scholarly journals Insulin Inhibits Intranuclear Nuclear Factor κB and Stimulates IκB in Mononuclear Cells in Obese Subjects: Evidence for an Anti-inflammatory Effect?

2001 ◽  
Vol 86 (7) ◽  
pp. 3257-3265 ◽  
Author(s):  
Paresh Dandona ◽  
Ahmad Aljada ◽  
Priya Mohanty ◽  
Husam Ghanim ◽  
Wael Hamouda ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Plasminogen Activator Inhibitor ◽  
Intercellular Adhesion Molecule ◽  
Ros Generation ◽  
Intercellular Adhesion Molecule 1 ◽  
Plasminogen Activator Inhibitor 1 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Anti Inflammatory ◽  
Pai 1 ◽  
Inflammatory Effect

In view of the fact that insulin resistance is associated with atherogenesis and that troglitazone, an insulin sensitizer, has anti-inflammatory effects, which may be potentially antiatherogenic in the long term, we have now investigated whether insulin has potential anti-inflammatory effects. We infused 2.0 to 2.5 IU/h in 5% dextrose (100 mL/h) iv into 10 obese subjects for 4 h followed by 5% dextrose alone for 2 h. The rate of insulin infusion was varied to maintain glucose concentrations as close to the baseline as possible. Blood samples were obtained before and at 2, 4, and 6 h. Subjects were also infused with 5% dextrose without insulin and with saline on separate occasions. Intranuclear nuclear factor κB (NFκB) in mononuclear cells fell at 2 and further at 4 h, reverting toward the baseline at 6 h (P < 0.05). IκB increased significantly at 2 h, increasing further at 4 h and remaining elevated at 6 h (P < 0.001). Reactive oxygen species (ROS) generation by mononuclear cells fell significantly at 2 h and fell further at 4 h; it partially reverted to baseline at 6 h (P < 0.005). p47phox subunit, the key protein of nicotinamide adenine dinucleotide phosphate oxidase also fell at 2 h and 4 h, reverting toward the baseline at 6 h (P < 0.05). In addition, soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) fell significantly following insulin infusion. Glucose or saline infusions without insulin caused no alteration in NFκB, IκB, ROS generation, p47phox subunit, sICAM-1, MCP-1, or PAI-1. We conclude that insulin has a potent acute anti-inflammatory effect including a reduction in intranuclear NFκB, an increase in IκB, and decreases in ROS generation, p47phox subunit, plasma soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1. This acute anti-inflammatory effect, if demonstrated in the long term, may have implications for atherosclerosis and its complications.

scholarly journals Circulating Concentrations of Monocyte Chemoattractant Protein-1, Plasminogen Activator Inhibitor-1, and Soluble Leukocyte Adhesion Molecule-1 in Overweight/Obese Men and Women Consuming Fructose- or Glucose-Sweetened Beverages for 10 Weeks

2011 ◽  
Vol 96 (12) ◽  
pp. E2034-E2038 ◽  
Author(s):  
Chad L. Cox ◽  
Kimber L. Stanhope ◽  
Jean Marc Schwarz ◽  
James L. Graham ◽  
Bonnie Hatcher ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Plasminogen Activator Inhibitor ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Plasminogen Activator Inhibitor 1 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Reactive Protein ◽  
Sweetened Beverages ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Context: Results from animal studies suggest that consumption of large amounts of fructose can promote inflammation and impair fibrinolysis. Data describing the effects of fructose consumption on circulating levels of proinflammatory and prothrombotic markers in humans are unavailable. Objective: Our objective was to determine the effects of 10 wk of dietary fructose or glucose consumption on plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), E-selectin, intercellular adhesion molecule-1, C-reactive protein, and IL-6. Design and Setting: This was a parallel-arm study with two inpatient phases (2 wk baseline, final 2 wk intervention), conducted in a clinical research facility, and an outpatient phase (8 wk) during which subjects resided at home. Participants: Participants were older (40–72 yr), overweight/obese (body mass index = 25–35 kg/m2) men (n = 16) and women (n = 15). Interventions: Participants consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 wk. Blood samples were collected at baseline and during the 10th week of intervention. Main Outcome Measures: Fasting concentrations of MCP-1 (P = 0.009), PAI-1 (P = 0.002), and E-selectin (P = 0.048) as well as postprandial concentrations of PAI-1 (P < 0.0001) increased in subjects consuming fructose but not in those consuming glucose. Fasting levels of C-reactive protein, IL-6, and intercellular adhesion molecule-1 were not changed in either group. Conclusions: Consumption of fructose for 10 wk leads to increases of MCP-1, PAI-1, and E-selectin. These findings suggest the possibility that fructose may contribute to the development of the metabolic syndrome via effects on proinflammatory and prothrombotic mediators.

