obtained from rice brain oil with many benefits to health, from immunological to metabolic. The aim of this study is to test the preventive effect of γOz on the physiopathological process related to nonalcoholic fatty liver disease in animals submitted to high sugar/fat diet. Male Wistar rats (±187 g) were randomly divided into four experimental groups to receive: control diet (C, n = 6), control diet plus γOz (C + γOz, n = 6), high sugar/fat diet (HSF, n = 6), or high sugar/fat diet plus γOz (HSF + γOz, n = 6) during 30 weeks. HSF groups also received water plus sucrose (25%). γOz was added to diets to reach 0.5% of final concentration. The HSF group presented MetS, liver inflammation and oxidative stress, and micro and macrovesicular steatosis. HSF plus γOz was protected against these changes. It is possible to conclude that gamma-oryzanol was effective in modulating the physiopathological process related to nonalcoholic fatty liver disease in animals submitted to a high sugar/fat diet.
... Oxidative stress and associated damage to the glucose transporter i.e., glucose transporter type 4 (GLUT4) and peroxisome proliferator-activated receptor-γ (PPAR-γ) underlie the mechanism of diabetes and obesity development. So, it can be assumed that foods of particular health-promoting value are those groups of grapes that, in addition to possessing the property of acting on glucose transporter type 4 (GLUT4) and peroxisome proliferatoractivated receptors-γ (PPAR-γ), also have high antioxidant properties, (providing oxidative protection to these receptors) [22]. ...
Non-commercial hybrid grapevine cultivars, usually used for dessert purposes or as ornamental garden plants, may contain a wealth of bioactive substances and thus can be regarded as highly valuable food resources. Antioxidant properties and selected groups of polyphenolic components in the three fractions of fruits: peel, pulp and juice; of five hybrid grape cultivars grown in Poland—Michigan, Alwood, Minnesota, V68021 and Beta—were analyzed and characterized. The liquid chromatography coupled with tandem mass spectrometry (LC-MS-PDA-Q/TOF and UPLC-PDA), total polyphenols, flavonoids and anthocyanins, and DPPH, ABTS and FRAP were used for evaluation of antioxidant potential qualitatively and quantitatively as well as simple reductive sugars were measured. The antioxidant activity and polyphenols content depend mainly on the grape fruit fraction, while they depend to a lesser extent on the cultivar of the hybrid grapes studied. It was confirmed that grape skins are characterized by high antioxidant activity and their bioactive characteristics are similar to many hybrid grape cultivars grown in southern and Mediterranean regions of Europe. Especially grape skins of Alwood and Beta cultivars were characterized by a particularly high content of polyphenolic compounds, mainly from the flavonoid and anthocyanin group and a low content of simple sugars.
... GLUT4 and GLUT1 are the two most important glucose transporters in skeletal muscle [36]. GLUT4 is sensitive to insulin, and researchers found oryzanol attenuates insulin resistance by increasing GLUT4 expression in skeletal muscle [37]. We found that GLUT1 is downregulated and GLUT4 is up-regulated during differentiation. ...
Glucose 6-P dehydrogenase (G6PD) is the first rate-limiting enzyme in pentose phosphate pathway (PPP), and it is proverbial that G6PD is absent in skeletal muscle. However, how and why G6PD is down-regulated during skeletal muscle development is unclear. In this study, we confirmed the expression of G6PD was down-regulated during myogenesis in vitro and in vivo. G6PD was absolutely silent in adult skeletal muscle. Histone H3 acetylation and DNA methylation act together on the expression of G6PD. Neither knock-down of G6PD nor over-expression of G6PD affects myogenic differentiation. Knock-down of G6PD significantly promotes the sensitivity and response of skeletal muscle cells to insulin; over-expression of G6PD significantly injures the sensitivity and response of skeletal muscle cells to insulin. High-fat diet treatment impairs insulin signaling by up-regulating G6PD, and knock-down of G6PD rescues the impaired insulin signaling and glucose uptake caused by high-fat diet treatment. Taken together, this study explored the importance of G6PD deficiency during myogenic differentiation, which provides new sight to treat insulin resistance and type-2 diabetes.
... It exhibits a variety of biological activities such as lowering serum cholesterol, reducing menopausal syndrome, improving insulin sensitivity, reducing skin-related diseases, and inhibiting the growth of cancer cell (Juliano et al., 2005;Mattei et al., 2021). Previous studies were reported that Orz could suppress H 2 O 2 -induced cell apoptosis by inhibiting ROS-mediated mitochondrial signaling pathway (Huang et al., 2020;Tang et al., 2016). ...
Gamma‐oryzanol (Orz), a mixture of the ferulic acid ester of triterpene alcohols and phytosterols, was found abundantly in rice bran and rice bran oil which could be available and served as an antioxidant. The present study was to explore the potential protective effects of Orz on oxidative stress and cell apoptosis in human hepatic cells (L02 cells) induced by hydrogen peroxide (H2O2). Flow cytometry detection and Hoechst 33258 staining showed that Orz significantly restored cell cycle and ameliorated apoptosis in H2O2‐challenged L02 cells. Orz pretreatment inhibited H2O2‐induced cell apoptosis by increasing the scavenging of hydroxyl radicals (OH·), and efficiently decreasing the production of nitric oxide (NO). Moreover, a loss of total antioxidant capacity (T‐AOC) and adenosine triphosphatase (ATPase) were enhanced in H2O2‐mediated L02 cells pretreated with Orz. Furthermore, preincubation with Orz reduced H2O2‐mediated the proapoptotic protein of Bak expression and the phosphorylation of ASK1, p38, JNK, and ERK, and increased the anti‐apoptotic protein of Bcl‐xl expression and anti‐oxidative stress proteins of Nrf2 and HO‐1 expression. The findings suggested that Orz exerts the cytoprotective effects in H2O2‐induced L02 cells apoptosis by ameliorating oxidative stress via inhibiting MAPK signaling pathway and activating Nrf2 signaling pathway.
Practical applications
Gamma‐oryzanol (Orz), a mixture of the ferulic acid ester of triterpene alcohols and phytosterols, was found abundantly in rice bran and rice bran oil which could be availably served as an antioxidant. In this study, it was found that Orz exerts the cytoprotective effects in H2O2‐induced L02 cell apoptosis by ameliorating oxidative stress via the inhibition of MAPK signaling pathway and the activation of Nrf2 signaling pathway, which provides a theoretical basis for dietary adding natural products to prevent or treat oxidative stress‐related diseases.
... γ-Oryzanol, initially reported as single component, is now known to be a mixture of 10 molecules, with cycloartenyl ferulate, 24-methylene cycloartanyl ferulate and campesteryl ferulate as major components (Sawada et al., 2021). The health benefits associated with γ-oryzanol include antinflammatory, antioxidant and chemopreventive properties (Burlando, and Cornara, 2014;Kim et al., 2012;Mattei et al., 2021). It has also been proposed in the treatment of diabetes mellitus and prostate cancer (Kozuka et al., 2015;Son et al., 2011). ...
A big challenge for our century concerns discovering new foods, including re-discovering ancient wheat. Phenolic and steryl ferulates composition of Tuscan and Campania wheat samples was evaluated by HPLC-DAD-MS/MS. Cinnamic acids and flavonoids were expressed as ferulic acid and schaftoside equivalents, respectively. Agronomic conditions with a higher rate of plants/m² promoted higher amounts of phenols in most of the Tuscan varieties. The ancient varieties Gentil Rosso (1137 µg/mg dry weight) and Carosella 2 (854 µg/mg dry weight) showed the highest phenols amount, determined by HPLC-DAD. Steryl ferulates were expressed as ferulic acid equivalents. Campestanyl and sitostanyl ferulates were found as main steryl ferulates compounds in wheat, differently from rice, millet and sorghum; 10 steryl ferulates and 2 caffeoyl phytosterols were tentatively identified. Total steryl ferulates in Tuscan and Campania wheat samples ranged from 37.6–62.3 µg/g dry weight and from 14.4–56.6 µg/g dry weight, respectively. Ancient whole wheat pasta showed 50 % higher steryl ferulates with respect to modern whole wheat pasta. The study compared for the first time the content of γ-oryzanol derivatives in ancient and modern wheat varieties.
