Flaxseed oil supplementation decreases C-reactive protein levels in chronic hemodialysis patients

Malnutrition and chronic inflammation in dialysis patients negatively impact their survival prognosis, and nutrients, such as omega-3 oils, are postulated to reduce proinflammatory response. In this randomized, double-blind, multicenter, placebo-controlled trial, we investigated the effects of flaxseed oil (FO) on the inflammatory state of patients with chronic renal failure undergoing renal replacement therapy with hemodialysis (HD). We hypothesized that FO supplementation lowers C-reactive protein (CRP) levels. One hundred sixty patients with chronic renal failure who received HD therapy of 3 dialysis units over a 3-month period in South Brazil were included. The patients received blind doses of FO (1 g twice a day) and placebo (mineral oil, 1 g twice a day) for a period of 120 days. Inflammation was observed in 89 patients (61%) at the beginning of the study. There was a correlation between CRP and the body mass index (R_s = 0.22; P = .022) and high-density lipoprotein cholesterol (R_s = −0.23; P = .032), and the CRP levels decreased significantly over time in the group that received FO compared with the control group (P < .001). During the study period, 33.3% of the FO group changed from an inflamed to a not-inflamed category, whereas only 16.9% changed in the mineral oil group (P = .04). We conclude that the administration of FO decreases the CRP levels and that inflammation in HD patients appears to be correlated to their body mass index and reduced high-density lipoprotein cholesterol levels. Studies with a larger number of patients and over a longer duration are necessary to corroborate these findings.     

Blood leptin and C-reactive protein provide more sensitive assessment than blood lipids and other inflammatory biomarkers in overweight university students

Overweight is an inflammatory disease, and today's overweight university students will be tomorrow's overweight employees and parents; however, few studies have focused on the link between overweight and inflammation in university students. We hypothesized that students at higher body mass index (BMI) and percent body fat (BF%) would have higher blood concentrations of lipids and inflammatory biomarkers. A cross-sectional study including 110 university students was conducted at Texas Tech University. Overweight was determined by BMI using measured height and weight, and BF% was determined using bioelectric impedance analysis. Serum triglyceride and cholesterol concentrations were measured using enzymatic methods. Plasma concentrations of leptin, adiponectin, C-reactive protein (CRP), interleukin-6, and tumor necrosis factor α were measured using an enzyme-linked immunosorbent assay. Our results showed that higher BMI was associated with increased blood concentrations of CRP, leptin, and triglyceride (only in male subjects) and decreased blood adiponectin concentrations in university students. In addition, BF% was significantly correlated with blood concentrations of leptin and CRP. Female students had significantly higher blood concentrations of leptin, adiponectin, and CRP than did male students. In conclusion, blood inflammatory biomarkers, especially leptin and CRP, provide a more sensitive and accurate assessment than blood cholesterol and triglyceride for overweight individuals in this population. Leptin, adiponectin, and CRP are sex-dependent inflammatory biomarkers.     

Globularia alypum aqueous extract decreases hypertriglyceridemia and ameliorates oxidative status of the muscle, kidney, and heart in rats fed a high-fructose diet

