Effects in humans of intravenously administered endotoxin on soluble cell-adhesion molecule and inflammatory markers: a model of human diseases.

1. Endotoxin, a component of the cell wall of Gram-negative bacteria, could be a predisposing mediator of many pathological disorders. The present study was undertaken to determine the effects and time-course of acute endotoxin challenge on inflammatory and cell-adhesion molecule markers shedding in the plasma as potential surrogates.

Acute suppressive effect of hydrocortisone on p47 subunit of nicotinamide adenine dinucleotide phosphate oxidase.

We have recently demonstrated that reactive oxygen species (ROS) generation by polymorphonuclear leukocytes (PMNL) and mononuclear cells (MNC) is inhibited following the intravenous administration of hydrocortisone. This is associated with a parallel decrease in intranuclear NFkappaB, known to modulate inflammatory responses including ROS generation. We have also shown that the plasma levels of interleukin-10 (IL-10), an anti-inflammatory and immunosuppressive cytokine produced by TH2 cells, are also increased after hydrocortisone administration.

Suppression of nuclear factor-kappaB and stimulation of inhibitor kappaB by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese.

To elucidate whether troglitazone exerts an antiinflammatory effect in humans, in vivo, we investigated the suppression of nuclear factor kappaB (NFkappaB) in mononuclear cells (MNC) by this drug. We measured intranuclear NFkappaB, total cellular NFkappaB, inhibitor kappaB (IkappaB)alpha, reactive oxygen species (ROS) generation, and p47(phox) subunit (a key component protein of nicotinamide adenine dinucleotide phosphate oxidase) in MNC. Plasma tumor necrosis factor (TNF)-alpha, soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor type 1 (PAI-1), C-reactive protein (CRP), and interleukin (IL)-10 (antiinflammatory cytokine) concentrations were also measured as mediators of inflammatory activity that are regulated by the proinflammatory transcription factor NFkappaB.

Insulin inhibits NFkappaB and MCP-1 expression in human aortic endothelial cells.

In view of our recent demonstration that insulin inhibits the expression of intercellular adhesion molecule-1 (ICAM-1) and the fact that ICAM-1 expression is known to be modulated by nuclear factor-kappaB (NFkappaB), we have now investigated whether insulin inhibits intranuclear NFkappaB binding activity. We have also investigated whether insulin inhibits the pro-inflammatory chemokine, monocyte chemoattractant protein-1 (MCP-1), which attracts leucocytes to the inflamed sites and is also regulated by NFkappaB. Insulin was incubated with cultured human aortic endothelial cells (HAEC) at 0, 100 and 1000 microU/mL.

The suppressive effect of dietary restriction and weight loss in the obese on the generation of reactive oxygen species by leukocytes, lipid peroxidation, and protein carbonylation.

Increased reactive oxygen species generation by the leukocytes of the obese may be responsible for increased oxidative injury to lipids and proteins and, hence, atherosclerosis. We have investigated whether reactive oxygen species generation by leukocytes and other indexes of oxidative damage in the body fall with short-term dietary restriction and weight loss. Nine nondiabetic obese subjects (body mass index, 32.

Estrogen receptor-alpha in the inhibition of cancer growth and angiogenesis.

A high level of estrogen receptor-alpha (ER-alpha) is believed to be favorable in the prognosis and treatment of certain female cancers. ER-alpha expression in the ER-negative breast cancer cell lines inhibits their proliferation and invasive, metastatic potential in vitro. We stably overexpressed the ER-alpha in the human endometrial cancer cell line Ishikawa and showed that, unlike estradiol, high levels of ER-alpha significantly inhibit the growth of tumors xenografted from the Ishikawa cells.

Brachial vascular reactivity in blacks.

Endothelial function was studied ultrasonographically in a healthy subset of African Americans (blacks) because they have an increased risk of hypertension and vascular disease. Twenty-four healthy black and 28 well-matched white subjects were investigated. Ischemia was induced by inflating a cuff over the forearm to 40 mm Hg higher than systolic pressure for 5 minutes.

Troglitazone reduces reactive oxygen species generation by leukocytes and lipid peroxidation and improves flow-mediated vasodilatation in obese subjects.