Type 2 diabetes mellitus (T2DM) is characterized by the dysregulation of glucose homeostasis, resulting in hyperglycemia. However, concerns have been raised about the safety and efficacy of current hypoglycemic drugs due to undesirable side effects. Increasing studies have shown that whole grains (WG) consumption is inversely associated with the risk of T2DM and its subsequent complications. Thus, dietary strategies involving functional components from the WG provide an intriguing approach to restoring and maintaining glucose homeostasis. This review provides a comprehensive understanding of the major functional components derived from WG and their positive effects on glucose homeostasis, demonstrates the underlying molecular mechanisms targeting hepatic glucose metabolism, and discusses the unclear aspects according to the latest viewpoints and current research. Improved glycemic response and insulin resistance were observed after consumption of WG-derived bioactive ingredients, which are involved in the integrated, multi-factorial, multi-targeted regulation of hepatic glucose metabolism. Promotion of glucose uptake, glycolysis, and glycogen synthesis pathways, while inhibition of gluconeogenesis, contributes to amelioration of abnormal hepatic glucose metabolism and insulin resistance by bioactive components. Hence, the development of WG-based functional food ingredients with potent hypoglycemic properties is necessary to manage insulin resistance and T2DM.
Skeletal muscle injuries are common, and damaged myofibers are repaired through proliferation and differentiation of muscle satellite cells. GLUT4 is enriched in GLUT4 storage vesicles (GSVs) and plays a crucial role in the maintenance of muscle function. ArfGAP3 regulates the vesicle transport especially for COPI coat assembly, but its effects on GSVs and the repair process after skeletal muscle injury remains unclear. In this study, datasets related to skeletal muscle injury and myoblast differentiation GSE469, GSE5413, GSE45577 and GSE108040 were retrieved through the GEO database and the expression of heptameric coat protein complex I (COPI) and Golgi vesicle transport-related genes in various datasets, as well as the expression correlation between ArfGAP2, ArfGAP3 and COPI-related genes COPA, COPB1, COPB2, COPE, COPZ1, COPZ2 were analyzed. The results suggested that ArfGAP3 was expressed in the process of repair after skeletal muscle injury and myoblast differentiation and that ArfGAP3 was positively correlated with COPI-related genes. In vitro experimental results showed that ArfGAP3 was colocalized with COPA, COPB, COPG protein, and GLUT4 in C2C12 myoblasts. After the downregulation of ArfGAP3 expression, intracellular vesicle transport, and glucose uptake were blocked, the proliferation of myoblasts under low glucose culture conditions was impaired, the proportion of apoptosis increased, and myotube differentiation was impaired. In summary, ArfGAP3 regulates COPI-associated vesicle and GSVs transport and affects the proliferation and differentiation ability of myoblasts by influencing glucose uptake, thereby modulating the repair process after skeletal muscle injury.
Muscle atrophy is a reduction of muscle mass and size that occurs after the age of 30. The effects of the solid dispersions of curcumin (CURSD) and gamma-oryzanol (GOSD) were investigated on skeletal muscle of middle-aged Sprague-Dawley rats (12 months old) and compared to young rats (4 months old). A mixture of CURSD and GOSD supplements (GO-CURSD) increased antioxidant enzymes through the Nrf2 pathway which caused a reduction in lipid peroxidation and pro-inflammations, resulting in less muscle damage. The GO-CURSD increased IRS1-AKT-mTOR activity and suppressed Atrogin-1 and MuRF-1 genes, resulting in increased muscle mass and cross-sectional area. In addition, the GO-CURSD increased muscular glucose uptake and glycogen via IRS1-Akt up-regulated GLUT4 expression. These results suggest that the synergistic effect of CURSD and GOSD against age-related muscle atrophy regulated by increasing the antioxidant and anti-inflammatory activities, as well as improving muscle energy storage via the Nrf2 and IGF1/Insulin-Akt-mTOR signaling pathway.
The prevalence of type 2 diabetes has been growing at an increasing rate worldwide. Dietary therapy is probably the easiest and least expensive method to prevent and treat diabetes. Previous studies have reported that coarse grains have anti-diabetic effects. Although considerable efforts have been made on the anti-diabetic function of different grains, the mechanisms of coarse grains on type 2 diabetes have not been systematically compared and summarized so far. Intestinal flora, reported as the main "organ" of action underlying coarse grains, is an important factor in the alleviation of type 2 diabetes by coarse grains. Furthermore, miRNA, as a new disease marker and "dark nutrient", plays a likely influential role in cross-border communication among coarse grains, intestinal flora, and hosts. Given this context, this paper reviews several possible mechanisms for the role of coarse grains on diabetes, incorporating resistance to inflammation and oxidative stress, repair of insulin signaling and β-cell dysfunction, and highlights the regulation of intestinal flora disorders and miRNAs expression, along with some novel insights. This article is protected by copyright. All rights reserved.
Insulin resistance is a salient player in the pathogenesis of obesity and its related abnormal glucose-insulin homeostasis. Red rice bran extract (RRBE) demonstrates several bioactive phytochemicals with anti-diabetic properties. However, little is known about its molecular mechanisms. Therefore, the present study was designed to investigate the anti-insulin resistant mechanisms of RRBE in a model of high-fat diet (HFD)-induced insulin resistance. In this study, mice were randomly divided into four groups: low-fat diet with distilled water (Group L), HFD with distilled water (Group H), HFD with 0.5 g/kg RRBE, and HFD with 1 g/kg RRBE. Metabolic parameters, histological changes in the pancreas, and gene expression levels were evaluated after treating HFD-fed mice with RRBE for six weeks. Mice from Group H exhibited significantly higher blood glucose levels prior to and after an oral glucose tolerance test, fasting serum insulin levels, islet size, pancreatic insulin expression levels, and lower skeletal muscle insulin-degrading enzyme (IDE) expression levels compared to Group L. In contrast, these were all significantly restored in the RRBE-treated groups. Also, RRBE treatment was found to upregulate the expression of insulin receptor substrate (IRS) and glucose transporter (GLUT) genes in the adipose tissues and GLUT genes in the muscles and livers of HFD-fed mice. According to our results, RRBE may ameliorate abnormal glucose-insulin metabolism by modulating the expression of insulin, IDE, IRS, and GLUT genes in the major metabolic target tissues of mice after being fed with HFD.
Background:
The effects of dietary fat on health are influenced by its fatty acid profile. We aimed to determine the effects of monounsaturated fatty acid (MUFA)-rich blended oils (BO) containing a balance of polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFAs) and with a low n-6/n-3 PUFA ratio on the health of rats fed normal or high-fat diets. The BO was obtained by mixing red palm oil, rice bran oil (RO), tea seed oil, and flaxseed oil in appropriate proportions.
Results:
BO consumption reduced the serum low-density lipoprotein cholesterol (LDL-C), non-esterified fatty acid (NEFA), insulin (INS), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1), high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), lipid peroxide (LPO) and oxidized LDL (ox-LDL) concentrations and the homeostasis model assessment of insulin resistance (HOMA-IR); and increased the high-density lipoprotein cholesterol (HDL-C), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) concentrations and the bone mineral density (BMD) versus control oil-containing normal and high-fat diets. BO also reduced the triglyceride (TG), hs-CRP, MDA, ox-LDL, and reactive oxygen species (ROS) concentrations; and increased the serum HDL-C and SOD, and BMD versus RO-containing high-fat diets. Finally, BO reduced the glucose (GLU) and INS, and HOMA-IR; and increased HDL-C, SOD, femoral weight, and BMD versus RO-containing normal diets.
Conclusion:
BOs with an appropriate fatty acid profile have beneficial effects on the glucolipid metabolism, inflammation, oxidative stress, and bone quality of rats when included in both normal and high-fat diets. This article is protected by copyright. All rights reserved.
