bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of nitric oxide synthesis by aminoguanidine increases intestinal damage in the acute phase of rat TNB‐colitis
Authors: Dikopoulos N. , Nüssler A. K. , Liptay S. , Bachem M. , Reinshagen M. , Stiegler M. , Schmid R. M. , Adler G. , Weidenbach H. 
Published: March 2003

The role of nitric oxide (NO) in the pathophysiology of inflammatory bowel diseases (IBD) is controversially discussed. The aim of the present study was to investigate the role of NO inhibition in the acute phase of rat 2,4,6‐trinitrobenzenesulphonic acid (TNB)‐colitis. To inhibit NO synthesis we used aminoguanidine (AG) as a selective inhibitor of inducible nitric oxide synthase (iNOS).TNB‐colitis was induced in rats with and without pretreatment with AG (200 mg kg−1 body weight in the drinking water). The severity of colitis was observed over a period of 7 days.On days 1 and 2, AG reduced concentrations of plasma nitrate and nitrite as well as of portal 6‐keto‐prostaglandin 1α. AG pretreatment increased colonic damage and inflammatory response, assessed by colonic myeloperoxidase and serum lactate dehydrogenase activity, macroscopic damage score, tumour necrosis factor‐α concentration in stool and colonic glutathione content. The AG‐treated group showed a higher and prolonged nuclear factor κB (NF‐κB)/Rel binding activity in the colon.We conclude that NOS inhibition by AG is not beneficial in acute intestinal inflammation. With regard to appropriate therapeutic strategies, NF‐κB/Rel activation might be a more suitable target.
New drug combinations for the treatment of murine AIDS and macrophage protection
Authors: Fraternale A. , Casabianca A. , Tonelli A. , Chiarantini L. , Brandi G. , Magnani M. 
Published: March 2003

The failure of highly active antiretroviral therapies (HAART) is mainly due to the existence of latent infected reservoirs, such as macrophages and resting CD4+ T cells. In this paper, we report the results that we obtained in a murine model of AIDS by alternating the administration of the lympholitic drug 2‐Fluoro‐ara‐AMP (Fludarabine) to eliminate the infected cells, with that of Azidothymidine (AZT) plus reduced glutathione (GSH) encapsulated in erythrocytes, to protect lymphocytes and macrophages not yet infected, respectively.Two groups of infected mice were treated as follows: one group was treated by alternating the administration of Fludarabine and AZT (treatment A), while the other group received the same treatment plus GSH‐loaded erythrocytes given with AZT (treatment A + L–RBC). Fludarabine was administered intraperitoneally, AZT in the drinking water and GSH was encapsulated in erythrocytes by a procedure of hypotonic dialysis and isotonic resealing.The results obtained show that GSH‐loaded erythrocytes provide additive effects in all the parameters examined.Alternation of a lympholitic drug and antiretroviral drug is effective in reducing the progression of murine AIDS. Addition of a system to protect macrophages provides additive effects in almost all the parameters considered, confirming that combination therapies aimed at protecting different infectable cell compartments are better than treatments protecting mainly lymphocytes.
Human parathyroid cell proliferation in response to calcium, NPS R‐467, calcitriol and phosphate
Authors: Roussanne M‐C. , Lieberherr M. , Souberbielle J. C. , Sarfati E. , Drüeke T. , Bourdeau A. 
Published: March 2003

It remains uncertain how calcium, phosphate and calcitriol regulate parathyroid cell growth. The present study was aimed at examining possible direct effects of these modulators and of the calcimimetic NPS R‐467 on parathyroid cell growth in vitro.Cell proliferation was determined by [3H]thymidine incorporation and cell cycle antigen Ki 67 expression in a parathyroid cell culture model derived from uraemic patients. The effect of NPS R‐467 on parathyroid hormone (PTH) secretion and intracellular [Ca2+]i response was also examined.Increasing the [Ca2+] in the medium from 0·5 to 1·7 mM increased DNA synthesis (P < 0·005) and the number of Ki 67‐positive cells (P < 0·005). However, NPS R‐467 (0·01–1 µM) inhibited 3[H]thymidine incorporation by 35% in the presence of 0·5 mM [Ca2+]e. Exposure of cells to Ca2+ or NPS R‐467 led to a rapid increase of intracellular Ca2+, although the pattern of increase differed. Addition of calcitriol (10−10−10−7 M) to the culture medium suppressed [3H]thymidine incorporation dose‐dependently. Finally, high levels of phosphate (3·5 mM) in the medium led to a significant (P < 0·05) increase in [3H]thymidine incorporation.The observed stimulatory effect of Ca2+ in the medium in vitro appears to be at variance with the inhibitory effect of calcimimetic NPS R‐467 in vitro. In an attempt to solve these apparent discrepancies, and based on the notion of a reduced calcium‐sensing receptor (CaR) expression in parathyroid tissues of uraemic patients, we hypothesize that Ca2+ may regulate parathyroid cell proliferation via two different pathways, with predominant growth inhibition in cases of high CaR expression or activation, but prevailing stimulation of proliferation in cases of low CaR expression.
Glutathione and α‐lipoate in diabetic rats: nerve function, blood flow and oxidative state
Authors: Van Dam P. S. , Van Asbeck B. S. , Van Oirschot J. F. L. M. , Biessels G. J. , Hamers F. P. T. , Marx J. J. M. 
Published: March 2003

