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P P Nawroth

Publications and source records attributed to P P Nawroth.

At least 19 recordsLinked to original sources
PubMed2006

[Glycotoxins and cellular dysfunction. A new mechanism for understanding the preventive effects of lifestyle modifications].

Recently the AGE-RAGE interaction was identified as a potential mechanism underlying chronic and inflammatory diseases like atherosclerosis, diabetes mellitus and kidney disease. Advanced glycation end products (AGEs) are the derivatives of glucose-protein or glucose-lipid reactions and are mainly generated from the diet (depending on intensity of heating, cooking time and oxygenation). Binding of AGEs or other ligands to the AGE receptor (RAGE) results in cellular activation, i.e. increased expression of inflammatory mediators and oxidative stress. Diet-derived AGEs thus induce deleterious effects on tissues and the cardiovascular system. Recent research also found that other lifestyle factors are associated with pronounced inflammatory activation, e.g. psychosocial stress and smoking. In addition, each intake of meals is associated with proinflammatory cellular changes. The AGE-RAGE model and investigations of the underlying cellular mechanisms thus may lead to a better understanding of the health benefits of diets (Mediterranean diet, uncooked vegetarian diets), caloric restriction and intermittent fasting. The clinical impact of low-AGE diets and fasting and the interaction between stress and food intake should be further investigated in controlled trials.

Cell Physiological Phenomena↗
PubMed2006

Postprandial mononuclear NF-kappaB activation is independent of the AGE-content of a single meal.

OBJECTIVE: Dietary uptake of Advanced Glycation Endproducts (AGE) is supposed to potentially contribute to inflammatory reactions linked to vascular dysfunction and late diabetic complications. One mechanism by which dietary AGE might exert these effects is by activation of the proinflammatory transcription factor NF-kappa-B. The aim of this study was to analyze the postprandial effects of a casein meal with low or high AGE content on postprandial NF-kappaB activation in peripheral blood mononuclear cells (pBMC) of healthy volunteers. RESEARCH DESIGN AND METHODS: Casein was heated for 40 h at 50 degrees C in the presence of sorbitol or glucose, resulting in either minimal (Sorbitol [S]-casein) or large (glucose [G]-casein) amounts of AGE-modified casein. Nine healthy volunteers ate 250 g of both types of casein, whereas both meals were separated at least by 2 weeks. Plasma and pBMC were taken before and 2 h after each meal. Thereafter, the defined AGE carboxymethyllysine (CML) was determined by ELISA and Western blot. NF-kappaB activation in pBMC was assayed using Electrophoretic Mobility Shift Assays (EMSA) and Western blot analysis. RESULTS: S-casein contained only minor amounts of CML and no pentosidine, while G-casein contained large amounts of both. 2 h after ingestion, the S-casein or the G-casein-meal, both, resulted in a non-significant increase in plasma CML and in the intracellular CML-content of pBMC. This was paralleled by a highly significant increase in postprandial mononuclear NF-kappaB-binding activity. Remarkably, neither the extent of NF-kappaB induction (178% for S-casein, 188% for G-casein), nor composition of the NF-kappaB heterodimer (mainly consisting of NF-kappaB p50/p65) were significantly different after intake of S-casein or G-casein. Consistently, Western blots confirmed an increased NF-kappaBp65 nuclear translocation and a decrease of NF-kappaBp65 in the cytoplasm, while no difference in postprandial NF-kappaB nuclear translocation was observed following intake of S-casein or G-casein. CONCLUSION: Postprandial mononuclear NF-kappaB activation after a single meal is independent of the AGE-content of the ingested protein.

Active Transport, Cell Nucleus↗
PubMed2005

The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy.