Physical exercise can be effective in preventing or ameliorating various diseases, including diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. However, not everyone may be able to participate in exercise due to illnesses, age-related frailty, or difficulty in long-term behavior change. An alternative option is to utilize pharmacological interventions that mimic the positive effects of exercise training. Recent studies have identified signaling pathways associated with the benefits of physical activity and discovered exercise mimetics that can partially simulate the systemic impact of exercise. This review describes the molecular targets for exercise mimetics and their effect on skeletal muscle and other tissues. We will also discuss the potential advantages of using natural products as a multi-targeting agent for mimicking the health-promoting effects of exercise.
Obesity associated with systemic inflammation induces insulin
resistance (IR), with consequent chronic hyperglycemia. A series of
reactions are involved in this process, including increased release
of proinflammatory cytokines, and activation of c-Jun N-terminal
kinase (JNK), nuclear factor-kappa B (NF-κB) and toll-like receptor
4 (TLR4) receptors. Among the therapeutic tools available
nowadays, physical exercise (PE) has a known hypoglycemic
effect explained by complex molecular mechanisms, including
an increase in insulin receptor phosphorylation, in AMP-activated
protein kinase (AMPK) activity, in the Ca2+/calmodulin-
dependent protein kinase kinase (CaMKK) pathway, with
subsequent activation of peroxisome proliferator-activated
receptor gamma coactivator 1-alpha (PGC-1α), Rac1, TBC1
domain family member 1 and 4 (TBC1D1 and TBC1D4), in
addition to a variety of signaling molecules, such as GTPases,
Rab and soluble N-ethylmaleimide-sensitive factor attached
protein receptor (SNARE) proteins. These pathways promote
greater translocation of GLUT4 and consequent glucose uptake
by the skeletal muscle. Phosphoinositide-dependent kinase
(PDK), atypical protein kinase C (aPKC) and some of its isoforms,
such as PKC-iota/lambda also seem to play a fundamental
role in the transport of glucose. In this sense, the association
between autophagy and exercise has also demonstrated a
relevant role in the uptake of muscle glucose. Insulin, in turn,
uses a phosphoinositide 3-kinase (PI3K)-dependent mechanism,
while exercise signal may be triggered by the release of calcium
from the sarcoplasmic reticulum. The objective of this review
is to describe the main molecular mechanisms of IR and the
relationship between PE and glucose uptake.
The system redox imbalance is one of the pathways related to obesity-related cardiac dysfunction. Lycopene is considered one of the best antioxidants. The aim of this study was to test if the tomato-oleoresin would be able to recovery cardiac function by improving β-adrenergic response due its antioxidant effect. A total of 40 animals were randomly divided into two experimental groups to receive either the control diet (Control, n = 20) or a high sugar-fat diet (HSF, n = 20) for 20 weeks. Once cardiac dysfunction was detected by echocardiogram in the HSF group, animals were re- divided to begin the treatment with Tomato-oleoresin or vehicle, performing four groups: Control (n = 6); (Control + Ly, n = 6); HSF (n = 6) and (HSF + Ly, n = 6). Tomato oleoresin (10 mg lycopene/kg body weight (BW) per day) was given orally every morning for a 10-week period. The analysis included nutritional and plasma biochemical parameters, systolic blood pressure, oxidative parameters in plasma, heart, and cardiac analyses in vivo and in vitro. A comparison among the groups was performed by two-way analysis of variance (ANOVA). Results: The HSF diet was able to induce obesity, insulin-resistance, cardiac dysfunction, and oxidative damage. However, the tomato-oleoresin supplementation improved insulin-resistance, cardiac remodeling, and dysfunction by improving the β-adrenergic response. It is possible to conclude that tomato-oleoresin is able to reduce the oxidative damage by improving the system’s β-adrenergic response, thus recovering cardiac function.
Background: The higher consumption of fat and sugar are associated with obesity development and its related diseases such as non-alcoholic fatty liver disease (NAFLD). Lycopene is an antioxidant whose protective potential on fatty liver degeneration has been investigated. The aim of this study was to present the therapeutic effects of lycopene on NAFLD related to the obesity induced by a hypercaloric diet. Methods: Wistar rats were distributed in two groups: Control (Co, n = 12) and hypercaloric (Ob, n = 12). After 20 weeks, the animals were redistributed into the control group (Co, n = 6), control group supplemented with lycopene (Co+Ly, n = 6), obese group (Ob, n = 6), and obese group supplemented with lycopene (Ob+Ly, n = 6). Ob groups also received water + sucrose (25%). Animals received lycopene solution (10 mg/kg/day) or vehicle (corn oil) via gavage for 10 weeks. Results: Animals which consumed the hypercaloric diet had higher adiposity index, increased fasting blood glucose, hepatic and blood triglycerides, and also presented in the liver macro and microvesicular steatosis, besides elevated levels of tumor necrosis factor-α (TNF-α). Lycopene has shown therapeutic effects on blood and hepatic lipids, increased high-density lipoprotein cholesterol (HDL), mitigated TNF-α, and malondialdehyde (MDA) and further improved the hepatic antioxidant capacity. Conclusion: Lycopene shows therapeutic potential to NAFLD.
Obesity is considered to significantly increase the risk of the development of a vast range of metabolic diseases. However, adipogenesis is a complex physiological process, necessary to sequester lipids effectively to avoid lipotoxicity in other tissues, like the liver, heart, muscle, essential for maintaining metabolic homeostasis and has a crucial role as a component of the innate immune system, far beyond than only being an inert mass of energy storage. In pathophysiological conditions, adipogenesis promotes a pro-inflammatory state, angiogenesis and the release of adipokines, which become dangerous to health. It results in a hypoxic state, causing oxidative stress and the synthesis and release of harmful free fatty acids. In this review, we try to explain the mechanisms occurring at the breaking point, at which adipogenesis leads to an uncontrolled lipotoxicity. This review highlights the types of adipose tissue and their functions, their way of storing lipids until a critical point, which is associated with hypoxia, inflammation, insulin resistance as well as lipodystrophy and adipogenesis modulation by Krüppel-like factors and miRNAs.
It is known that green tea helps prevent obesity and diabetes mellitus. In this study, we aimed to determine whether green tea ameliorates hyperglycemia and the mechanism involved in diabetic rodents. Green tea consumption reduced blood glucose and ameliorated glucose intolerance, which was assessed using an oral glucose tolerance test in both streptozotocin-induced type 1 diabetic rats and type 2 diabetic KK-Ay mice. Green tea also reduced the plasma fructosamine and glycated hemoglobin concentrations in both models. Furthermore, it increased glucose uptake into the skeletal muscle of both model animals, which was accompanied by greater translocation of glucose transporter 4 (GLUT4). Moreover, epigallocatechin gallate (EGCG), the principal catechin in green tea, also ameliorated glucose intolerance in high-fat diet-induced obese and diabetic mice. These results suggest that green tea can ameliorate hyperglycemia in diabetic rodents by stimulating GLUT4-mediated glucose uptake in skeletal muscle, and that EGCG is one of the effective compounds that mediate this effect.
Oxidative stress is implicated in the pathogenesis of neurodegeneration and other aging-related diseases. Previous studies have found that the whole herb of Centipeda minima has remarkable antioxidant activities. However, there have been no reports on the neuroprotective effects of C. minima , and the underlying mechanism of its antioxidant properties is unclear. Here, we examined the underlying mechanism of the antioxidant activities of the ethanol extract of C. minima (ECM) both in vivo and in vitro and found that ECM treatment attenuated glutamate and tert-butyl hydroperoxide (tBHP)-induced neuronal death, reactive oxygen species (ROS) production, and mitochondria dysfunction. tBHP-induced phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinases (JNK) was reduced by ECM, and ECM sustained phosphorylation level of extracellular signal regulated kinase (ERK) in SH-SY5Y and PC12 cells. Moreover, ECM induced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the upregulation of phase II detoxification enzymes, including heme oxygenase-1 (HO-1), superoxide dismutase-2 (SOD2), and NAD(P)H quinone oxidoreductase-1 (NQO-1) in both two cell types. In a D-galactose (D-gal) and aluminum muriate (AlCl 3 )-induced neurodegenerative mouse model, administration of ECM improved the learning and memory of mice in the Morris water maze test and ameliorated the effects of neurodegenerative disorders. ECM sustained the expression level of postsynaptic density 95 (PSD95) and synaptophysin (SYN), activated the Nrf2 signaling pathway, and restored the levels of cellular antioxidants in the hippocampus of mice. In addition, four sesquiterpenoids were isolated from C. minima to identify the bioactive components responsible for the antioxidant activity of C. minima ; 6- O -angeloylplenolin and arnicolide D were found to be the active compounds responsible for the activation of the Nrf2 signaling pathway and inhibition of ROS production. Our study examined the mechanism of C. minima and its active components in the amelioration of oxidative stress, which holds the promise for the treatment of neurodegenerative disease.
