Role of inflammatory pathways in the development and cardiovascular complications of type 2 diabetes.

Experimental and epidemiologic studies support the role of inflammation in the development of type 2 diabetes and atherosclerosis. Serum levels of inflammatory markers, in particular highly sensitive C-reactive protein, have been found to be strong predictors of increased risk for type 2 diabetes and cardiovascular disease independent of traditional risk factors. A beneficial effect of thiazolidinediones, angiotensin-converting enzyme inhibitors, and statins in the prevention of type 2 diabetes and cardiovascular events has recently been reported, and potential anti-inflammatory mechanisms of action for these compounds have been described.

12-lipoxygenase pathway increases aldosterone production, 3',5'-cyclic adenosine monophosphate response element-binding protein phosphorylation, and p38 mitogen-activated protein kinase activation in H295R human adrenocortical cells.

Evidence suggests that the 12-lipoxygenase (LO) pathway mediates angiotensin II (Ang II)-induced aldosterone synthesis in adrenal glomerulosa cells. To study the mechanisms of 12-LO pathway on aldosterone synthesis, the human adrenocortical cell line, H295R, was transiently transfected with a mouse leukocyte type of 12-LO. Overexpression of 12-LO stimulated aldosterone production 2.

Open-label study of a twice-daily indinavir 800-mg/ritonavir 200-mg regimen in HIV-infected adults failing a protease inhibitor regimen.

There is no standard treatment of HIV-infected patients who fail protease inhibitor (PI)-containing antiretroviral therapy. This open-label, noncomparative 24-week study with a 24-week extension evaluated the efficacy, safety, and tolerability of twice-daily indinavir/ritonavir 800/200 mg plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) in this population. Presented here are the results of the 24-week study.

Key role of P38 mitogen-activated protein kinase and the lipoxygenase pathway in angiotensin II actions in H295R adrenocortical cells.

Angiotensin II (ANG II) can activate the mitogen-activated protein kinases (MAPKs) and stress-activated protein kinases in several cell types. We have previously shown that the 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism is a mediator of ANG II-induced aldosterone synthesis in adrenal glomerulosa cells. To evaluate the role of MAPK activation in ANG II and the effects of LO on aldosterone synthesis, experiments were performed using the human adrenocortical cell line H295R, which secretes aldosterone in response to ANG II.

Interaction of MAPK and 12-lipoxygenase pathways in growth and matrix protein expression in mesangial cells.

The lipoxygenase (LO) pathway of arachidonate metabolism and mitogen-activated protein kinases (MAPKs) can mediate cellular growth and ANG II effects in vascular smooth muscle cells. However, their role in renal mesangial cells (MC) is not very clear. ANG II treatment of rat MC significantly increased 12-LO mRNA expression and formation of the 12-LO product 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE; P < 0.

The anti-inflammatory compound lisofylline prevents Type I diabetes in non-obese diabetic mice.

Aims/hypothesis: Pro-inflammatory cytokines are increased during the active stages of Type I (insulin-dependent) diabetes mellitus. The aim of this study was to investigate the applicability of using a new anti-inflammatory compound, Lisofylline, to prevent diabetes in non-obese diabetic (NOD) mice. Lisofylline has previously been shown to block Th1 cell differentiation and to reduce IL-1 beta-induced dysfunction in rat islets.

Induction of cyclooxygenase-2 gene in pancreatic beta-cells by 12-lipoxygenase pathway product 12-hydroxyeicosatetraenoic acid.

Cyclooxygenase-2 (COX-2) gene and 12-lipoxygenase (12-LO) gene are preferentially expressed over other types of cyclooxygenase and lipoxygenase in pancreatic beta-cells. Inhibition of either COX-2 or 12-LO can prevent cytokine-induced pancreatic beta-cell dysfunction as defined by inhibition of glucose-stimulated insulin secretion. As cellular stress induces both genes and their respective end products in pancreatic beta-cells, we evaluated the role of 12-hydroxyeicosatetraenoic acid (HETE) on COX-2 gene expression, protein expression, and prostaglandin E2 (PGE2) production.

Predicting death from HIV/AIDS: a case-control study from Florida public HIV/AIDS clinics.

Background: After markedly decreasing for 3 years, HIV/AIDS mortality declined only slightly in 1999.