Oxidative stress and nuclear factor-kappaB (NF-kappaB) activation are linked to the pathogenesis of many metabolic, degenerative, and chronic inflammatory diseases. Activation of the receptor for advanced glycation end products (RAGE) by its specific ligand N(epsilon)-carboxymethyllysine (CML) results in the activation of NF-kappaB and the production of proinflammatory cytokines. To determine whether engagement of RAGE contributes to the pathogenesis of inflammatory myopathies, we performed immunohistochemical studies on the presence of CML-modified proteins, RAGE and activated NF-kappaB in muscle biopsies of patients with polymyositis (PM, n=10), dermatomyositis (DM, n=10), limb girdle muscular dystrophy (LGMD, n=10) and in 10 controls with normal muscle biopsy results. In inflammatory myopathies CML, RAGE and NF-kappaB were detected in mononuclear cells and in regenerating muscle fibers. CML, NF-kappaB and, to a lesser extent, RAGE were also found in degenerating muscle fibers, but colocalization of CML, RAGE and NF-kappaB was only seen in infiltrating mononuclear cells and regenerating muscle fibers. Immunofluorescence double labeling demonstrated an expression of CML, RAGE and NF-kappaB in CD4-, CD8-, CD22- and CD68-positive mononuclear cells. Western blot analysis showed an increased immunoreactivity for CML-modified proteins in PM and DM. In LGMD, CML, RAGE and NF-kappaB were found in regenerating muscle fibers and less frequently in degenerating muscle fibers, and with lower staining intensities than in inflammatory myopathies. Our data suggests that the CML-RAGE-NF-kappaB pathway is an evident proinflammatory pathomechanism in mononuclear effector cells in PM and DM. RAGE-mediated NF-kappaB activation may be involved in muscle fiber regeneration in inflammatory myopathies and LGMD.

Adult↗
PubMed2005

Adult vascular progenitor cells and tissue regeneration in metabolic syndrome.

Adult vascular progenitor cells (for example endothelial progenitor cells, EPC) have been studied for their contribution to vascular repair and angiogenesis. These cells can differentiate from bone marrow cells as well as circulating cells carrying hematopoetic stem cell markers. In vivo, they take part in vasculogenesis in different animal models of limb ischemia, myocardial infarction and wound healing. In metabolic disease, the outgrowth and function of EPC in vitro is defective and numbers of EPC correlate with classical risk factors of cardiovascular disease suggesting a role of EPC in the development of vascular complications. Pilot studies for the treatment of myocardial infarction and limb ischemia with autologous bone marrow showed a distinct therapeutic benefit that is presumably mediated by vasculogenesis in damaged tissues. However, little is known about the nature of EPC and their capability to differentiate into functional cells for tissue regeneration. In this article, we review and discuss the hitherto identified physiological function of EPC, the mechanisms leading to dysfunction of these cells and potential therapeutic applications in patients with metabolic syndrome or diabetes mellitus and vascular complications.

Adult↗
PubMed2005

Locally applied mononuclear bone marrow cells restore angiogenesis and promote wound healing in a type 2 diabetic patient.

We treated a patient with type 2 diabetes suffering from chronic venous and neuro-ischemic wounds not healing under standard care with local application of autologous bone marrow cells (mBMC) isolated from bone marrow aspirate. This procedure led to a reduction of wound size, a markedly increased vascularization and infiltration of mononuclear cells, 7 days after treatment, without any signs of a systemic reaction to treatment. Locally applied mBMC could, therefore, provide a treatment option in end stage diabetic wound healing disorders.

Bone Marrow Cells↗
PubMed2005

[Coagulation, inflammation and immune response -- an evolutionary conserved plan as cause for disseminated intravasal coagulation?].

The concomitant activation of the immune response and the coagulation system in response to injury represents a phylogenetic old and adaptive principle already present in the early eukaryotic development. The close connection between coagulation, inflammation, and immune defense has been conserved during evolution and can still be found in humans in a number of physiologic reactions to potentially detrimental effects.

Biological Evolution↗
PubMed2005

The role of junctional adhesion molecules in cell-cell interactions.

Cell-cell-interactions are important for the regulation of tissue integrity, the generation of barriers between different tissues and body compartments thereby providing an effective defence against toxic or pathogenic agents, as well as for the regulation of inflammatory cell recruitment. Intercellular interactions are regulated by adhesion receptors on adjacent cells which upon extracellular ligand binding mediate intracellular signals. In the vasculature, neighbouring endothelial cells interact with each other through various adhesion molecules leading to the generation of junctional complexes like tight junctions (TJs) and adherens junctions (AJs) which regulate both leukocyte endothelial interactions and paracellular permeability. In this context, emerging evidence points to the importance of the family of junctional adhesion molecules (JAMs), which are localized in tight junctions of endothelial and epithelial cells and are implicated in the regulation of both leukocyte extravasation as well as junction formation and permeability.

Animals↗
PubMed2004

NF-kappaB as a molecular link between psychosocial stress and organ dysfunction.