Because troglitazone has been shown to have antioxidant properties, we investigated whether troglitazone administration to obese subjects causes a reduction in (1) reactive oxygen species (ROS) generation by polymorphonuclear leukocytes (PMNLs) and mononuclear cells (MNCs) and (2) lipid peroxidation as reflected in the plasma concentrations of 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE). Seven obese subjects were given 400 mg/d troglitazone for 4 weeks. Blood samples were obtained before troglitazone administration and at weekly intervals thereafter.

Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes.

Diabetes mellitus is associated with increased ROS generation, oxidative injury and obesity. To elucidate the relationship between nutrition and ROS generation, we have investigated the effect of glucose challenge on ROS generation by leucocytes, p47phox protein, a key protein in the enzyme NADPH oxidase and alpha-tocopherol levels. Blood samples were drawn from 14 normal subjects prior to, at 1, 2 and 3 h following ingestion of 75 g glucose.

Nadolol inhibits reactive oxygen species generation by leukocytes and linoleic acid oxidation.

We studied the effect of short-term nadolol administration on the reactive oxygen species (ROS) generation by polymorphonuclear leukocytes and mononuclear cells in 8 normal subjects. At a oral dose of 40 mg/day for 5 days, nadolol produced a decrease in the ROS generation by leukocytes. ROS generation by polymorphonuclear leukocytes decreased by 38% from 134 +/- 44 mV at baseline to 83 +/- 34 mV after 5 days (p = 0.

Insulin inhibits the expression of intercellular adhesion molecule-1 by human aortic endothelial cells through stimulation of nitric oxide.

Intercellular adhesion molecule-1 (ICAM-1) is expressed by endothelial and other cell types and participates in inflammation and atherosclerosis. It serves as a ligand for leukocyte function-associated antigen-1 on leukocytes and is partially responsible for the adhesion of lymphocytes, granulocytes, and monocytes to cytokine-stimulated endothelial cells and the subsequent transendothelial migration. Its expression on endothelial cells is increased in inflammation and atherosclerosis.

Effect of triiodothyronine on reactive oxygen species generation by leukocytes, indices of oxidative damage, and antioxidant reserve.

We have examined the effect of short-term triiodothyronine (T3) administration on reactive oxygen species (ROS) generation by leukocytes in 9 euthyroid subjects. At a dose of 60 microg/d orally for 7 days, T3 induced a significant increase in ROS generation by mononuclear cells (MNCs) from 183 +/- 102 mV at baseline to 313 +/- 111 mV on the seventh day (P < .02), and by polymorphonuclear leukocytes (PMNLs) from 195 +/- 94 mV at baseline to 302 +/- 104 mV on the seventh day (P < .

Severe myopathy associated with vitamin D deficiency in western New York.

Five cases of severe myopathy associated with vitamin D deficiency are described. Each patient was confined to a wheelchair because of weakness and immobility. Two were elderly, 1 was a 37-year-old African American with type 1 diabetes mellitus, 1 was being treated for carcinoid syndrome, and 1 was severely malnourished due to poor oral intake.

A diabetic patient with a black penile tip.

This is a report of a patient with diabetes mellitus type II who presented with the rare complication of penile gangrene. The gangrene was unilateral and was associated with ipsilateral partial stenosis of the common iliac artery. An angioplasty followed by insertion of a stent, rehydration, and improved diabetic control did not improve the penile lesion, and penile amputation was carried out.

Differential alterations of spontaneous and stimulated 45Ca(2+) uptake by platelets from patients with type I and type II diabetes mellitus.

Diabetes mellitus (DM) is associated with hyperaggregability of platelets. Although the mechanisms underlying this abnormality remain unknown, Ca(2+) imbalance has been implicated. Both activators (alpha-adrenoceptor agonists, collagen, and ADP) and inhibitors (beta-adrenoceptor agonists, iloprost and dibutyryl cAMP) of platelet function, respectively, elicit the uptake of [45Ca(2+)] in human platelets.

Effect of insulin on human aortic endothelial nitric oxide synthase.