Objectives:
Rice bran oil (RBO) is a major source of monounsaturated fatty acid and gamma-oryzanol, which may assist in lowering blood lipids and oxidative stress. This study examined the effects of RBO containing different amounts of gamma-oryzanol on blood lipid, antioxidant, and inflammatory markers.
Materials and methods:
A total of 59 hyperlipidemic subjects completed the study. They were divided into four groups: RBO1 (4,000 ppm gamma-oryzanol, n = 14), RBO2 (8,000 ppm gamma-oryzanol, n = 15), RBO3 (11,000 ppm gamma-oryzanol, n = 15), and control (soybean oil, n = 15). The assigned oil (30 mL) was incorporated into three cooked meals each day for 4 weeks. Anthropometrical measurements and blood samples were taken to evaluate body weight, body composition, lipid parameters, antioxidant status, and inflammatory markers before and after the intervention.
Results:
Compared with the control, consumption of RBO significantly decreased low-density lipoprotein cholesterol (LDL-C) levels (percentage change: -0.8% [control]; -8% [RBO1]; -11.8% [RBO2]; and -12.2% [RBO3], p = 0.012) with the greatest change found in RBO2 and RBO3. In addition, antioxidant status also improved significantly. Levels of oxygen radical absorbance capacity (ORAC) and ferric reducing antioxidant power (FRAP) increased after consumption of a diet with RBO compared with consumption of a diet with soybean oil (ORAC: -2.7% [control]; 4.1% [RBO1]; 8.6% [RBO2]; and 10.1% [RBO3], p < 0.001; FRAP: -4.4% [control]; 4.7% [RBO1]; 7.4% [RBO2]; and 7.6% [RBO3], p < 0.001).
Conclusions:
RBO with gamma-oryzanol could decrease LDL-C levels and increase antioxidant capacity in hyperlipidemic subjects. Therefore, RBO consumption may reduce cardiovascular disease risk factors.
The kidney is an important organ in the maintenance of body homeostasis. Dietary compounds, reactive metabolites, obesity, and metabolic syndrome (MetS) can affect renal filtration and whole body homeostasis, increasing the risk of chronic kidney disease (CKD) development. Gamma oryzanol ( γ Oz) is a compound with antioxidant and anti-inflammatory activity that has shown a positive action in the treatment of obesity and metabolic diseases. Aim . To evaluate the effect of γ Oz to recover renal function in obese animals by high sugar-fat diet by modulation of adiponectin receptor 2/PPAR- α axis Methods . Male Wistar rats were initially randomly divided into 2 experimental groups: control and high sugar-fat diet (HSF) for 20 weeks. When proteinuria was detected, HSF animals were allocated to receive γ Oz or maintain HSF for more than 10 weeks. The following were analyzed: nutritional and biochemical parameters, systolic blood pressure, and renal function. In the kidney, the following were evaluated: inflammation, oxidative stress, and protein expression by Western blot. Results . After 10 weeks of γ Oz treatment, γ Oz was effective to improve inflammation, increase antioxidant enzyme activities, increase the protein expression of adiponectin receptor 2 and PPAR- α , and recover renal function. Conclusion . These results permit us to confirm that γ Oz is able to modulate PPAR- α expression, inflammation, and oxidative stress pathways improving obesity-induced renal disease.
Objective:
Through dynamic means, etiological factors, including chronic inflammation and insulin resistance have the potential to perpetuate metabolic incidences such as type 2 diabetes and obesity. Abatement of such syndromes can be achieved by complex mechanisms initiated through bioactive compounds such as polyphenols derived from fruits. Using a whole-fruit approach, the effects of dietary red raspberry, which is rich in polyphenols, on inflammatory responses and insulin resistance in the skeletal muscles of Mus musculus were studied along with the potential role of AMP-activated protein kinase (AMPK) to act as a key mediator.
Subjects:
Wild-type (WT) mice and mice deficient in the catalytic subunit (α1) of AMPK (AMPKα1-/-) were fed with a high-fat diet (HFD) or HFD supplemented with raspberry (5% dry weight) for 10 weeks. Factors involved in inflammatory responses, insulin signaling transduction, and mitochondrial biogenesis were evaluated.
Results:
Dietary raspberry reduced ectopic lipid storage, alleviated inflammation responses, improved whole-body insulin sensitivity, and promoted mitochondrial biogenesis in the skeletal muscle of WT mice, but not AMPKα1-/- mice.
Conclusions:
AMPKα1 is an important mediator for the beneficial effects of raspberry through alleviating inflammatory responses and sensitizing insulin signaling in skeletal muscle of HFD-fed mice.
Background:
The high consumption of fat and sugar contributes to the development of obesity and co-morbidities, such as diabetes, and cardiovascular and kidney diseases. Different strategies have been used to prevent these diseases associated with obesity, such as changes in eating habits and/or the addition of dietary components with anti-inflammatory and anti-oxidant properties, such as gamma-oryzanol (γOz) present mainly in bran layers and rice germ.
Methods:
Animals were randomly divided into four experimental groups and fed ad libitum for 20 weeks with control diet (C, n = 8), control diet + γOz (C + γOz, n = 8), high-sugar and high-fat diet (HSF, n = 8), and high-sugar and high-fat diet + γOz (HSF + γOz, n = 8). HSF groups also received water + sucrose (25%). The dose of γOz was added to diets to reach 0.5% of final concentration (w/w). Evaluation in animals included food and caloric intake, body weight, plasma glucose, insulin, triglycerides, uric acid, HOMA-IR, glomerular filtration rate, protein/creatinine ratio, systolic blood pressure, and Doppler echocardiographic.
Results:
Animals that consumed the HSF diet had weight gain compared to group C, increased insulin, HOMA, glucose and triglycerides, there were also atrial and ventricular structural alterations, deterioration of systolic and diastolic function, decreased glomerular filtration rate, and proteinuria. Gamma-oryzanol is significantly protective against effects on body weight, hypertriglyceridemia, renal damage, and against structural and functional alteration of the heart.
Conclusion:
Gamma-oryzanol shows potential as a therapeutic to prevent Cardiorenal Metabolic Syndrome.
The effects of hydroethanolic extract of Yacon leaves (HEYL) on antioxidant, glycemic, and inflammatory biomarkers were tested in diabetic rats. Outcome parameters included glucose, insulin, interleukin-6 (IL-6), and hydrophilic antioxidant capacity (HAC) in serum and IL-6, HAC, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in soleus. The rats (10/group) were divided as follows: C, controls; C + Y, HEYL treated; DM, diabetic controls; and DM + Y, diabetic rats treated with HEYL. Diabetes mellitus was induced by administration of streptozotocin. C + Y and DM + Y groups received 100 mg/kg HEYL daily via gavage for 30 d. Hyperglycemia was improved in the DM + Y versus DM group. Insulin was reduced in DM versus C group. DM rats had higher IL-6 and MDA and lower HAC in the soleus muscle. HEYL treatment decreased IL-6 and MDA and increased HAC in DM rats. DM + Y rats had the highest CAT activity versus the other groups; GPx was higher in C + Y and DM + Y versus their respective controls. The apparent benefit of HEYL may be mediated via improving glucoregulation and ameliorating oxidative stress and inflammation, particularly in diabetic rats.
Background
The aim of this study is to test the hypothesis that obesity induced by a diet rich in saturated fats and balanced in carbohydrates is associated with the development of systemic complications and comorbidities.