Fructose is widely used as a food ingredient and has potential to increase oxidative stress. Moreover, the beneficial health effects of plant polyphenols are frequently attributed to their potent antioxidant effects. We hypothesized that administration of Globularia alypum (Ga) aqueous extract would reduce metabolic disorders and oxidative stress induced in rats fed a high-fructose diet. Male Wistar rats (n = 24) weighing 242 ± 13 g were divided into 4 groups and fed, during 14 week, diets containing 20% casein and 61% cornstarch (control diet, or C) or fructose (F), and Ga supplementation (0.5%; CGa and FGa). Compared with control group, rats fed a high-fructose diet increased plasma triglycerides (TG; +48%) and very low-density lipoprotein-TG (+45%) levels. In addition, thiobarbituric acid reactive substances were increased in the liver (+31%), heart (+55%), and muscle (+58%). Moreover, activities of superoxide dismutase in the liver and heart, catalase in liver and glutathione peroxidase in the heart were diminished. In the FGa group, a hypertriglyceridemic effect was observed concomitantly with a low level of TG in very low-density lipoprotein and high-density lipoprotein 2, compared with the F group. Thiobarbituric acid reactive substance concentrations were reduced in the kidney (−42%)and muscle (−76%), and antioxidant enzymes activity was increased for superoxide dismutase in the muscle (+81%) and heart (+28%), and for glutathione peroxidase, in the kidney (+70%) and heart (+30%). In conclusion, the Ga extract has a beneficial effect on plasma TG and gives a promising perspective for hypertriglyceridemia treatment. Moreover, in the muscle and kidney, Ga is effective by lowering lipid peroxidation and improves antioxidant enzymes.     

Dietary fat level affects tissue iron levels but not the iron regulatory gene HAMP in rats

Because dietary fats affect the regulation and use of body iron, we hypothesized that iron regulatory and transport genes may be affected by dietary fat. A model of early-stage I to II, nonalcoholic fatty liver was used in which rats were fed standard (35% energy from fat) or high-fat (71% energy from fat) liquid diets with normal iron content (STD/HF groups). In addition, intraperitoneal injections of iron dextran were given to iron-loaded (STD+/HF+ groups) and iron-deficient diets to STD−/HF− groups. Plasma osmolality, hemoglobin level, and mean corpuscular hemoglobin concentration were increased in all STD diet groups compared with all HF diet groups. Plasma iron and transferrin saturation were affected by an interaction between dietary fat and iron. They were high in the STD group (normal iron) compared with their respective HF group. Similarly, this group also showed a 4-fold increase in the messenger RNA expression of the hepatic hemochromatosis gene. Spleen iron was high in the iron-loaded STD+ group compared with all other groups. Hepatic iron and messenger RNA expression of peroxisome proliferator–activated receptor-γ, CCAAT/enhancer binding protein α, interleukin-6, and iron transport genes (transferrin receptor 2, divalent metal transporter 1 iron-responsive element, and divalent metal transporter 1 non–iron-responsive element) were increased, whereas tumor necrosis factor α was decreased in the HF diet groups. The expression of iron regulatory gene HAMP was not increased in the HF diet groups. Iron regulatory and transport genes involved in cellular and systemic iron homeostasis may be affected by the macronutrient composition of the diet.     

Modified apple polysaccharides suppress the migration and invasion of colorectal cancer cells induced by lipopolysaccharide

Metastasis is the major cause of death in colorectal cancer (CRC). In colitis-associated carcinogenesis, the activation of nuclear factor-κB (NF-κB) occurs via lipopolysaccharide (LPS) binding to the toll-like receptor 4 (TLR4). The LPS/TLR4/NF-κB pathway contributes to the development and metastasis of colitis-associated colon cancer. In the present study, we hypothesized that an extracted modified Fuji apple polysaccharide (MAP) would alter the LPS/TLR4/NF-κB pathway. Thus, we evaluated the effect of MAP in vitro on the LPS/TLR4/NF-κB pathway in CRC cells (HT-29 and SW620 cells). The results suggest that (i) MAP competed with LPS for binding to TLR4 to reduce LPS-induced NF-κB expression and (ii) MAP suppressed the nuclear translocation of NF-κB p65. MAP significantly decreased LPS-induced expression of TLR4, cyclooxygenase-2, matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 2, inducible nitric oxide synthase, and prostaglandin E2, and it increased the protein expression of the inhibitor of κBα and NF-κB p65 in cytoplasm when it was given in combination with LPS. These results indicate that MAP suppressed LPS-induced migration and invasiveness of CRC cells by targeting the LPS/TLR4/NF-κB pathway. Therefore, we propose that MAP has potential for the clinical prevention of CRC cell metastasis.     