It has recently been shown that insulin induces vasodilation in human arteries and veins in vivo. This effect of insulin has been shown to be a direct one on the human vein. In view of these observations and the fact that insulin-induced vasodilation is impaired in insulin-resistant states like type 2 diabetes and obesity, we have investigated the hypothesis that insulin may induce the expression of endothelial nitric oxide synthase (e-NOS) in endothelial cells grown from human aortae (HAECs), human lower-limb veins, and human umbilical veins (HUVECs), and microvascular endothelial cells (MVECs) from human adipose tissue.

Carvedilol inhibits reactive oxygen species generation by leukocytes and oxidative damage to amino acids.

Background: The purpose of this study was to test whether carvedilol has an antioxidant effect in humans in vivo.

Methods And Results: We administered 3.125 mg of carvedilol twice daily to normal subjects for 1 week.

Heparin inhibits reactive oxygen species generation by polymorphonuclear and mononuclear leucocytes.

To examine the hypothesis that heparin may affect leukocyte function and that it may have anti-inflammatory properties, we investigated the effect of heparin on reactive oxygen species (ROS) generation by leucocytes. Heparin was injected intravenously at a dose of 10000 units into eight normal subjects. Blood samples were collected from the antecubital vein sequentially, prior to and following heparin at 0, 0.

Insulin-induced vasodilatation of internal carotid artery.

The increase in leg and forearm blood flow induced by insulin could be secondary to its metabolic effect on glucose uptake. We therefore investigated whether insulin causes vasodilation of the internal carotid artery, since the brain is not dependent on insulin for glucose uptake, to demonstrate that the vasodilatory effect of insulin is primary and independent of its metabolic effect. Internal carotid artery diameter was continuously monitored using a 7.

Hydrocortisone-induced inhibition of reactive oxygen species by polymorphonuclear neutrophils.

Objective: To determine whether hydrocortisone given intravenously inhibits reactive oxygen species (ROS) generation by polymorphonuclear neutrophils (PMNLs) in vivo and, if so, to describe the pharmacodynamics of this effect.

Design: A prospective, open label study in normal subjects.

Setting: A clinical research unit of a tertiary referral center for diabetes and endocrinology.

Increased IkappaB expression and diminished nuclear NF-kappaB in human mononuclear cells following hydrocortisone injection.

We have recently demonstrated that hydrocortisone and other glucocorticoids inhibit reactive oxygen species (ROS) generation by mononuclear (MNC) and polymorphonuclear leucocytes (PMNL). Since NF-kappaB/IkappaB system regulates the transcription of proinflammatory genes, including those responsible for ROS generation, we tested the hypothesis that hydrocortisone may stimulate IkappaB production thus inhibiting NF-kappaB translocation from the cytosol into the nucleus in MNC, in vivo. One hundred milligram of hydrocortisone was injected intravenously into 4 normal subjects.

Stable over-expression of estrogen receptor-alpha in ECV304 cells inhibits proliferation and levels of secreted endothelin-1 and vascular endothelial growth factor.

Studies with mammalian vascular cells have suggested growth inhibitory effects of estrogen on the vascular wall. To investigate the involvement of estrogen receptor-alpha (ER) in the control of endothelial cell proliferation, we have stably transfected human estrogen receptor-alpha cDNA into the endothelial cell line ECV304. The clone ECV-ER, thus obtained, over-expresses estrogen receptor to a level approximately 10-fold higher than the parent cell line.

Effect of dexamethasone on reactive oxygen species generation by leukocytes and plasma interleukin-10 concentrations: a pharmacodynamic study.

After the demonstration that hydrocortisone inhibits reactive oxygen species (ROS) generation by leukocytes in vivo in a highly predictable manner, we investigated the effect of dexamethasone at a dose of 4 mg, which is thought to be roughly equivalent to 100 mg hydrocortisone. We also tested the hypothesis that dexamethasone may increase the plasma concentration of interleukin-10 (IL-10), an immunomodulatory cytokine that inhibits T(H)1 cells. Dexamethasone (4 mg given intravenously) markedly inhibited ROS generation by mononuclear cells and polymorphonuclear leukocytes.