Methods
Thirty-seven 60-day-old male Wistar rats were randomized into two groups: control (C, n = 18, standard diet) and obese (OB, n = 19, high-saturated fat diet), for 33 weeks. Nutritional profile: food and caloric intake, feed efficiency, body weight, and adiposity index. Complications: in plasma were analyzed dyslipidemia, insulin resistance (HOMA-IR), glucose intolerance, hyperleptinemia, hyperinsulinemia, plasmatic C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α); in the myocardial and epididymal adipose tissue were assessed IL-6 and TNF-α. Comorbidities: diabetes mellitus and systemic blood pressure (SBP). Student’s t test, ANOVA, and Bonferroni P < 0.05.
Results
The final body weight, feed efficiency, and adiposity index were higher in OB group than in control; although food intake was lower in OB group, caloric intake was similar in both groups. Specific parameters, such as LDL, cholesterol, triglycerides, HOMA-IR, CRP, TNF-α in epididymal adipose tissue, and IL-6 in the myocardium, were higher in obese rats than in controls. SBP, baseline glucose, and glucose after 2 h of overload were significantly increased in OB group; however, the severity was not enough to classify the animals as diabetic and hypertensive.
Conclusion
Obesity induced by a diet high in saturated fatty acids with balanced carbohydrates for 33 weeks in Wistar rats was effective in triggering complications but unable to develop comorbidities.
Dietary gamma oryzanol plays a significant role in the anti-inflammatory activity of rice bran oil by decreasing pro-inflammatory mediators secreted by peritoneal
Metabolic syndrome (MetS) has a high prevalence around the world. Considering the components used to classify MetS, it is clear that it is closely related to obesity. These two conditions begin with an increase in abdominal adipose tissue, which is metabolically more active, containing a greater amount of resident macrophages compared to other fat deposits. Abdominal adiposity promotes inflammation and oxidative stress, which are precursors of various complications involving MetS components, namely insulin resistance, hypertension and hyperlipidemia. One way to block the effects of oxidative stress would be through the antioxidant defense system, which offsets the excess free radicals. It is known that individuals with metabolic syndrome and obesity have high consumption of fats and sugars originated from processed foods containing high levels of sodium as well as low intake of fruits and vegetables, thus maintaining a state of oxidative stress, that can speed up the onset of MetS. Healthy eating habits could prevent or delay MetS by adding antioxidant-rich foods into the diet.
Ricebran oil (RBO) is promoted as heart friendly oil because of its ability to maintain serum lipids at desirable levels. Inflammation also plays an important role on cardiovascular health. The role of minor constituents present in unsaponifiable fraction (UF) of RBO on inflammatory markers is not well understood. To evaluate this, we have taken RBO with UF (RBO-N), RBO stripped of UF (RBO-MCR) and RBO-MCR supplemented with UF from RBO (UFRBO) or Gamma-Oryzanol (γ-ORY) were added in AIN-93 diets which was then fed to Wistar rats for a period of 60 days. Groundnut oil with UF (GNO-N), UF removed GNO (GNO-MCR) and GNO-MCR supplemented with UF from RBO or γ-ORY was also used for comparison. The peritoneal macrophages from the rats were activated and pro-inflammatory mediators such as Reactive Oxygen Species (ROS), eicosanoids, cytokines, hydrolytic enzymes of lysosomal origin were monitored. The results indicated that UF of RBO and γ-ORY supplemented in the dietary oils play a significant role in reducing the secretion of pro-inflammatory mediators by macrophages. Hence γ-ORY in RBO significantly contributed to the anti-inflammatory properties of RBO.
Ƴ-oryzanol (Orz), a steryl ferulate extracted from rice bran layer, exerts a wide spectrum of biological activities. In addition to its antioxidant activity, Orz is often associated with cholesterol-lowering, anti-inflammatory, anti-cancer and anti-diabetic effects. In recent years, the usefulness of Orz has been studied for the treatment of metabolic diseases, as it acts to ameliorate insulin activity, cholesterol metabolism, and associated chronic inflammation. Previous studies have shown the direct action of Orz when downregulating the expression of genes that encode proteins related to adiposity (CCAAT/enhancer binding proteins (C/EBPs)), inflammatory responses (nuclear factor kappa-B (NF-κB)), and metabolic syndrome (peroxisome proliferator-activated receptors (PPARs)). It is likely that this wide range of beneficial activities results from a complex network of interactions and signals triggered, and/or inhibited by its antioxidant properties. This review focuses on the significance of Orz in metabolic disorders, which feature remarkable oxidative imbalance, such as impaired glucose metabolism, obesity, and inflammation.
Obesity resulting from the delivery of an excess amount of energy to adipose tissue from glucose or free fatty acids is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) have been implicated as contributors to both the onset and the progression of insulin resistance. ROS can be generated by overloading the mitochondrial oxidative phosphorylation system, and also by nicotinamide adenine dinucleotide phosphate oxidases (NOX) produced by either adipocytes, which only produce NOX4, or by macrophages, which produce mainly NOX2. The source of the ROS might differ in the early, intermediate and late stages of obesity, switching from NOX4-dependence in the early phases to NOX2-dependence, in the intermediate phase, and transiting to mitochondria-dependence later in the time course of obesity. Thus, depending on the stage of obesity, ROS can be generated by three distinct mechanisms: i.e., NOX4, NOX2, and mitochondria. In this review, we will discuss whether NOX4-, NOX2-, and/or mitochondria-derived ROS is/are causal in the onset of adipocyte insulin resistance as obesity progresses. Moreover, we will review the pathophysiological roles of NOX4, NOX2, and mitochondria-derived ROS on adipose tissue inflammation.
Background
Diabetes mellitus (DM) is associated with mitochondrial oxidative stress. We have shown that myocardial oxidative stress leads to diastolic dysfunction in a hypertensive mouse model. Therefore, we hypothesized that diabetes mellitus could cause diastolic dysfunction through mitochondrial oxidative stress and that a mitochondria‐targeted antioxidant (MitoTEMPO) could prevent diastolic dysfunction in a diabetic mouse model.
Methods and Results
C57BL/6J mice were fed either 60 kcal % fat diet (high‐fat diet [HFD]) or normal chow (control) for 8 weeks with or without concurrent MitoTEMPO administration, followed by in vivo assessment of diastolic function and ex vivo studies. HFD mice developed impaired glucose tolerance compared with the control (serum glucose=495±45 mg/dL versus 236±30 mg/dL at 60 minutes after intraperitoneal glucose injection, P<0.05). Myocardial tagged cardiac magnetic resonance imaging showed significantly reduced diastolic circumferential strain (Ecc) rate in the HFD mice compared with controls (5.0±0.3 1/s versus 7.4±0.5 1/s, P<0.05), indicating diastolic dysfunction in the HFD mice. Systolic function was comparable in both groups (left ventricular ejection fraction=66.4±1.4% versus 66.7±1.2%, P>0.05). MitoTEMPO‐treated HFD mice showed significant reduction in mitochondria reactive oxygen species, S‐glutathionylation of cardiac myosin binding protein C, and diastolic dysfunction, comparable to the control. The fasting insulin levels of MitoTEMPO‐treated HFD mice were also comparable to the controls (P>0.05).
Conclusions
MitoTEMPO treatment prevented insulin resistance and diastolic dysfunction, suggesting that mitochondrial oxidative stress may be involved in the pathophysiology of both conditions.
Background
Metabolic syndrome is a growing worldwide health problem. We evaluated the effects of wine grape powder (WGP), rich in antioxidants and fiber, in a rat model of metabolic syndrome induced by a high fructose diet. We tested whether WGP supplementation may prevent glucose intolerance and decrease oxidative stress in rats fed with a high fructose diet.
Methods
Male Sprague–Dawley rats weighing 180 g were divided into four groups according to their feeding protocols. Rats were fed with control diet (C), control plus 20 % WGP (C + WGP), 50 % high fructose (HF) or 50 % fructose plus 20 % WGP (HF + WGP) for 16 weeks. Blood glucose, insulin and triglycerides, weight, and arterial blood pressure were measured. Homeostasis model assessment (HOMA) index was calculated using insulin and glucose values. A glucose tolerance test was performed 2 days before the end of the experiment. As an index of oxidative stress, thiobarbituric acid reactive substances (TBARS) level was measured in plasma and kidney, and superoxide dismutase was measured in the kidney.