Background Increased oxidative stress is considered to be a causal factor in the development of diabetic complications, among which peripheral neuropathy. The pathophysiology of nerve dysfunction in diabetes has been explained both by reduced endoneurial microcirculation and alterations in endoneurial metabolism. It is unclear whether antioxidants primarily improve nerve blood flow or normalise systemic or endoneurial oxidative metabolism. Therefore, we evaluated the effects of the antioxidants glutathione and α‐lipoic acid on both nerve microcirculation and the antioxidative capacity and lipid peroxidation in experimentally diabetic rats.Materials and Methods Streptozotocin‐diabetic rats were treated with different doses of α‐lipoic acid, reduced glutathione or placebo, and were compared with nondiabetic controls. We measured systemic and endoneurial antioxidants, malondialdehyde and whole blood hydrogen peroxide. Furthermore, we evaluated sciatic and tibial motor and sensory nerve conduction velocity, caudal nerve conduction velocity, and assessed sciatic nerve blood flow and vascular resistance by Laser‐Doppler flowmetry.Results We observed a rise in erythrocyte glutathione by 27 % (P < 0·05), and a trend towards decreased plasma malondialdehyde in α‐lipoic acid, but not in glutathione‐treated animals in comparison with the placebo group. Simultaneously, sciatic nerve blood flow and vascular resistance were improved by daily α‐lipoic acid administration by 38% (P < 0·05). Peripheral nerve conduction velocity and endoneurial glutathione were not significantly influenced by antioxidant treatment.Conclusions Only minor beneficial effects of α‐lipoic acid on nerve blood flow and oxidative state occur at the given doses; these effects were insufficient to improve nerve conduction deficits.
Characterization of platelet‐derived growth factor‐induced p38 mitogen‐activated protein kinase activation in vascular smooth muscle cells
Authors: Yamaguchi H. , Igarashi M. , Hirata A. , Tsuchiya H. , Susa S. , Tominaga M. , Daimon M. , Kato T. 
Published: March 2003

Background The mitogen‐activated protein (MAP) kinase super‐family plays a crucial role in cell growth and differentiation and even in programmed cell death in response to diverse extracellular stimuli. The platelet‐derived growth factor (PDGF)‐BB is well known to promote the proliferation of vascular smooth muscle cells (VSMC) via extracellular‐regulated protein kinases (ERKs), leading to the development of cardiovascular diseases. However, it has not yet been clarified whether PDGFs that include other isoforms can activate the other parallel signal transduction pathways, c‐jun NH2‐terminal protein kinase (JNK) and p38 MAP kinase (p38), in VSMC. In this study, we investigated the effect of PDGFs on p38 activation in cultured rat VSMC.Materials and methods After stimulation by PDGFs with SB‐203580 or PD‐98059, the cells were solubilized, and the expressions of MAP kinases, MAP kinase kinases (MKKs), phosphorylated DNA‐binding proteins, and cyclooxigenases (COXs) were examined by immunoblot analysis.Results PDGFs activated p38 phosphorylation dose‐dependently, and the phosphorylations were specifically inhibited by SB‐203580 but not by PD‐98059. PDGFs also activated the phosphorylation of MKK 3/MKK 6 but not that of either stress‐activated protein kinase/ERK kinase or JNK. PDGFs affected the activation of a cyclic AMP response‐element binding protein, which was inhibited by SB‐203580. However, the activating transcription factor‐2 was not activated by PDGFs. Interestingly, the stimulation of PDGFs for 72 h enhanced the level of COX‐2, and these levels were decreased by SB‐203580.Conclusion These results have clarified that PDGFs activate the p38 cascade via an MKK 3/6 pathway, independently of the ERK cascade, and subsequently regulate the level of COX‐2 in rat VSMC, providing that PDGFs influence the inflammatory process in the vascular wall.
Loop diuretics alter the diurnal rhythm of endogenous parathyroid hormone secretion. A randomized‐controlled study on the effects of loop‐ and thiazide‐diuretics on the diurnal rhythms of calcitropic hormones and biochemical bone markers in postmenopausal women
Authors: Rejnmark L. , Vestergaard P. , Heickendorff L. , Andreasen F. , Mosekilde L. 
Published: March 2003