Methods: The authors conducted a case-control study in four Florida urban public health HIV clinics to evaluate modifiable factors associated with HIV/AIDS mortality in a non-research setting. Structured chart review was conducted for 120 case-patients who died in 1999 and for 240 randomly selected control-patients.

Suppression of autoimmune diabetes by viral IL-10 gene transfer.

Th1 cell activation and cytokine production shift the balance between Th1 and Th2, favoring the up-regulation of proinflammatory activity that leads to destruction of insulin-producing pancreatic beta cells in type 1 diabetes. Th2-type cytokines, such as IL-10, have immune regulatory function. Administration of IL-10, or IL-10 gene transfer, prevents autoimmune diabetes in nonobese diabetic (NOD) mice.

Both myo-inositol to chiro-inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues of GK type 2 diabetic rats compared to Wistar controls.

Previous data from our and other labs demonstrated a decreased chiro-inositol content in urine and tissues of human subjects and animals with type 2 diabetes. In urine this decrease in chiro-inositol was accompanied by an increase in myo-inositol content. Decreased urine levels of chiro-inositol in monkeys were next correlated with the severity of underlying insulin resistance determined by five separate assays.

Lisofylline, a novel antiinflammatory agent, protects pancreatic beta-cells from proinflammatory cytokine damage by promoting mitochondrial metabolism.

Proinflammatory cytokine-mediated pancreatic beta-cell dysfunction is a key pathological event in type I diabetes mellitus. Lisofylline (LSF), an anti-inflammatory agent, has been shown to protect pancreatic islets from IL-1 beta-induced inhibitory effects on insulin release. However, the mechanism of LSF action is not known.

Quantitative and morphological analysis of dentate granule cells with recurrent basal dendrites from normal and epileptic rats.

Granule cells with recurrent basal dendrites (RBDs) were previously reported in both control and epileptic rats. RBDs are dendrites that arise from the basal half of granule cell bodies and curve toward and extend into the molecular layer. They are increased in frequency in the pilocarpine model of epilepsy.

In-situ measurement of ammonium and nitrate in the activated sludge process.

A new in-situ probe is presented for the continuous measurement of ammonium and nitrate in wastewater. It requires no sample preparation and is installed directly in the process liquid. This new low-cost probe significantly reduces investment and operating costs and requires minimum maintenance.

A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy.

Objective: To compare the effect of treatment decisions guided by phenotypic resistance testing (PRT) or standard of care (SOC) on short-term virological response.

Design: A prospective, randomized, controlled clinical trial conducted in 25 university and private practice centers in the United States.

Participants: A total of 272 subjects who failed to achieve or maintain virological suppression (HIV-1-RNA plasma level > 2000 copies/ml) with previous exposure to two or more nucleoside reverse transcriptase inhibitors and one protease inhibitor.

Role of 12-lipoxygenase and oxidant stress in hyperglycaemia-induced acceleration of atherosclerosis in a diabetic pig model.

Aims/hypothesis: We previously showed that vascular smooth muscle cells and endothelial cells cultured under high glucose conditions produced more 12(S)-hydroxyeicosatetraenoic acid (12-HETE), the 12-lipoxygenase (12-LO) product of arachidonate metabolism, relative to normal glucose. Because the lipoxygenase (LO) pathway has been associated with oxidant stress and the pathogenesis of atherosclerosis, we now examined 12-LO activation in vivo in a pig model of diabetes-induced accelerated atherosclerosis which displays human characteristics.

Methods: The animal model was developed in pigs who were fed a normal or high fat diet and given streptozotocin injections to produce normolipemic-normoglycaemic (NLNG), normolipemic-hyperglycaemic (NLHG), hyperlipemic-normoglycaemic (HLNG) and hyperlipemic-hyperglycaemic (HLHG) pigs.

Daily dosing of highly active antiretroviral therapy.

Complex treatment schedules for human immunodeficiency virus (HIV) disease, which can have a high pill burden and can include multiple daily doses, in addition to the adverse effects that the medications can cause, may reduce patient adherence to therapy. Reduced adherence prevents achievement of the desired goal of full suppression of HIV replication, and it also promotes the development of drug-resistant strains of HIV. Thus, the focus of treatment has shifted toward the use of simpler regimens.

The oxidized lipid and lipoxygenase product 12(S)-hydroxyeicosatetraenoic acid induces hypertrophy and fibronectin transcription in vascular smooth muscle cells via p38 MAPK and cAMP response element-binding protein activation. Mediation of angiotensin II effects.