It is well accepted that psychosocial stress contributes to the pathogenesis of hypertension, cardiovascular disease, and renal disease. Although even lay persons are aware that stress can be dangerous to health, the molecular mechanisms by which psychosocial events contribute to cellular dysfunction have hitherto been poorly understood by scientists. The pro-inflammatory transcription factor NF-kappaB has recently been identified as a potential critical bridge between stress and cellular activation. NF-kappaB activation, in turn, is known to play a pivotal role in vascular and renal disease. Activation of NF-kappaB, evoked by psychosocial stress, may directly target vessels and kidneys and thus represent an additional risk factor for cardiovascular and renal disease.

Animals↗
PubMed2004

[Role of the innate immune response in sepsis].

The innate immune system succeeds against the majority of infections before the adaptive immune system is activated. New findings contribute to a better understanding of the pathophysiology of sepsis and lead to the development of new therapeutic strategies. The innate immune system, being responsible for the first response to infections, can trigger adaptive immune responses in case the initial response is ineffective. Both arms of the immune system interact with each other, mainly via cell-cell-interactions but also by soluble factors, such as cytokines and chemokines. Two sub-populations of helper T-cells direct both balanced activation and inhibition of the two arms of the immune systems using specific patterns of cytokine release. Results obtained in new animal models of sepsis, taking a progressive growth of bacteria into account, have implied that existing knowledge has to be reanalyzed. The idea of sepsis as a mere "over-reaction to inflammation" has to be abandoned. Various so-called pattern recognition receptors (e.g. toll-like receptors, TLRs, NOD proteins) are located intracellularly or in the plasma membrane of innate immune cells and recognize certain patterns expressed exclusively by extracellular pathogens. Upon receptor engagement, intracellular signaling pathways lead to cellular activation, followed by release of various cytokines and anti-microbial substances. During the course of sepsis a cytokine shift towards increasing immune suppression occurs. The innate immune system also contributes to the migration of leukocytes in inflammed tissue, involving chemokines and adhesion molecules. Leukocytes also secrete the tissue factor leading to formation of thrombin. The environment in sepsis can cause disseminated intravascular coagulation (DIC), but at the same time thrombin triggers the release of chemokines and adhesion molecules through endothelial cells, which represents a positive feedback mechanism for innate immune responses. New therapeutic strategies for sepsis try to establish a well-balanced immune response. Intervention is accomplished through inhibition of inflammatory cytokines, their receptors or through activation of immunostimulatory responses.

Animals↗
PubMed2004

[Liposome-mediated transfection of thrombomodulin in vascular smooth muscle cells--a gene therapy concept to inhibit recurrent stenosis].

PURPOSE: Thrombomodulin (TM), an integral endothelial receptor, is known for its anticoagulant functions. Moreover, there is evidence of growth-modulating effects of this cell surface -protein. The aim of our study was to establish by in vitro transfection a stable cell line of vascular smooth muscle cells with overexpression of TM for further investigations concerning the influence of TM on cellular proliferation and its potential role during the formation of restenosis. METHODS: Aortic smooth muscle cells of the rat were transfected with cDNA of mouse TM or one of its three mutants (M1, M2, M4) by a liposome-mediated technique. The expression of mouse TM mRNA in the selected clones was proven with the help of RT-PCR. Changes of cell proliferation were determined by proliferation kinetics over 24 days. The quantification of the total protein TM was made by Western blots. RESULTS: In 44 of 100 cases the RT-PCR confirmed a successful transfection of mouse-TM. The clones with transfected TM, M1 or M2 showed an inhibited cell growth, whereas M4 demonstrated an increased proliferation compared with controls. The comparison of amounts of total TM with cell growth of individual clones resulted in a negative correlation between proliferation and TM-expression (coefficient of correlation for TM -0.87, for M1 -0.59). CONCLUSIONS: It is possible to reproduce stable cell-lines of vascular smooth muscle cells with overexpression of TM by the presented model of in vitro transfection. Thus, a basis exists for detailed examinations of growth-regulating mechanisms by TM.

Analysis of Variance↗
PubMed2004

A 63bp deletion in the promoter of rage correlates with a decreased risk for nephropathy in patients with type 2 diabetes.