Results
Thiobarbituric acid reactive substances in plasma and renal tissue were significantly higher when compared to the control group. In addition, the area under the curve of the glucose tolerance test was higher in HF fed animals. Furthermore, fasting blood glucose, plasma insulin levels, and the HOMA index, were also increased. WGP supplementation prevented these alterations in rats fed with the HF diet. We did not find any significant difference in body weight or systolic blood pressure in any of the groups.
Conclusions
Our results show that WGP supplementation prevented hyperglycemia, insulin resistance and reduced oxidative stress in rats fed with HF diet. We propose that WGP may be used as a supplement in human food as well.
Background
Metabolic syndrome is a growing worldwide health problem. We evaluated the effects of wine grape powder (WGP), rich in antioxidants and fiber, in a rat model of metabolic syndrome induced by a high fructose diet. We tested whether WGP supplementation may prevent glucose intolerance and decrease oxidative stress in rats fed with a high fructose diet.
Methods
Male Sprague–Dawley rats weighing 180 g were divided into four groups according to their feeding protocols. Rats were fed with control diet (C), control plus 20 % WGP (C + WGP), 50 % high fructose (HF) or 50 % fructose plus 20 % WGP (HF + WGP) for 16 weeks. Blood glucose, insulin and triglycerides, weight, and arterial blood pressure were measured. Homeostasis model assessment (HOMA) index was calculated using insulin and glucose values. A glucose tolerance test was performed 2 days before the end of the experiment. As an index of oxidative stress, thiobarbituric acid reactive substances (TBARS) level was measured in plasma and kidney, and superoxide dismutase was measured in the kidney.
Results
Thiobarbituric acid reactive substances in plasma and renal tissue were significantly higher when compared to the control group. In addition, the area under the curve of the glucose tolerance test was higher in HF fed animals. Furthermore, fasting blood glucose, plasma insulin levels, and the HOMA index, were also increased. WGP supplementation prevented these alterations in rats fed with the HF diet. We did not find any significant difference in body weight or systolic blood pressure in any of the groups.
Conclusions
Our results show that WGP supplementation prevented hyperglycemia, insulin resistance and reduced oxidative stress in rats fed with HF diet. We propose that WGP may be used as a supplement in human food as well.
Obesity has been shown to impair myocardial performance. Some factors have been suggested as responsible for possible cardiac abnormalities in models of obesity, among them beta-adrenergic (βA) system, an important mechanism of regulation of myocardial contraction and relaxation. The objective of present study was to evaluate the involvement of βA system components in myocardial dysfunction induced by obesity. Thirty-day-old male Wistar rats were distributed in control (C, n = 25) and obese (Ob, n = 25) groups. The C group was fed a standard diet and Ob group was fed four unsaturated high-fat diets for 15 weeks. Cardiac function was evaluated by isolated papillary muscle preparation and βA system evaluated by using cumulative concentrations of isoproterenol and Western blot. After 15 weeks, the Ob rats developed higher adiposity index than C rats and several comorbidities; however, were not associated with changes in systolic blood pressure. Obesity caused structural changes and the myocardial responsiveness to post-rest contraction stimulus and increased extracellular calcium (Ca2+) was compromised. There were no changes in cardiac function between groups after βA stimulation. The obesity was not accompanied by changes in protein expression of G protein subunit alpha (Gsα) and βA receptors (β1AR and β2AR). In conclusion, the myocardial dysfunction caused by unsaturated high-fat diet-induced obesity, after 15 weeks, is not related to βAR system impairment at the receptor-signalling pathway.
Metabolic disturbances in white adipose tissue in obese individuals contribute to the pathogenesis of insulin resistance and the development of type 2 diabetes mellitus. Impaired insulin action in adipocytes is associated with elevated lipolysis and increased free fatty acids leading to ectopic fat deposition in liver and skeletal muscle. Chronic adipose tissue hypoxia has been suggested to be part of pathomechanisms causing dysfunction of adipocytes. Hypoxia can provoke oxidative stress in human and animal adipocytes and reduce the production of beneficial adipokines, such as adiponectin. However, time-dose responses to hypoxia relativize the effects of hypoxic stress. Long-term exposure of fat cells to hypoxia can lead to the production of beneficial substances such as leptin. Knowledge of time-dose responses of hypoxia on white adipose tissue and the time course of generation of oxidative stress in adipocytes is still scarce. This paper reviews the potential links between adipose tissue hypoxia, oxidative stress, mitochondrial dysfunction, and low-grade inflammation caused by adipocyte hypertrophy, macrophage infiltration and production of inflammatory mediators.
Recent studies show that brown rice improves glucose intolerance and potentially the risk of diabetes, although the underlying molecular mechanisms remain unclear. One of the phytochemicals found in high concentration in brown rice is γ-oryzanol (Orz), a group of ferulic acid esters of phytosterols and triterpene alcohols. Here, we found that Orz stimulated differentiation of 3T3-L1 preadipocytes and increased the protein expression of adipogenic marker genes such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT/enhanced binding protein alpha (C/EBPα). Moreover, Orz significantly increased the glucose uptake in insulin-resistant cells and translocation of glucose transporter type 4 (GLUT4) from the cytosol to the cell surface. To investigate the mechanism by which Orz stimulated cell differentiation, we examined its effects on cellular signaling of the mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth and proliferation. The Orz treatment increased mTORC1 kinase activity based on phosphorylation of 70-kDa ribosomal S6 kinase 1 (S6K1). The effect of Orz on adipocyte differentiation was dependent on mTORC1 activity because rapamycin blocks cell differentiation in Orz-treated cells. Collectively, our results indicate that Orz stimulates adipocyte differentiation, enhances glucose uptake, and may be associated with cellular signaling mediated by PPAR-γ and mTORC1.
The prevalence of obesity has increased in the past two decades. This growth has been attributed to changes in dietary habits, especially increased consumption of fats and sugars. It is clear that obesity is a risk factor for cardiovascular disease and insulin resistance, and the inflammatory process favors this context. Aim: To address the inflammatory aspects of obesity and associated metabolic complications. Data Sources: Original data from articles found through search of scientific databases. Summary of findings: Micro hypoxia, reticulum stress, and activation of toll-like receptor 4 are responsible for triggering inflammation in adipose tissue, which is the place where the process begins. Thus, there is an increased production of various adipokines, such as IL-6 and TNF-α, which impair insulin signaling pathway, leading to resistance to hormone, one of the first complications of obesity. From this, with the intensity of stimulation, the condition may worsen triggering type 2 diabetes and other comorbidities. Conclusion: Thus, the elucidation of the roles and mechanisms of the main adipokines lead to a better understanding of the pathogenesis of obesity-related disorders.
Abstract Bioactive components in rice vary depending on the variety and growing condition. Fat-soluble components such as γ-oryzanol, tocopherols, tocotrienols, carotenoids, and fatty acids were analyzed in brown, sugary brown, red, and black rice varieties using established high-performance liquid chromatography (HPLC) and GC methodologies. In addition, these colored rice varieties were further analyzed using a high-resolution liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) (LTQ-Orbitrap XL) to identify the [M-H](-) ions of γ-oryzanol, ranging from m/z 573.3949 to 617.4211. The highest content of tocopherols (α-, 1.5; γ-, 0.5 mg/100 g) and carotenoids (lutein 244; trans-β carotene 25 μg/100 g) were observed in black rice; tocotrienols (α-, 0.07; γ-, 0.14 mg/100 g) in red rice, and γ-oryzanol (115 mg/100 g) in sugary brown rice. In all colored rice varieties, the major fatty acids were palmitic (16:0), oleic (18:1n-9), and linoleic (18:2n-6) acids. When the γ-oryzanol components were further analyzed by LC-MS/MS, 3, 10, 8, and 8 triterpene alcohols or sterol ferulates were identified in brown, sugary brown, red, and black rice varieties, respectively. Such structural identification can lead to the elucidation of biological function of each component at the molecular level. Consumption of colored rice rich in beneficial bioactive compounds may be a useful dietary strategy for achieving optimal health.