Evidence suggests that the arachidonic acid metabolite of 12-lipoxygenase, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), not only mediates the effects of angiotensin II (AngII), but also has direct effects on hypertrophy and matrix protein production in vascular smooth muscle cells (VSMCs). This study is aimed at identifying the signaling pathways involved in these events. Treatment of porcine VSMCs with 12(S)-HETE led to the activation of Ras and p38 MAPK.

Glutamate receptor involvement in dentate granule cell epileptiform activity evoked by mossy fiber stimulation.

In many persons with temporal lobe epilepsy, dentate granule cells form an interconnected synaptic network. This recurrent mossy fiber circuit mediates reverberating excitation that may facilitate seizure propagation by synchronizing granule cell discharge. The involvement of specific glutamate receptors in granule cell epileptiform activity evoked by stimulating the mossy fibers was investigated with use of rat hippocampal slices superfused with bicuculline, with or without increasing [K+](o) to 6 mM.

Synaptically-released zinc inhibits N-methyl-D-aspartate receptor activation at recurrent mossy fiber synapses.

Hippocampal slices from pilocarpine-treated rats were used to explore the effect of zinc released at mossy fiber synapses on dentate granule cells. Chelation of zinc enhanced the N-methyl-D-aspartate (NMDA) receptor-mediated component of the excitatory postsynaptic current (EPSC), but did not affect the AMPA/kainate receptor-mediated component. Its effect was detectable only at negative membrane potentials and was pathway specific.

Diabetes-induced accelerated atherosclerosis in swine.

Patients with diabetes are at higher risk for atherosclerotic disease than nondiabetic individuals with other comparable risk factors. Studies examining mechanisms underlying diabetes-accelerated atherosclerosis have been limited by the lack of suitable humanoid animal models. In this study, diabetes was superimposed on a well-characterized swine model of atherosclerosis by injection of the beta-cell cytotoxin streptozotocin (STZ), resulting in a >80% reduction in beta-cells and an increase in plasma glucose to diabetic levels.

Lack of effect of mossy fiber-released zinc on granule cell GABA(A) receptors in the pilocarpine model of epilepsy.

The recurrent mossy fiber pathway of the dentate gyrus expands dramatically in the epileptic brain and serves as a mechanism for synchronization of granule cell epileptiform activity. It has been suggested that this pathway also promotes epileptiform activity by inhibiting GABA(A) receptor function through release of zinc. Hippocampal slices from pilocarpine-treated rats were used to evaluate this hypothesis.

Adenoviral delivery of a leukocyte-type 12 lipoxygenase ribozyme inhibits effects of glucose and platelet-derived growth factor in vascular endothelial and smooth muscle cells.

The lipoxygenase (LO) pathway has been implicated as an important mediator of chronic glucose and platelet-derived growth factor (PDGF)-induced effects in the vascular system. Endothelial cells treated with 12LO products or cultured in high glucose showed enhanced monocyte adhesion, an important step in atherogenesis. We have previously reported that PDGF increased HETE levels in porcine aortic smooth muscle cells.

12-lipoxygenase is increased in glucose-stimulated mesangial cells and in experimental diabetic nephropathy.

Background: Arachidonic acid-derived 12-lipoxygenase (12-LO) products have potent growth and chemotactic properties. The present studies examined whether 12-LO and fibronectin are induced in cultured rat mesangial cells (MCs) exposed to high glucose and whether they are expressed in experimental diabetic nephropathy.

Methods: To determine the effect of high glucose on MC 12-LO mRNA and protein expression, rat MCs were incubated with RPMI medium containing 100 (NG) or 450 mg/dL glucose (HG).

Ribozyme-mediated inhibition of rat leukocyte-type 12-lipoxygenase prevents intimal hyperplasia in balloon-injured rat carotid arteries.

Background: 12-Lipoxygenase (12-LO) products of arachidonate metabolism have growth and chemotactic effects in vascular smooth muscle cells. We have also recently demonstrated increased 12-LO mRNA and protein expression in the neointima of balloon-injured rat carotid arteries. In this study, we evaluated whether 12-LO activation plays a role in neointimal thickening in this rat model by using a specific ribozyme (Rz) directed to rat 12-LO.