Several polymorphisms have been identified in the RAGE-promoter region that might modulate the outcome of disease. Here we analyse the association of a 63bp deletion (delta63) spanning from bp - 407 to bp - 345 with diabetic nephropathy. The deletion was determined using the polymerase chain reaction (PCR) in a cross-sectional study with 1087 patients with type 1 diabetes (n = 559) and type 2 diabetes (n = 528). 475 patients with osteoporosis served as disease independent control. The prevalence of the heterozygous genotype did not significantly differ between the three groups (type 1: 2.15 %, type 2: 2.27 %, controls: 1.47 %), indicating that heterozygous delta63 is not related to the manifestation of diabetes. Homozygous carriers were not identified in this study. The heterozygous delta63 genotype, was associated with a reduced prevalence of diabetic nephropathy in patients with type 2 diabetes (OR = 0.06; 95 % CI: [0.05, 0.07]), but not in patients with type 1 (OR = 1.49; 95 % CI: [1.14, 1.94]). We conclude, that patients with type 2 diabetes and the 63bp deletion in the promoter of RAGE seem to be protected from diabetic nephropathy. The observed difference between type 1 and type 2 diabetes might point to diverse pathomechanisms of nephropathy in both types of diabetes.

Diabetes Mellitus, Type 1↗
PubMed2003

Glimepiride reduces mononuclear activation of the redox-sensitive transcription factor nuclear factor-kappa B.

AIMS: Glimepiride has the lowest ratio of insulin release to glucose decrease compared with other sulphonylureas. This prompted us to study in vitro and in vivo in a placebo-controlled study the effect of glimepiride on the redox-sensitive transcription factor nuclear factor-kappa B (NF-kappaB). METHODS: Fifteen patients with type 2 diabetes on glibenclamide with a stable HbA1c over the last 6 months were included. After sampling for determination of baseline values, 10 patients were changed to an equivalent dose of glimepiride, while the placebo group was maintained at glibenclamide plus placebo. The glimepiride dose in these patients was adjusted so that no change in glucose control occurred, allowing for direct comparison. The others were kept on glibenclamide and received additional placebo. After 4 weeks of glimepiride or glibenclamide plus placebo, a second blood sample was taken. Mononuclear cells were isolated and assayed in a tissue-culture-independent electrophoretic mobility shift assay (EMSA)-based detection system for NF-kappaB binding activity, and by Western Blot for nuclear localization of NF-kappaB-p65, the cytoplasmic content of IkappaBalpha and the NF-kappaB-controlled haemoxygenase-1. Glimepiride dose-dependent inhibition of carboxymethyllysin (CML) albumin or tumour necrosis factor alpha (TNFalpha)- and H2O2-induced activation of NF-kappaB binding were determined, using isolated peripheral blood mononuclear cells from healthy volunteers, and transcriptional activity of bovine aortic endothelial cells either left untreated or induced with CML albumin incubated with or without glimepiride. Furthermore, in-vitro studies were implemented to demonstrate radical quenching properties of glimepiride in the cell-free 2,2'-azo-bis(2-aminopropane)-dihydrochloride system. RESULTS: Baseline glucose and HbA1c remained stable in the patients switched from glibenclamide to a corresponding dose of glimepiride or kept on glibenclamide plus placebo. While in the group of patients only taking glibenclamide plus placebo the NF-kappaB binding activity did not change significantly (p = 0.58), the NF-kappaB binding activity in the group of patients taking glimepiride was reduced from 19.3 relative NF-kappaB-p65-equivalents to 15.5 relative NF-kappaB-p65-equivalents (p = 0.04). The nuclear translocation of NF-kappaB-p65 was reduced from 100% at baseline to 58% after 4 weeks (p = 0.04); the cytoplasmic localization of NF-kappaB-p65 increased from 100% to 129% (p = 0.03) and the cytoplasmic content of IkappaBalpha increased from 100% to 109% (p = 0.06). The redox-sensitive haemoxygenase-1 antigen was reduced from 100% to 82% (p = 0.04). To prove directly that glimepiride reduces NF-kappaB activation, we isolated peripheral blood mononuclear cells (PBMC) from healthy volunteers. In vitro, glimepiride reduced TNFalpha-(1 nmol/l) and CML albumin (800 nmol/l)-induced NF-kappaB activation dose dependently, being half maximal at 120 micromol/l. H2O2-mediated NF-kappaB activation was only partially reduced. In addition, glimepiride reduced NF-kappaB-dependent gene expression using a NF-kappaB-driven luciferase reporter system. Finally, a cell-free detection system showed that glimepiride has radical quenching properties. CONCLUSION: Glimepiride can affect the activation of the redox-sensitive transcription factor NF-kappaB in vitro and in vivo.