Capsaicin attenuates palmitate-induced expression of macrophage inflammatory protein 1 and interleukin 8 by increasing palmitate oxidation and reducing c-Jun activation in THP-1 (human acute monocytic leukemia cell) cells

Capsaicin, a spicy component of hot peppers, has been shown to improve inflammatory disease and obesity. In this study, we tested the hypothesis that the anti-inflammatory activity of capsaicin can be used to improve free fatty acid (FFA)-induced inflammation by reducing gene expression of macrophage inflammatory protein 1 (MIP-1) and interleukin 8 (IL-8) in THP-1 (human acute monocytic leukemia cell) macrophages. To investigate whether capsaicin ameliorates palmitate-induced MIP-1 and IL-8 gene expressions, we treated THP-1 cells with palmitate in the presence or absence of capsaicin and measured MIP-1 and IL-8 by real-time polymerase chain reaction. To elucidate the mechanism by which capsaicin effects on palmitate-induced MIP-1 and IL-8 gene expressions, we performed immunoblotting with stress kinase-related antibodies and measured palmitate oxidation and palmitate oxidation-related gene expression. Palmitate and stearate but not the unsaturated FFA oleate significantly increased MIP-1 and IL-8 expressions in THP-1 macrophages. Treatment with capsaicin or FFA oxidation stimulators inhibited palmitate-induced MIP-1 and IL-8 expressions in THP-1 macrophages. Capsaicin increased the gene expression of carnitine palmitoyltransferase 1 and the β-oxidation of palmitate. Furthermore, capsaicin significantly reduced palmitate-stimulated activation of c-Jun N-terminal kinase, c-Jun, and p38. Our data suggest that the attenuation of palmitate-induced MIP-1 and IL-8 gene expressions by capsaicin is associated with reduced activation of c-Jun N-terminal kinase, c-Jun, and p38 and preserved β-oxidation activity.     

Phycocyanin prevents hypertension and low serum adiponectin level in a rat model of metabolic syndrome

Endothelial dysfunction is associated with hypertension, atherosclerosis, and metabolic syndrome. Phycocyanin is a pigment found in the blue-green algae, Spirulina, which possesses antihypertensive effect. In this study, we hypothesized that phycocyanin derived from Spirulina exerts antihypertensive actions by improving endothelial dysfunction in metabolic syndrome. Spontaneously hypertensive/NIH-corpulent (SHR/NDmcr-cp) rats were divided into 4 groups then fed a normal diet with or without phycocyanin (2500-, 5000-, or 10?000-mg/kg diet) for 25 weeks. At 34 weeks of age, although systolic blood pressure was not significantly different among groups, phycocyanin-fed groups exhibited a dose-dependent decrease in blood pressure. Serum levels of adiponectin and messenger RNA levels of adiponectin and CCAAT/enhancer-binding protein α in the adipose tissue of rats fed diets containing phycocyanin tended to be higher than those of rats fed a normal diet, but the differences were not statistically significant. Immunohistochemistry analysis showed a significant and positive correlation between aortic endothelial nitric oxide synthase (eNOS) expression levels, a downstream target of the adiponectin receptor, and serum adiponectin levels, although there were no significant differences in eNOS expression among groups. There was also no significant correlation between eNOS expression levels and systolic blood pressure. These results suggest that long-term administration of phycocyanin may ameliorate systemic blood pressure by enhancing eNOS expression in aorta that is stimulated by adiponectin. Phycocyanin may be beneficial for preventing endothelial dysfunction-related diseases in metabolic syndrome.     