Background Thiazide diuretics (TD) reduce urinary calcium, bone loss and fracture risk. Loop diuretics (LD) may have opposite effects. These effects could depend on induced rhythmic changes in bone and calcium homeostasis.Design After a run‐in period of 7 days, we studied (in a factorial design) the diurnal rhythms of plasma levels of calcium, phosphate, parathyroid hormone (PTH), 1,25‐dihydroxyvitamin D and osteocalcin, as well as renal excretions rates of calcium, phosphate, and cross‐linked N‐terminal telopeptide of type 1 collagen (NTx) in 50 postmenopausal women randomized to treatment with either a thiazide diuretic (TD; bendroflumethiazide, n = 14), a loop diuretic (LD; bumetanide, n = 13), LD plus TD (bendroflumethiazide plus bumetanide, n = 11), or placebo (n = 12).Results In all four groups, all measured quantities showed a diurnal variation. LD caused a steep increase, with a subsequent decrease, in urinary calcium and plasma PTH. The mean 24 h plasma PTH concentration was increased (8·5 ± 0·9 mmol L−1) compared with placebo (4·4 ± 0·4 mmol L−1), whereas net 24 h renal calcium excretion did not differ from that of the placebo group due to a rebound hypocalciuria. Compared with placebo, diurnal rhythms of plasma phosphate and osteocalcin were changed with an increase during daytime and a decrease during the night. TD did not alter the diurnal rhythm of any of the measured quantities. However, the 24‐h renal calcium excretion decreased, whereas the mean 24‐h plasma calcium concentration increased without PTH suppression. LD plus TD caused changes similar to those observed with LD alone.Conclusion One daily dose of LD increases parathyroid activity with alterations in the diurnal pattern of osteocalcin. This could indicate a potential anabolic effect of LD.
Serum chromogranin A as a screening test for gastric enterochromaffin‐like cell hyperplasia during acid‐suppressive therapy
Authors: Sanduleanu S. , De Bruïne A. , Stridsberg M. , Jonkers D. , Biemond I. , Hameeteman W. , Lundqvist G. , Stockbrügger R. W. 
Published: March 2003

Background Serum chromogranin A (CgA), a marker of neuroendocrine neoplasia, increases during profound gastric acid inhibition, possibly reflecting the trophic effect of gastrin on the enterochromaffin‐like (ECL) cells.Aims This study investigated the clinical value of serum CgA as a screening test for gastric fundic enterochromaffin‐like (ECL) cell hyperplasia during acid‐suppressive therapy.Method A consecutive series of 230 dyspeptic patients referred for upper gastrointestinal endoscopy was investigated in a cross‐sectional design. They were 154 patients on continuous medium‐term (6 weeks to one year) or long‐term (longer than one year) acid inhibition with either proton pump inhibitors (PPIs, n = 117) or histamine2‐receptor antagonists (H2RAs, n = 37) for gastro‐oesophageal reflux disease, and 76 nontreated subjects, with normal endoscopic findings (control group). Fasting blood samples were analysed for gastrin and CgA. Gastric biopsy specimens (oxyntic mucosa) were examined for histological evaluation of gastritis (Sydney classification) and of ECL cell hyperplasia (Solcia classification).Results Serum CgA levels correlated positively with serum gastrin, following a quadratic function (r = 0·78, P < 0·0001). Elevated serum CgA values during long‐term acid inhibition correlated with the presence and severity of fundic ECL cell hyperplasia. Multivariate analysis identified hypergastrinaemia (P < 0·0001), duration of acid inhibition (P < 0·0001), H. pylori infection (P = 0·008), ECL cell hyperplasia (P = 0·012), and body gland atrophy (P = 0·043) as independent predictors of elevated serum CgA. In subjects on long‐term acid inhibition (n = 123), serum CgA was equally sensitive but more specific than serum gastrin for the detection of ECL cell hyperplasia (sensitivity, 91·3% for both; specificity, 73% vs. 43%, P < 0·0001).Conclusions During long‐term gastric acid inhibition, serum CgA levels reflect the presence and severity of fundic ECL cell hyperplasia. Serum CgA is therefore a useful screening test for gastric ECL cell proliferative changes within this context.
Interactions between major histocompatibility complex class II surface expression and HIV: implications for pathogenesis
Authors: Kamp W. , Breij E. C. W. , Nottet H. S. L. M. , Berk M. B. 
Published: March 2003