scholarly journals Butanolic Extract of Noni Inhibits Proliferation, Inflammation, and Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Expression in Cultured Smooth Muscle Cells

2020 ◽  
Vol 15 (6) ◽  
pp. 1934578X2093203
Author(s):  
Takanori Matsui ◽  
Yuji Ishibashi ◽  
Ami Sotokawauchi ◽  
Fumiyuki Isami ◽  
Yumi Abe ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Intercellular Adhesion Molecule ◽  
Ros Generation ◽  
Atherosclerotic Cardiovascular Disease ◽  
Proprotein Convertase ◽  
Intercellular Adhesion Molecule 1 ◽  
Inflammatory Reactions ◽  
Monocyte Chemoattractant Protein 1 ◽  
Butanolic Extract ◽  
Gene And Protein Expression

Platelet-derived growth factor-BB (PDGF-BB) plays a central role in smooth muscle cell (SMC) proliferation and inflammation, being involved in atherosclerotic cardiovascular disease. We have previously found that butanolic extract of noni, a tropical plant belonging to the family Rubiaceae, exerts anti-inflammatory effects on endothelial cells exposed to advanced glycation end products (AGEs). Here, we examined the effects of noni extract on oxidative stress production, growth, and inflammatory reactions in PDGF-BB or AGE-exposed SMCs. Reactive oxygen species (ROS) generation, cell proliferation, and adhesion were measured by a fluorescent dye, a colorimetric agent, and labeled THP-1 cells, respectively. Gene and protein expression was evaluated by real-time reverse transcription-polymerase chain reaction and Western blot analysis. Butanolic extract of noni reduced ROS production, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, and proprotein convertase subtilisin kexin type 9 (PCSK9) expression, and proliferation in, and THP-1 cell adhesion to, PDGF-BB-exposed SMCs. Gene expression and protein level of receptor for AGEs (RAGE) were significantly decreased by noni extract in SMCs. Furthermore, AGEs significantly increased PCSK9 mRNA and protein levels in SMCs, which were inhibited by noni extract or an antioxidant N-acetylcysteine. Our present study suggests that butanolic extract of noni not only inhibits the PDGF-BB-induced proliferation and inflammatory reactions in SMCs through its antioxidative properties but also reduces PCSK9 levels in AGE-exposed SMCs via suppression of RAGE expression. Butanolic extract of noni may play a protective role against atherosclerosis.

scholarly journals Hydroxytyrosol Modulates Adipocyte Gene and miRNA Expression Under Inflammatory Condition

Nutrients ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 2493 ◽  
Author(s):  
Egeria Scoditti ◽  
Sara Carpi ◽  
Marika Massaro ◽  
Mariangela Pellegrino ◽  
Beatrice Polini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucose Transporter ◽  
Matrix Metalloproteinase 2 ◽  
Intercellular Adhesion Molecule ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Intercellular Adhesion Molecule 1 ◽  
Plasminogen Activator Inhibitor 1 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Tnf Α

Chronic inflammation of the adipose tissue (AT) is a major contributor to obesity-associated cardiometabolic complications. The olive oil polyphenol hydroxytyrosol (HT) contributes to Mediterranean diet cardiometabolic benefits through mechanisms still partially unknown. We investigated HT (1 and 10 μmol/L) effects on gene expression (mRNA and microRNA) related to inflammation induced by 10 ng/mL tumor necrosis factor (TNF)-α in human Simpson–Golabi–Behmel Syndrome (SGBS) adipocytes. At real-time PCR, HT significantly inhibited TNF-α-induced mRNA levels, of monocyte chemoattractant protein-1, C-X-C Motif Ligand-10, interleukin (IL)-1β, IL-6, vascular endothelial growth factor, plasminogen activator inhibitor-1, cyclooxygenase-2, macrophage colony-stimulating factor, matrix metalloproteinase-2, Cu/Zn superoxide dismutase-1, and glutathione peroxidase, as well as surface expression of intercellular adhesion molecule-1, and reverted the TNF-α-mediated inhibition of endothelial nitric oxide synthase, peroxisome proliferator-activated receptor coactivator-1α, and glucose transporter-4. We found similar effects in adipocytes stimulated by macrophage-conditioned media. Accordingly, HT significantly counteracted miR-155-5p, miR-34a-5p, and let-7c-5p expression in both cells and exosomes, and prevented NF-κB activation and production of reactive oxygen species. HT can therefore modulate adipocyte gene expression profile through mechanisms involving a reduction of oxidative stress and NF-κB inhibition. By such mechanisms, HT may blunt macrophage recruitment and improve AT inflammation, preventing the deregulation of pathways involved in obesity-related diseases.