A high ratio of dietary n-3/n-6 polyunsaturated fatty acids improves obesity-linked inflammation and insulin resistance through suppressing activation of TLR4 in SD rats

Dietary ratios of n-3/n-6 polyunsaturated fatty acids (PUFAs) have been implicated in controlling markers of metabolic disorders, including obesity, insulin resistance (IR), inflammation, and lipid profiles, which are also presumed to be partly related to type 2 diabetes mellitus (T2DM). However, molecular mechanisms of the different PUFAs related to metabolic disorders have not been systematically addressed. The present study aimed to investigate the impact of dietary n-3/n-6 PUFA ratios on obesity and IR and, further, to determine the underlying mechanisms. For 16 weeks, 32 SD male rats, randomly divided into four groups (n = 8 per group), received one of the following diets: normal chow, high saturated fatty acid (SFA), high n-3/n-6 PUFA ratio (1∶1, PUFA^1:1), or low n-3/n-6 PUFA ratio (1∶4, PUFA^1:4). Following the experimental diet period, metabolic parameters related to obesity and IR were measured. Compared to SFA diet-fed rats, PUFA^1:1 diet-fed rats exhibited decreased body and visceral fat weight, lowered blood lipids, and improved glucose tolerance and insulin sensitivity. Interestingly, these changes were accompanied with decreased expression levels of circulating pro-inflammatory cytokines, including tumor necrosis factor α, interleukin-6, and C-reactive protein. Moreover, the TLR4 protein and mRNA levels were markedly down-regulated by PUFA^1:1 compared with SFA; however, PUFA^1:4 diet-fed rats failed to exhibit these changes. Cumulatively, our data highlight a role for a PUFA^1:1 diet in the prevention of obesity and related metabolic disorders by suppressing the activation of TLR4, a critical modulator of pro-inflammatory cytokines.     

Green tea extract reduces blood pressure,inflammatory biomarkers,and oxidative stress and improves parameters associated with insulin resistance in obese,hypertensive patients

Green tea (GT) consumption is known to be associated with enhanced cardiovascular and metabolic health. The purpose of this study is to examine the hypothesis that supplementation with GT alters insulin resistance and associated cardiovascular risk factors in obese, hypertensive patients. In a double-blind, placebo-controlled trial, 56 obese, hypertensive subjects were randomized to receive a daily supplement of 1 capsule that contained either 379 mg of GT extract (GTE) or a matching placebo, for 3 months. At baseline and after 3 months of treatment, the anthropometric parameters, blood pressure, plasma lipid levels, glucose levels, creatinine levels, tumor necrosis factor α levels, C-reactive protein levels, total antioxidant status, and insulin levels were assessed. Insulin resistance was evaluated according to the homeostasis model assessment–insulin resistance protocol. After 3 months of supplementation, both systolic and diastolic blood pressures had significantly decreased in the GTE group as compared with the placebo group (P < .01). Considerable (P < .01) reductions in fasting serum glucose and insulin levels and insulin resistance were observed in the GTE group when compared with the placebo group. Serum tumor necrosis factor α and C-reactive protein were significantly lower, whereas total antioxidant status increased in the GTE group compared with the placebo (P < .05). Supplementation also contributed to significant (P < .05) decreases in the total and low-density lipoprotein cholesterol and triglycerides, but an increase in high-density lipoprotein cholesterol. In conclusion, daily supplementation with 379 mg of GTE favorably influences blood pressure, insulin resistance, inflammation and oxidative stress, and lipid profile in patients with obesity-related hypertension.     

Glutamine reduces the expression of leukocyte integrins leukocyte function–associated antigen-1 and macrophage antigen-1 in mice exposed to arsenic