To evaluate the hepatoprotective and immunotherapeutic effects of aqueous extract of turmeric rhizome in CCl4 intoxicated Swiss albino mice.
First group of mice (n=5) received CCl4 treatment at a dose of 0.5 mL/kg bw (i.p.) for 7 days. Second group was fed orally the aqueous extract of turmeric at a dose of 50 mg/kg bw for 15 days. The third group was given both the turmeric extract (for 15 days, orally) and CCl4 (for last 7 days, i.p.). The fourth group was kept as a control. To study the liver function, the transaminase enzymes (SGOT and SGPT) and bilirubin level were measured in the serum of respective groups. For assaying the immunotherapeutic action of Curcuma longa (C. longa), non specific host response parameters like morphological alteration, phagocytosis, nitric oxide release, myeloperoxidase release and intracellular killing capacity of peritoneal macrophages were studied from the respective groups.
The result of present study suggested that CCl4 administration increased the level of SGOT and SGPT and bilirubin level in serum. However, the aqueous extract of turmeric reduced the level of SGOT, SGPT and bilirubin in CCl4 intoxicated mice. Apart from damaging the liver system, CCl4 also reduced non specific host response parameters like morphological alteration, phagocytosis, nitric oxide release, myeloperoxidase release and intracellular killing capacity of peritoneal macrophages. Administration of aqueous extract of C. longa offered significant protection from these damaging actions of CCl4 on the non specific host response in the peritoneal macrophages of CCl4 intoxicated mice.
In conclusion, the present study suggests that C. longa has immunotherapeutic properties along with its ability to ameliorate hepatotoxicity.
Although physical activity (PA) is a key element in the prevention and management of type 2 diabetes, many with this chronic disease do not become or remain regularly active. High-quality studies establishing the importance of exercise and fitness in diabetes were lacking until recently, but it is now well established that participation in regular PA improves blood glucose control and can prevent or delay type 2 diabetes, along with positively affecting lipids, blood pressure, cardiovascular events, mortality, and quality of life. Structured interventions combining PA and modest weight loss have been shown to lower type 2 diabetes risk by up to 58% in high-risk populations. Most benefits of PA on diabetes management are realized through acute and chronic improvements in insulin action, accomplished with both aerobic and resistance training. The benefits of physical training are discussed, along with recommendations for varying activities, PA-associated blood glucose management, diabetes prevention, gestational diabetes mellitus, and safe and effective practices for PA with diabetes-related complications.
Peroxisome proliferator-activated receptor (PPAR)-α, a member of a large nuclear receptor superfamily, plays a major role in the regulation of lipid metabolism. Recently, PPARα activation has been shown to confer additional benefits on endothelial function, kidney function, and anti-inflammation, suggesting that PPARα agonists may be good candidates for treating acute renal failure. In clinical application, PPAR-α activators, such as hypolipidemic drugs in fibric acid class, were proven to have therapeutic effects on metabolic syndrome and cardiovascular disease. This paper focuses on signaling pathways, ligand selectivity, and physio-pathological roles of PPARα in kidney diseases and the therapeutic utility of PPARα modulators in the treatment of diabetes and inflammation-induced nephropathy. Implication of new and more potent PPAR-α activators could provide important insights into the overall benefits of activating PPAR-α clinically for the treatment of dyslipidemia and the prevention of diabetic or inflammation-induced nephropathy in the future.
The prevalence of metabolic syndrome including central obesity, insulin resistance, impaired glucose tolerance, hypertension, and dyslipidemia is increasing. Development of adequate therapy for metabolic syndrome requires an animal model that mimics the human disease state. Therefore, we have characterized the metabolic, cardiovascular, hepatic, renal, and pancreatic changes in male Wistar rats (8-9 weeks old) fed on a high-carbohydrate, high-fat diet including condensed milk (39.5%), beef tallow (20%), and fructose (17.5%) together with 25% fructose in drinking water; control rats were fed a cornstarch diet. During 16 weeks on this diet, rats showed progressive increases in body weight, energy intake, abdominal fat deposition, and abdominal circumference along with impaired glucose tolerance, dyslipidemia, hyperinsulinemia, and increased plasma leptin and malondialdehyde concentrations. Cardiovascular signs included increased systolic blood pressure and endothelial dysfunction together with inflammation, fibrosis, hypertrophy, increased stiffness, and delayed repolarization in the left ventricle of the heart. The liver showed increased wet weight, fat deposition, inflammation, and fibrosis with increased plasma activity of liver enzymes. The kidneys showed inflammation and fibrosis, whereas the pancreas showed increased islet size. In comparison with other models of diabetes and obesity, this diet-induced model more closely mimics the changes observed in human metabolic syndrome.
Ethnopharmacological relevance:
Mulberry (Morus alba L.) leaves have been widely applied to controlling blood glucose as an efficacious traditional Chinese medicine or salutary medical supplement. The extracts of mulberry leaf suppress inflammatory mediators and oxidative stress, protect the pancreatic β-cells and modulate glucose metabolism in diabetic rats. Our previous studies and others have shown that mulberry leaf extract has excellent therapeutic effects on type 2 diabetes mellitus (T2DM), however, the underlying mechanism remains to be studied.
Aim of the study:
Skeletal muscle insulin resistance (IR) plays an important role in the pathogenesis of T2DM. The aim of this study was to investigate the effects and mechanisms of Mulberry leaf flavonoids (MLF) in L6 skeletal muscle cells and db/db mice.
Materials and methods:
L6 skeletal muscle cells were cultured and treated with/without MLF for in vitro studies. For in vivo studies, the db/db mice with/without MLF therapy were used.
Results:
MLF and metformin significantly ameliorated muscle glucose uptake and mitochondrial function in L6 muscle cells. MLF also increased the phosphorylation of AMPK and the expression of PGC-1α, and upregulated the protein levels of m-GLUT4 and T-GLUT4. These effects were reversed by the AMPK inhibitor compound C. In db/db mice, MLF improve diabetes symptoms and insulin resistance. Moreover, MLF elevated the levels of p-AMPK and PGC-1α, raised m-GLUT4 and T-GLUT4 protein expression, and ameliorated mitochondrial function in skeletal muscle of db/db mice.
Conclusions:
MLF significantly improved skeletal muscle insulin resistance and mitochondrial function in db/db mice and L6 myocytes through AMPK-PGC-1α signaling pathway, and our findings support the therapeutic effects of MLF on type 2 diabetes.
Considering the anti‐photoaging effect of antioxidant compounds, we investigated the protective capacity of grape peel extract (GPE) and resveratrol on ultraviolet (UV)‐induced skin wrinkle formation. Total phenolic, total anthocyanin, and total flavonoid content in GPE prepared from peel of Campbell Early variety were 23.96 ± 0.09, 3.27 ± 0.40, and 1.24 ± 0.09 mg/g dry weight, respectively. Additionally, trans‐resveratrol and piceid content of the resulting GPE were 117.14 ± 19.97 and 85.23 ± 8.89 µg/g dry weight, respectively. Oral administration of either 2 g GPE or 2 mg resveratrol per kg body weight in mice attenuated UVB‐induced epidermal thickening (the thickness was reduced by about 63% and 55% with GPE and resveratrol consumption prior to exposure to UVB, respectively, compared to only UVB‐treated condition) and had marginally protective effect on wrinkle formation of skin exposed to UVB. As introduction of either GPE or resveratrol induced Nrf2‐dependent antioxidant enzymes including heme oxygenase‐1 (HO‐1) in liver and skin as well as inhibited metalloproteinases, it is highly probable that the extract or resveratrol mitigated UVB‐induced photoaging through activation of Nrf2/HO‐1 signaling pathway.
Practical Application
This study proved that resveratrol and the extract of grape peel, a common by‐product of grape juice processing, provide effective protection from UV‐induced skin wrinkle formation. Therefore, grape peel extract, which contains an appreciable amount of bioactive compound resveratrol, can be utilized as functional food ingredient for the manufacture of inner beauty products.