Inhibition of endothelial nitric oxyde synthase increases capillary formation via Rac1-dependent induction of hypoxia-inducible factor-1α and plasminogen activator inhibitor-1

2012 ◽  
Vol 108 (11) ◽  
pp. 849-862 ◽  
Author(s):  
Michael Weitnauer ◽  
Andreas Petry ◽  
Rachida BelAiba ◽  
Agnes Görlach
Keyword(s):  
Endothelial Cells ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Fine Tuning ◽  
Ros Generation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Capillary Formation ◽  
Angiogenic Response ◽  
Activator Inhibitor ◽  
Pai 1

SummaryDisruption of endothelial homeostasis results in endothelial dysfunction, characterised by a dysbalance between nitric oxide (NO) and reactive oxygen species (ROS) levels often accompanied by a prothrombotic and proproliferative state. The serine protease thrombin not only is instrumental in formation of the fibrin clot, but also exerts direct effects on the vessel wall by activating proliferative and angiogenic responses. In endothelial cells, thrombin can induce NO as well as ROS levels. However, the relative contribution of these reactive species to the angiogenic response towards thrombin is not completely clear. Since plasminogen activator inhibitor-1 (PAI-1), a direct target of the proangiogenic transcription factors hypoxia-inducible factors (HIFs), exerts prothrombotic and proangiogenic activities we investigated the role of ROS and NO in the regulation of HIF-1α, PAI-1 and capillary formation in response to thrombin. Thrombin enhanced the formation of NO as well as ROS generation involving the GTPase Rac1 in endothelial cells. Rac1-dependent ROS formation promoted induction of HIF-1α, PAI-1 and capillary formation by thrombin, while NO reduced ROS bioavailability and subsequently limited induction of HIF-1α, PAI-1 and the angiogenic response. Importantly, thrombin activation of Rac1 was diminished by NO, but enhanced by ROS. Thus, our findings show that capillary formation induced by thrombin via Rac1-dependent activation of HIF-1 and PAI-1 is limited by the concomitant release of NO which reduced ROS bioavailability. Rac1 activity is sensitive to ROS and NO, thereby playing an essential role in fine tuning the endothelial response to thrombin.

scholarly journals CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis

Biomedicines ◽  
2020 ◽  
Vol 8 (6) ◽  
pp. 149
Author(s):  
Robin C. Su ◽  
Emily A. Warner ◽  
Joshua D. Breidenbach ◽  
Apurva Lad ◽  
Thomas M. Blomquist ◽  
...  
Keyword(s):  
Weight Loss ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Monocyte Chemoattractant Protein 1 ◽  
The World ◽  
Colonic Ulceration ◽  
Bloody Stools ◽  
Pai 1

Inflammatory Bowel Disease (IBD) is one of the most common gastrointestinal (GI) disorders around the world, and includes diagnoses such as Crohn’s disease and ulcerative colitis. The etiology of IBD is influenced by genetic and environmental factors. One environmental perturbagen that is not well studied within the intestines is microcystin-leucine arginine (MC-LR), which is a toxin produced by cyanobacteria in freshwater environments around the world. We recently reported that MC-LR has limited effects within the intestines of healthy mice, yet interestingly has significant toxicity within the intestines of mice with pre-existing colitis induced by dextran sulfate sodium (DSS). MC-LR was found to prolong DSS-induced weight loss, prolong DSS-induced bloody stools, exacerbate DSS-induced colonic shortening, exacerbate DSS-induced colonic ulceration, and exacerbate DSS-induced inflammatory cytokine upregulation. In addition, we previously reported a significant increase in expression of the pro-inflammatory receptor CD40 in the colons of these mice, along with downstream products of CD40 activation, including plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1). In the current study, we demonstrate that knocking out CD40 attenuates the effects of MC-LR in mice with pre-existing colitis by decreasing the severity of weight loss, allowing a full recovery in bloody stools, preventing the exacerbation of colonic shortening, preventing the exacerbation of colonic ulceration, and preventing the upregulation of the pro-inflammatory and pro-fibrotic cytokines IL-1β, MCP-1, and PAI-1. We also demonstrate the promising efficacy of a CD40 receptor blocking peptide to ameliorate the effects of MC-LR exposure in a proof-of-concept study. Our findings suggest for the first time that MC-LR acts through a CD40-dependent mechanism to exacerbate colitis.