Chronic arsenic exposure results in an increased oxidative stress and inflammation in the body. Glutamine (GLN) is an amino acid considered to have immunomodulatory effects and attenuate the inflammatory reaction. This study was designed to examine the effect of GLN supplementation on inflammatory-related leukocyte integrin expression and in vitro splenocyte cytokine production in mice exposed to arsenic. Mice were assigned to the control and experimental groups. The control group drank deionized water, whereas the experimental group drank deionized water containing 50 ppm of sodium arsenite. Each control and experimental group was further divided into 2 subgroups and fed diets for 5 weeks. One subgroup was fed a semipurified diet, whereas the other subgroup was fed a diet where part of the casein was replaced with GLN, which provided 25% of the total amino acid nitrogen. The results showed that plasma GLN levels of mice in the arsenic group were significantly lower than those in the control groups. Glutamine supplementation reversed the depletion of plasma GLN in the arsenic group. β₂ intergins, including leukocyte function–associated antigen-1 and macrophage antigen-1 expressed by leukocytes, were significantly higher in the arsenic group than the control groups. Glutamine supplementation reduced leukocyte integrin expression in mice exposed to arsenic. There were no differences in interleukin 4, interleukin 6, interferon γ, and tumor necrosis factor α production between the 2 arsenic groups when splenocytes were stimulated with mitogen. These results suggest that arsenic exposure results in depletion of plasma GLN and higher leukocyte integrin expression. Glutamine supplementation normalized the plasma GLN levels and reduced leukocyte leukocyte function–associated antigen-1 and macrophage antigen-1 expression. However, cytokine modulation may not be responsible for reducing leukocyte integrin expression in mice exposed to arsenic.     

An acute intake of a walnut-enriched meal improves postprandial adiponectin response in healthy young adults

A deficit in adiponectin plays an important causal role in insulin resistance and metabolic syndrome. We hypothesized that as seen during the fasting state, the intake of a walnut-enriched meal increased postprandial adiponectin. Twenty-one healthy white men followed a 4-week baseline diet and then consumed 3 fat-loaded meals that included 1 g fat/kg body weight (65% fat) according to a randomized crossover design: olive oil–enriched meal (22% saturated fatty acids [SFA], 38% monounsaturated fatty acids [MUFA], 4% polyunsaturated fatty acids [PUFA]), butter-enriched meal (35% SFA, 22% MUFA, 4% PUFA), and walnut-enriched meal (20% SFA, 24% MUFA, 16% PUFA, and 4% α-linolenic acid). Leptin, resistin, adiponectin, and free fatty acids were determined at 0, 3, 6, and 8.5 hours after the fat load. After the walnut-enriched meal, plasma adiponectin concentrations were higher at 3 and 6 hours (P = .011, P = .046, respectively) compared with the butter-enriched meal and higher at 6 hours compared with the olive oil–enriched meal (P = .036). Free fatty acid levels decreased from baseline at 3 hours after the walnut-enriched meal (P = .001). No differences were observed between the 3 meals for leptin and resistin responses. Our data confirmed a beneficial profile in the postprandial response to walnuts, source of omega-3 PUFA with an increased postprandial adiponectin and lower postprandial free fatty acid responses. These findings suggest that the postprandial state is important for understanding the possible cardioprotective effects associated with omega-3 PUFA dietary fat.     

A mixture of Salacia reticulata (Kotala himbutu) aqueous extract and cyclodextrin reduces body weight gain,visceral fat accumulation,and total cholesterol and insulin increases in male Wistar fatty rats

This study examined the effects of a mixture of an aqueous extract of Salacia reticulata (Kotala himbutu) and cyclodextrin (SRCD) on various metabolic parameters and cecal fermentation in obese fa/fa male Wistar fatty rats, a model of type 2 diabetes mellitus. Wistar fatty rats were fed 0% (control group) or 0.2% SRCD-supplemented diets and weighed weekly. The plasma glucose, triacylglycerol, total cholesterol, insulin, and adiponectin concentrations were measured at weeks 0, 2, 4, and 5. SRCD supplementation suppressed the time-dependent increase in the plasma total cholesterol and insulin concentrations. After 6 weeks of a 0.2% SRCD-supplemented diet, the body weight gain, food intake, visceral fat mass, liver mass, and liver triacylglycerol content of the rats were significantly lower, whereas the plasma adiponectin concentrations were significantly higher than those of the control group. SRCD supplementation had no significant effect on plasma glucose and triacylglycerol concentrations. SRCD supplementation significantly increased cecum mass, whereas it significantly decreased the cecal butyrate and short-chain fatty acid (sum of the acetate, butyrate, and propionate) concentrations. All of the rats were subjected to an oral glucose tolerance test at the beginning of week 6. The area under the curve for insulin was significantly smaller with SRCD supplementation and showed no change in glucose tolerance compared to that of the control group. These results suggest that bioactive compounds in SRCD may suppress the development of type 2 diabetes mellitus by influencing glucose and lipid metabolism in male Wistar fatty rats and that SRCD may influence cecal fermentation.     

