Background-In view of the increase in plasma concentrations of proinflammatory mediators tumor necrosis factor-␣ (TNF-␣), interleukin-6 (IL-6), and C-reactive protein (CRP) in obesity, we investigated whether peripheral blood mononuclear cells (MNC) from obese subjects are in a proinflammatory state. Methods and Results-MNC were prepared from fasting blood samples of obese (nϭ16; body mass index[BMI]ϭ37.7Ϯ5.0 kg/m 2 ) and normal-weight control (nϭ16; BMIϭ23.8Ϯ1.9 kg/m 2 ) subjects. Nuclear factor B (NF-B) binding to DNA in nuclear extracts was elevated (PϽ0.05) and the inhibitor of NFB-␤ (IB-␤) was significantly lower (PϽ0.001) in the obese group. Reverse transcription-polymerase chain reaction revealed elevated levels of migration inhibitor factor (MIF), IL-6, TNF-␣, and matrix metalloproteinase-9 (MMP-9) mRNA expression in the obese subjects (PϽ0.05). Plasma concentrations of MIF, IL-6, TNF-␣, MMP-9, and CRP were also significantly higher. Plasma glucose, insulin, and free fatty acids (FFAs) were measured, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Plasma FFA concentration related significantly to BMI, IL-6, and TNF-␣ mRNA expression and plasma CRP levels but not to HOMA-IR. On the other hand, the inflammatory mediators were significantly related to BMI and HOMA-IR. Conclusions-These data show (1) for the first time that MNC in obesity are in a proinflammatory state with an increase in intranuclear NF-B binding, a decrease in IB-␤, and an increase in the transcription of proinflammatory genes regulated by NF-B; (2) that plasma FFAs are a modulator of inflammation; and (3) that insulin resistance is a function of inflammatory mediators.
To test the possible acute proinflammatory effects of fatty acids, we induced an increase in plasma free fatty acid (FFA) concentrations after a lipid and heparin infusion for 4 h in 10 healthy subjects. We determined the nuclear factor-B (NF-B) binding activity in mononuclear cells (MNCs), the p65 subunit of NF-B, reactive oxygen species (ROS) generation by MNC, and polymorphonuclear leukocytes (PMN). Brachial artery reactivity, using postischemic flow-mediated dilation, was also measured. NF-B binding activity in the MNC nuclear extracts increased to 163 ؎ 17% and 144 ؎ 14% as compared with basal levels at 2 and 4 h (P < 0.005) and remained elevated (P < 0.05) at 6 h (2 h after cessation of lipid infusion). NF-B p65 subunit protein expression in MNC homogenates also increased at 2, 4, and 6 h (P < 0.05). ROS generation by PMNs increased significantly at 2 and 4 h (P < 0.005), whereas that by MNCs increased at 4 h (P < 0.05). Plasma macrophage migration inhibitory factor increased at 2 (P < 0.05) and 4 h (P < 0.005), respectively, and declined to baseline at 6 h. The postischemic flow-mediated dilation of brachial artery decreased from 6.3 ؎ 1.1% at baseline to 4.3 ؎ 1.9% and 2.7 ؎ 2.1% (P < 0.01) at 2, 4, and 6 h, respectively. We conclude that an increase in FFA concentration induces oxidative stress and has a proinflammatory effect; it also impairs postischemic flowmediated vasodilation of the brachial artery. Diabetes
We have recently demonstrated a potent antiinflammatory effect of troglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) and a partial agonist of PPARalpha in both the nondiabetic obese and diabetic obese subjects. We have now investigated the antiinflammatory actions of rosiglitazone, a selective PPARgamma agonist. Eleven nondiabetic obese subjects and 11 obese diabetic subjects were each given 4 mg of rosiglitazone daily for a period of 6 wk. Fasting blood samples were obtained at 0, 1, 2, 4, 6, and 12 wk (6 wk after the cessation of rosiglitazone). Eight obese subjects and five obese diabetic subjects were also included in the study as control groups. Fasting blood samples were obtained from the control groups at 0, 1, 2, 4, and 6 wk only. Nuclear factor kappaB (NFkappaB)-binding activity in mononuclear cells, plasma monocyte chemoattractant protein-1 (MCP-1), TNF-alpha, soluble intercellular adhesion molecule-1, C-reactive protein (CRP), and serum amyloid A (SAA) were measured. Blood glucose concentration changed significantly at 6 wk only in the obese diabetic subjects after rosiglitazone treatment for 6 wk, whereas insulin concentration decreased significantly at 6 wk in both groups. NFkappaB-binding activity in mononuclear cell nuclear extract fell in both obese and obese diabetic subjects (P < 0.02). Rosiglitazone treatment resulted in a reduction in plasma MCP-1 and CRP in both groups (P < 0.05). Plasma TNF-alpha and SAA concentrations were inhibited significantly in the obese group (P < 0.05) but not in the obese diabetic subjects. NFkappaB-binding activity and plasma MCP-1, CRP, SAA, and TNF-alpha did not change in the obese and obese diabetic control groups. We conclude that rosiglitazone, a selective PPARgamma agonist, exerts an antiinflammatory effect at the cellular and molecular level, and in plasma. These observations may have implications for atherogenesis in the long term in subjects treated with rosiglitazone and possibly other thiazolidinediones.