Although it has been almost 20 years since the first cases of acquired immunodeficiency syndrome (AIDS) were documented, the pathogenesis is still not completely understood. Interactions between major histocompatibility complex (MHC) Class I and human immunodeficiency virus (HIV), resulting in down‐regulation of MHC‐I surface expression, have been reported to contribute to pathogenesis by suppressing the host's immune response. Interactions between MHC Class II and HIV have also been described, but it is unclear how these contribute to the pathogenesis. MHC‐II surface expression on HIV‐infected monocytes and monocytic cell lines has been described to be increased as well as decreased when compared to uninfected control monocytes. HIV‐specific mechanisms appear to down‐regulate MHC‐II expression on blood monocytes during HIV‐1 infection, whereas host mechanisms up‐regulate MHC‐II expression in response to infection of blood monocytes as well as brain macrophages. A balance between these two may determine MHC‐II expression levels in individual patients.Altogether, HIV seems to be able to benefit from both low and high levels of MHC‐II surface expression. The first results in reduced immune surveillance of the host, allowing the virus to replicate faster; the second increases infectivity of the virus as a result of higher MHC‐II density on macrophages and virion particles.
Endogenous anti‐inflammatory response after coronary injury in a porcine model
Authors: Fantidis P. , Pérez de Prada T. , Fernández‐Ortiz A. , Sanmartín M. , Alfonso F. , Hernández R. , Escaned J. , Bañuelos C. , Sabaté M. , Macaya C. 
Published: March 2003

Background Corticotropin‐releasing hormone (CRH)/adrenocorticotropic hormone (ACTH)/cortisol is the major anti‐inflammatory system. After percutaneous translumenal angioplasty, an inflammatory process is triggered. We investigate whether CRH/ACTH/cortisol axis is activated after deep vessel wall injury (DVWI).Materials and methods Plasma and leukocyte CRH and ACTH, serum cortisol and IL‐1β, and leukocyte cAMP were measured (ELISA) in 16 pigs after anaesthesia (baseline), 60 min into anaesthesia without causing vascular injury and 90 min after DVWI of the left anterior descending (LAD) coronary artery induced by percutaneous directional atherectomy (Atherocath GTO 7F; DVI, Inc., Temecula, USA). Biochemical variables were also measured at baseline, 60 and 180 min into anaesthesia in six additional pigs without coronary intervention.Results MANOVA showed that CRH/ACTH/Cortisol, cAMP and IL‐1β production was not modified during anaesthesia. Post‐DVWI plasma CRH (0·077 ± 0·046 ng mL−1), and cellular cAMP (0·14 ± 0·067 pmol 10−6 cells) increased significantly (P = 0·001) with respect to their baseline values (CRH = 0·036 ± 0·013 ng mL−1; cAMP = 0·081 ± 0·034 pmol 10−6). There was also a statistically significant increase (P = 0·02) in post‐DVWI IL‐1β (from 46·6 ± 12·8 to 64·05 ± 13·5 pg mL−1), and in serum cortisol (P = 0·05) compared to its baseline values (8·98 ± 3·2 µgr dL−1 vs. 6·57 ± 2·3 µgr dL−1, respectively).Conclusion In our experimental model, coronary vessel wall injury‐activated CRH/ACTH/cortisol axis caused a significant increase in plasma CRH, cortisol and cellular cAMP levels, which may influence the response of coronary arteries to injury.
Polymorphisms in the TNF‐α and TNF‐receptor genes in patients with coronary artery disease
Authors: Allen R. A. , Lee E. M. , Roberts D. H. , Park B. K. , Pirmohamed M. 
Published: March 2003

Background Coronary artery disease (CAD) is both multifactorial and polygenic in nature. Atheroma formation, the pathological hallmark of CAD, is an inflammatory process, with pro‐inflammatory cytokines, such as tumour necrosis factor‐α (TNF‐α), having a major role in its pathogenesis. We have therefore investigated whether polymorphisms in the TNF‐α (− 238 and − 308), TNF receptor 1 (position − 609 and + 10, intron 6) and TNF receptor 2 (position + 422, codon 198) genes show an association with CAD.Materials and methods Patients with angiographically proven single vessel (n = 58) and multivessel (n = 122) CAD were compared to patients with angiographically proven normal coronary arteries (n = 79) and volunteers without clinical evidence of CAD (n = 250). Genotyping was performed by PCR‐RFLP analysis. For the TNF‐α polymorphisms, a meta‐analysis of all published studies was also undertaken.Results No significant differences in allele or genotype frequencies were found between the normal coronary artery group or healthy volunteers and patients with CAD for any of the polymorphisms. There was also no difference in allele frequency between patients with single‐ and multivessel disease. For the − 308 and − 238 TNRα gene polymorphisms, a meta‐analysis of our data and previously published studies failed to demonstrate any significant association with CAD.Conclusions Polymorphisms in the TNF‐α promoter region and TNF‐receptor genes are not associated with the development of CAD.
Renal proximal tubular cell growth and differentiation are differentially modulated by renotropic growth factors and tyrosine kinase inhibitors
Authors: Ernst F. , Hetzel S. , Stracke S. , Czock D. , Vargas G. , P. Lutz M. , Keller F. , Jehle P. M. 
Published: March 2003