A Mediterranean-style, low-glycemic-load diet reduces the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in mononuclear cells and plasma insulin in women with metabolic syndrome

We evaluated changes in low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase gene expression in women with metabolic syndrome and elevated plasma LDL cholesterol (LDL-C). We hypothesized that expression of these 2 genes would be modulated by our dietary intervention. Twenty-five women were instructed to follow a Mediterranean-style low-glycemic-load diet for 12 weeks. Quantitative real-time polymerase chain reaction was used to measure messenger RNA (mRNA) abundance of the LDL receptor and HMG-CoA reductase in mononuclear cells, which were used as a proxy of liver expression of these 2 genes. All women experienced favorable impacts on metabolic syndrome variables, with decreases in waist circumference (P < .001), plasma triglycerides (P < .05), and systolic blood pressure (P < .05) compared with baseline. Furthermore, participants had reductions in LDL-C (P < .01), plasma insulin (P < .001), and homeostatic model assessment score for insulin resistance (P < .001) over time. In addition, significant decreases were found in plasma tumor necrosis factor α (P < .01), which might have contributed to the improvements observed in insulin resistance. Although no changes in LDL-receptor mRNA levels were observed, HMG-CoA-reductase gene expression was reduced (P < .001) after 12 weeks. The reductions in plasma insulin correlated with changes in HMG-CoA-reductase mRNA levels (r = 0.45, P < .01). In conclusion, the observed reductions in plasma insulin may have affected the expression of a key regulatory gene of cholesterol synthesis, HMG-CoA reductase. The decreased HMG-CoA-reductase expression may be related to lower secretion of very low density lipoprotein (VLDL)-cholesterol, which, in turn, would account for the reductions in LDL-C.     

Acute exposure to high-fat diets increases hepatic expression of genes related to cell repair and remodeling in female rats

High-fat diets (HFD) promote the development of both obesity and fatty liver disease through the up-regulation of hepatic lipogenesis. Insulin resistance, a hallmark of both conditions, causes dysfunctional fuel partitioning and increases in lipogenesis. Recent work has demonstrated that systemic insulin resistance occurs in as little as the first 72 hours of an HFD, suggesting the potential for hepatic disruption with HFD at this time point. The current study sought to determine differences in expression of lipogenic genes between sexes in 3-month-old male and female Long-Evans rats after 72 hours of a 40% HFD or a 17% fat (chow) diet. Owing to the response of estrogen on hepatic signaling, we hypothesized that a sexual dimorphic response would occur in the expression of lipogenic enzymes, inflammatory cytokines, apoptotic, and cell repair and remodeling genes. Both sexes consumed more energy when fed an HFD compared with their low fat–fed controls. However, only the males fed the HFD had a significant increase in body fat. Regardless of sex, HFD caused down-regulation of lipogenic and inflammatory genes. Interestingly, females fed an HFD had up-regulated expression of apoptotic and cell repair–related genes compared with the males. This may suggest that females are more responsive to the acute hepatic injury effects caused by HFDs. In summary, neither male nor female rats displayed disrupted hepatic metabolic pathways after 72 hours of the HFD treatment. In addition, female rats appear to have protection from increases in fat deposition, possibly due to increased caloric expenditure; male rats fed an HFD were less active, as demonstrated by distance traveled in their home cage.