Background-The clinical benefits of insulin previously observed in acute ST-segment-elevation myocardial infarction (STEMI) may be partially explained by an anti-inflammatory effect. We assessed this potential effect of insulin in STEMI patients treated with fibrinolytics. Methods and Results-Thirty-two patients receiving reteplase were randomly assigned infusions of either insulin at 2.5 U/h, dextrose, and potassium (GIK) or normal saline and potassium (C) for 48 hours. Plasma concentrations of high-sensitivity C-reactive protein (CRP), serum amyloid A (SAA), plasminogen activator inhibitor-1 (PAI-1), creatine kinase (CK), and CK-MB were measured at baseline and sequentially for 48 hours. Total p47 phox protein in mononuclear cells was measured in a subgroup of 13 subjects. Baseline CRP and SAA were significantly increased (2-to 4-fold) at 24 and 48 hours in each group (PϽ0.01). However, in the insulin group, there was a significant (PϽ0.05) attenuation of the absolute rise in concentration of CRP and SAA from baseline. The absolute increase of CRP and SAA was reduced by 40% (CRP) and 50% (SAA) at 24 hours and at 48 hours compared with the control group. The absolute increase in PAI-1 from baseline and the percentage increase in p47 phox over 48 hours were significantly (PϽ0.05) lower in the insulin-treated group. CK-MB peaked earlier and tended to be lower in insulin-treated subjects, especially in patients with inferior MI.
In view of the pro-oxidant and proinflammatory effects of angiotensin II, we have tested the hypothesis that valsartan, an angiotensin receptor blocker, may exert a suppressive action on reactive oxygen species (ROS) generation, nuclear factor kappa B (NF-kappa B) in mononuclear cells. Four groups of eight normal subjects were given 1) 160 mg daily of valsartan, 2) 80 mg daily of simvastatin, 3) 40 mg quinapril, or 4) no treatment. Fasting blood samples were obtained before treatment and at d 1, 8, and 14 (7 d after the cessation of the drug). After valsartan, ROS generation by polymorphonuclear cells and mononuclear cells fell significantly by more than 40% (P < 0.01). NF-kappa B binding activity and the expression of total cellular p65, a protein component of NF-kappa B, fell significantly (P < 0.01). The expression of inhibitor kappa B (I kappa B) increased significantly (P < 0.05). Plasma C-reactive protein (CRP) concentration fell significantly (P < 0.01). All indices, except I kappa B, reverted toward baseline, 7 d after the cessation of the drug. I kappa B persisted in an elevated state. Neither quinapril nor simvastatin given for 7 d produced a suppression of ROS generation, intranuclear NF-kappa B, p65, or CRP, and these two agents did not alter cellular I kappa B either. The untreated controls also did not demonstrate a change in their ROS generation or NF-kappa B binding activity or plasma CRP concentration. We conclude that valsartan at a modest dose exerts a profound and rapid ROS and inflammation-suppressive effect that may be relevant to its potential beneficial effects in atherosclerosis, diabetes, and congestive cardiac failure. In contrast, quinapril and simvastatin produced no similar effect over the period of 1 wk. Our observations may also have implications to clinical situations in which a rapid antiinflammatory effect is required.
Glucose induces proinflammatory changes, including increases in AP-1, Egr-1, MMPs, and TF, the factors that regulate processes that are potentially relevant to atherosclerotic plaque rupture and thrombosis.
Background and Aim: Epidemiology of Helicobacter pylori infection has regional variation. Effect of eradication of H. pylori on symptoms of functional dyspepsia is uncertain, and the data in Asian scenario are scanty. The study aimed to see H. pylori positivity rate in patients of functional dyspepsia and the effect of its eradication on symptoms. Methods: Randomized, double-blind, placebo-controlled study was the study design used. Patients of functional dyspepsia defined as per Rome 2 criteria were tested for H. pylori infection by rapid urease test and gastric biopsy. H. pylori-positive patients were randomly allocated to triple therapy (20 mg of omeprazole, 500 mg of clarithromycin, and 1000 mg of amoxicillin orally two times daily) and omeperazole plus identical placebo for 2 weeks. Symptoms were assessed with the weekly Likert scale.
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