Ethnopharmacological relevance:
Astragali radix (Huang Qi, HQ), a well-known Chinese herbal medicine, is widely coadministered with many other drugs for treating diseases. The potential herb-drug interactions (HDIs) possibly occur during the combination therapy. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are the crucial targets that mediate the production of HDIs. We previously observed that HQ and its three main bioactive compounds, including Astragaloside IV (AS-IV), calycosin (CS) and formononetin (FMNT), could significantly induce the expression of P-gp and BCRP in HepG2 cells in vitro. However, their modulations on the function of P-gp and BCRP remain unknown; their impact on these two proteins expression in vivo is not clear; the exact regulatory mechanism has also not yet been explored.
Aim of the study:
This study aimed to investigate the impact of HQ, AS-IV, CS and FMNT on P-gp and BCRP in vivo, and the exact regulatory mechanism involved. The effects of HQ and these compounds on the function of P-gp and BCRP were also studied.
Materials and methods:
Wild-type C57BL/6 mice and nuclear factor E2-related factor-2 knockout (Nrf2-/-) C57BL/6 mice were orally treated with HQ, AS-IV, CS or FMNT. The protein levels of P-gp and BCRP in the liver of mice were measured by using Western blot and immunohistochemistry. The mRNA levels were measured by using real-time PCR. The activation of the drugs on the antioxidant response element (ARE)-luciferin activity was studied by using reporter assay in a stably transfected HepG2-C8 cells. The efflux activity of P-gp and BCRP in HepG2 cells were tested by using flow cytometer with typical probes.
Results:
HQ, AS-IV, CS and FMNT significantly upregulated the P-gp and BCRP expression in the liver of wild-type mice. The induction was significantly reversed in the Nrf2-/- mice. HQ and these compounds significantly increased the Nrf2 expression in wild-type mice. HQ and these compounds also markedly enhanced the ARE-luciferin activity and promoted the nuclear translocation of Nrf2 in cells. Besides, HQ and these compounds significantly enhanced the efflux activity of P-gp and BCRP, and increased the intracellular ATP levels.
Conclusions:
Our results proved that HQ and its main bioactive compounds could induce the P-gp and BCRP expression through the activation of the Nrf2-mediated signaling pathway. HQ and these compounds also significantly enhanced the efflux activity of P-gp and BCRP, and the increased intracellular ATP levels were likely involved in the increased P-gp and BCRP function. These results suggested that potentially HDIs likely occurred when HQ was used concomitantly with other drugs that are substrates of P-gp and BCRP.
Obesity is associated with chronic inflammation, which contributes to insulin resistance and type 2 diabetes mellitus. Under normal conditions, skeletal muscle is responsible for the majority of insulin-stimulated whole-body glucose disposal; thus, dysregulation of skeletal muscle metabolism can strongly influence whole-body glucose homeostasis and insulin sensitivity. Increasing evidence suggests that inflammation occurs in skeletal muscle in obesity and is mainly manifested by increased immune cell infiltration and proinflammatory activation in intermyocellular and perimuscular adipose tissue. By secreting proinflammatory molecules, immune cells may induce myocyte inflammation, adversely regulate myocyte metabolism, and contribute to insulin resistance via paracrine effects. Increased influx of fatty acids and inflammatory molecules from other tissues, particularly visceral adipose tissue, can also induce muscle inflammation and negatively regulate myocyte metabolism, leading to insulin resistance.
The condition of oxidative stress arises when oxidant production exceeds antioxidant activity in cells and plasma. The overabundance of oxidants is mechanistically connected to the multifactorial etiology of insulin resistance, primarily in skeletal muscle tissue, and the subsequent development of type 2 diabetes. Two important mechanisms for this oxidant excess are (1) the mitochondrial overproduction of hydrogen peroxide and superoxide ion under conditions of energy surplus and (2) the enhanced activation of cellular NADPH oxidase via angiotensin II receptors. Several recent studies are reviewed that support the concept that direct exposure of mammalian skeletal muscle to an oxidant stress (including hydrogen peroxide) results in stimulation of the serine kinase p38 mitogen-activated protein kinase (p38 MAPK), and that the engagement of this stress-activated p38 MAPK signaling is mechanistically associated with diminished insulin-dependent stimulation of insulin signaling elements and glucose transport activity. The beneficial interactions between the antioxidant α-lipoic acid and the advanced glycation end-product inhibitor pyridoxamine that ameliorate oxidant stress-associated defects in whole-body and skeletal-muscle insulin action in the obese Zucker rat, a model of prediabetes, are also addressed. Overall, this review highlights the importance of oxidative stress in the development of insulin resistance in mammalian skeletal muscle tissue, at least in part via a p38-MAPK-dependent mechanism, and indicates that interventions that reduce this oxidative stress and oxidative damage can improve insulin action in insulin-resistant animal models. Strategies to prevent and ameliorate oxidative stress remain important in the overall treatment of insulin resistance and type 2 diabetes.
Gamma-oryzanol is a component of rice bran oil (RBO) with purported health benefits. This study evaluated the effects of gamma-oryzanol on insulin resistance and lipid metabolism in Wistar rats with type 2 diabetes (T2DM). The rats were divided into three groups and consumed one of the following diets for 5 weeks: 15 % soybean oil (control group); 15 % palm oil (PO); and 15 % PO with the addition of 5.25 g gamma-oryzanol (POO). The results showed that PO markedly increased plasma low-density-lipoprotein cholesterol, plasma triglycerides, and hepatic triglyceride levels, but did not reduce the area under the curve for glucose and insulin significantly, compared with the control group. Adding gamma-oryzanol to PO improved the negative influence of PO on lipid metabolism in T2DM rats. In addition, gamma-oryzanol tended to increase insulin sensitivity in T2DM rats compared to control and PO groups. Longer-term studies are needed to evaluate these effects further.
A thiobarbituric acid (TBA) test procedure with reasonable reproducibility applicable to the assay of lipoperoxides in various animal tissue homogenates is described. It was concluded that the deproteinization of homogenate prior to coloration is not needed, but double wavelength measurement is necessary to avoid interference and the reaction should be performed with phosphoric acid at a definite pH near 2.0. The most reproducible procedure is as follows: To 0.5 ml of 10% homogenate of the tissue sample, add 3 ml of 1% H3PO4 and 1 ml of 0.6% TBA aqueous solution; stir and heat the mixture on a boiling water bath for 45 min. After cooling, add 4 ml of n-butanol, shake, and separate the butanol layer by centrifugation; determine the optical density of the butanol layer at 535 and 520 nm; and calculate the difference of optical density between the two determinations to be taken as the TBA value.
A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
Extracellular-superoxide dismutase is a tetrameric enzyme containing four copper atoms. It has previously been shown to catalyse the decay of the superoxide radical, but the resulting product was not determined. In a xanthine oxidase-xanthine system in which about 30% of the electron flux resulted in superoxide radical formation, accumulation of hydrogen peroxide was determined. Catalysis of superoxide radical decay by extracellular-superoxide dismutase was found to result in hydrogen peroxide formation. The catalysed reaction is thus identical to those of previously investigated superoxide dismutases. Human manganese superoxide dismutase was also found to dismute the superoxide radical to hydrogen peroxide and water.
Publisher Summary Catalase exerts a dual function: (1) decomposition of H 2 O 2 to give H 2 O and O 2 (catalytic activity) and (2) oxidation of H donors, for example, methanol, ethanol, formic acid, phenols, with the consumption of 1 mol of peroxide (peroxide activity). The kinetics of catalase does not obey the normal pattern. Measurements of enzyme activity at substrate saturation or determination of the K s is therefore impossible. In contrast to reactions proceeding at substrate saturation, the enzymic decomposition of H 2 O 2 is a first-order reaction, the rate of which is always proportional to the peroxide concentration present. Consequently, to avoid a rapid decrease in the initial rate of the reaction, the assay must be carried out with relatively low concentrations of H 2 O 2 (about 0.01 M). This chapter discusses the catalytic activity of catalase. The method of choice for biological material, however, is ultraviolet (UV) spectrophotometry. Titrimetric methods are suitable for comparative studies. For large series of measurements, there are either simple screening tests, which give a quick indication of the approximative catalase activity, or automated methods.
Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An
induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity
and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats
caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for
TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.
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