scholarly journals Dietary Acacetin Reduces Airway Hyperresponsiveness and Eosinophil Infiltration by Modulating Eotaxin-1 and Th2 Cytokines in a Mouse Model of Asthma

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Wen-Chung Huang ◽  
Chian-Jiun Liou
Keyword(s):  
Adhesion Molecule ◽  
Airway Hyperresponsiveness ◽  
Lavage Fluid ◽  
Intercellular Adhesion Molecule ◽  
Eosinophil Infiltration ◽  
Intercellular Adhesion Molecule 1 ◽  
Cell Hyperplasia ◽  
Anti Inflammatory ◽  
Inflammatory Effect

A previous study found that eosinophil infiltration and Th2 cell recruitment are important causes of chronic lung inflammation in asthma. The plant flavonoid acacetin is known to have an anti-inflammatory effectin vitro. This study aims to investigate the anti-inflammatory effect of orally administered acacetin in ovalbumin- (OVA-) sensitized asthmatic mice and its underlying molecular mechanism. BALB/c mice were sensitized by intraperitoneal OVA injection. OVA-sensitized mice were fed acacetin from days 21 to 27. Acacetin treatment attenuated airway hyperresponsiveness and reduced eosinophil infiltration and goblet cell hyperplasia in lung tissue. Additionally, eotaxin-1- and Th2-associated cytokines were inhibited in bronchoalveolar lavage fluid and suppressed the level of OVA-IgE in serum. Human bronchial epithelial (BEAS-2B) cells were used to examine the effect of acacetin on proinflammatory cytokines, chemokines, and cell adhesion molecule productionin vitro. At the molecular level, acacetin significantly reduced IL-6, IL-8, intercellular adhesion molecule-1, and eotaxin-1 in activated BEAS-2B cells. Acacetin also significantly suppressed the ability of eosinophils to adhere to inflammatory BEAS-2B cells. These results suggest that dietary acacetin may improve asthma symptoms in OVA-sensitized mice.

Inhibitors of Plasminogen Activator in Neutrophils and Mononuclear Cells from Septic Patients

1995 ◽  
Vol 74 (06) ◽  
pp. 1528-1532 ◽  
Author(s):  
Montaser A Haj ◽  
Linda A Robbie ◽  
Gillian D Adey ◽  
Bruce Bennett
Keyword(s):  
Plasminogen Activator ◽  
Mononuclear Cells ◽  
Human Subjects ◽  
Plasminogen Activator Inhibitor ◽  
Normal Subjects ◽  
Pathological Process ◽  
Plasminogen Activator Inhibitor 1 ◽  
Systemic Complications ◽  
Normal Individuals ◽  
Pai 1

SummaryLeucocytes, both polymorphs and mononuclear cells, play a variety of roles in the evolution of human response to sepsis, both local and generalised. In this study, inhibitors of plasminogen activator were measured in leucocytes from normal and septic patients. Plasminogen activator inhibitor-1 (PAI-1) was identified in polymorphs from normal individuals and levels rose significantly in polymorphs from septic patients: neutrophils from normal subjects did not contain PAI-2 but this protein was detectable in significant quantities in polymorph preparations from septic patients. In contrast, mononuclear cells from normal and septic patients contained no detectable quantities of PAI-1. Significant amounts of PAI-2 were present in normal mononuclear cells, and the levels rose significantly in monocytes from septic patients. PAI-2 is thus here identified in human subjects, distinct from those with pregnancy or malignancy, as playing a role in a pathological process. The increased levels of both inhibitors produced by leucocytes may clearly contribute directly to the persistence of fibrin, a characteristic feature of the response to infection, local or general; they may thus participate in successful localisation of infections (abscess formation etc.) and in the evolution of the major systemic complications of disseminated sepsis characterised by microvascular occlusion by fibrin such as renal failure, shock lung or digital ischaemia.

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