Background The renotropic growth factors (GFs), hepatocyte GF (HGF), epidermal GF (EGF), and insulin‐like GF‐I (IGF‐I) accelerate renal regeneration in animal models after toxic or ischemic injury. These GFs initiate their biological effects on renal tubular cells by interaction with specific transmembrane receptor tyrosine kinases.Materials and methods In the proximal tubular cell line PT‐1, the biological effects of HGF, EGF, and IGF‐I and the growth‐inhibitory effects of different tyrosine kinase inhibitors (TKIs) were investigated. Receptor binding and tyrosine kinase phosphorylation were determined by ligand binding studies and Western blot analysis.Results HGF, EGF, and IGF‐I bound with nanomolar affinity to their specific cell membrane receptor tyrosine kinases. In contrast to EGF or IGF‐I, HGF induced a variety of cell morphological changes, including cell scattering, formation of tubular structures, and expression of long microvilli on the apical cell membrane. HGF was a 10‐fold more potent and more effective growth promoter than EGF or IGF‐I. Among the TKIs tested, the mitogenic effect of HGF could be more specifically inhibited by emodin and tyrphostin, that of EGF by methyl‐2,5‐dihydroxycinnamate, lavendustin A, and genistein, and that of IGF‐I by geldanamycin.Conclusions In contrast to EGF and IGF‐I, HGF stimulated both growth and differentiation of renal proximal tubular cells, demonstrating the amazing biological potency of this renotropic growth factor. Selective TKIs may be a promising approach to modulate diseases with abnormalities in protein kinase signalling pathways such as renal cell carcinoma.
PON1 L55M polymorphism is not a predictor of coronary atherosclerosis either alone or in combination with Q192R polymorphism in an Italian population
Authors: Arca M. , Ombres D. , Montali A. , Campagna F. , Mangieri E. , Tanzilli G. , Campa P. P. , Ricci G. , Verna R. , Pannitteri G. 
Published: March 2003

Abstract Background  The present study evaluated the role of the PON1 L55M polymorphism independently and in conjunction with the Q192R polymorphism on the risk of coronary atherosclerosis in an Italian population.Materials and methods  Three hundred and ninety‐one subjects with significant coronary stenosis (> 50%) (coronary artery disease‐positive; CAD+), 196 subjects with normal coronary arteries (< 10% stenosis) (CAD−) and 178 healthy controls were screened using a combination of polymerase chain reaction and restriction enzyme digestion.Results  In the pooled population, the frequencies of L and M alleles were 0·63 and 0·37, respectively; the most common haplotypes were QQ/LM (24·2%) and QR/LL (21·8%) and a strong linkage disequilibrium between L/55 and R/192 alleles was observed (D′ = −0·91; P < 0·0001). CAD+ subjects did not show any significant differences in the distribution of PON1–55 genotypes as compared to CAD− subjects and population controls (χ2 = 1·5, P = 0·8). After controlling for other risk factors, the low‐concentration M allele was not associated with a significant change of CAD risk (OR 1·02; 95% CI 0·80–1·29; P = 0·87). Moreover, the L55M polymorphism did not show any interaction with other risk factors such as smoking, diabetes, hypertension, low levels of high‐density lipoprotein (HDL) or high ratios of low‐density to high‐density lipoproteins. The combination of L55M with the Q192R polymorphism did not show any effect on CAD risk. However, a marginal decrease in myocardial infarction risk was detected when QQ/MM carriers (OR 0·51; 95% CI 0·26–0·99; P = 0·048), but not LL/RR carriers, were compared with subjects not homozygous for an L or R allele.Conclusions  These findings did not indicate a major effect of the PON1 L55M polymorphism, either alone or in combination with the Q192R polymorphism, on CAD risk. Additional studies are needed for a better evaluation of the role of the 55/192 PON1 genotypes in combination on myocardial infarction risk.