Aged↗
PubMed2002

[The "needle man": more than 40,000 injections in 40 years].

HISTORY AND ADMISSION FINDINGS: A now 65-year-old man had undergone a subtotal thyroidectomy over 40 years ago, which postoperatively resulted in hypoparathyroidism. His doctor began daily intravenous injections of a calcium preparation (1880 mg to 3760 mg calcium per day, over 40000 injections during this period), a regimen continued subsequently by a total of more than 15 other doctors for over 40 years. On admission the patient complained of oral paresthesias and paresthesias of the limbs. INVESTIGATIONS: Low calcium and parathormone levels confirmed the diagnosis of hypoparathyroidism. TREATMENT AND COURSE: Normal levels of calcium were achieved after a short course of 1.25-dihydroxycalciferol. This was followed by the administration of cholecalciferol and calcium. The patient soon became symptom-free and calcium levels returned to normal. Late sequelae have been calcification of the basal ganglia, first signs of nephrocalcinosis and bilateral cataract. CONCLUSION: This case demonstrates that appropriate treatment of hypoparathyroidism [corrected] might not be given in every case.

Aged↗
PubMed2002

Recurrent deep venous thrombosis caused by congenital interruption of the inferior vena cava and heterozygous factor V Leiden mutation.

A case of a 44-year-old patient with recurrent deep venous thrombosis (DVT) caused by congenital dysgenesis of the inferior vena cava (IVC) in coincidence with heterozygous factor V Leiden mutation is presented. The IVC malformation was a fortuitous finding because the vascular malformation of the collateral draining thoracic veins were suspected to be a malignant mass in chest X-ray. This vascular abnormality is a rare finding but recent epidemiological research suggests that there may be an association between the congenital absence of the IVC and DVT. In our case, the patient is even at higher risk combining the malformation probably affecting venous blood flow and the hypercoagulabilic state by heterozygous presence of the factor V Leidenmutation.

Adult↗
PubMed2002

Erythropoietin-mediated decrease of the redox-sensitive transcription factor NF-kappaB is inversely correlated with the hemoglobin level.

The aim of this study was to determine the effect of rh-EPO on the redox-sensitive transcription factor (NF-kappaB) in vivo and in vitro. Ten patients (7 female, 3 male), mean age 69.2 +/- 11 years, with end-stage renal failure and anemia prior to initiation of regular hemodialysis were enrolled and divided into 2 groups (group A "good responder", 7 patients and group B "poor responder", 3 patients) in accordance to the response to rh-EPO therapy. Nuclear binding activity of NF-kappaB was determined in ex vivo isolated mononuclear cells before, 4 and 8 weeks after onset of regular hemodialysis and rh-EPO therapy by electrophoretic mobility shift assays (EMSA). In group A, a reduction of NF-KB binding activity from 100% to 56 +/- 6% was observed within the first four weeks of rh-EPO treatment, while mean hemoglobin rose from 8.2 +/- 0.4 g/dl to 11.1 +/- 0.2 g/dl. However, this effect was abrogated after another 4 weeks of treatment when NF-kappaB signal increased back to 85.2 +/- 10.6% despite consistent mean hemoglobin level of 11.3 +/- 0.4 g/dl. Group B demonstrated a slight increase of NF-kappaB signal from 100% to 129 +/- 18.5%, while mean hemoglobin only moderately rose from 7.6 +/- 0.3 g/dl to 8.3 +/- 0.1 g/dl within the first 4 weeks, and it further rose to 180 +/- 45% after 8 weeks of treatment, while mean hemoglobin (9.5 +/- 0.1 g/dl) remained low. The NF-kappaB binding activity differed significantly when comparing both groups (p = 0.007). Binding activity of Oct-1, serving as control, did not change notably in either group (p = 0.34). In vitro studies showed that rh-EPO did not directly affect NF-KB binding activity in THP-1 cells. However, coincubation of THP-1 cells with erythrocytes led to a reduction of NF-kappaB binding activity only in THP-1 cells with a hemoglobin level adjusted to 11 g/dl compared to 8 g/dl in the presence of rh-EPO. In vivo and in vitro data implicate a complex interaction between rh-EPO, stimulated RBC and the redox-sensitive transcription factor NF-kappaB in mononuclear cells.

Aged↗