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PubMed2004

RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice.

Receptor for Advanced Glycation Endproducts (RAGE), a multiligand receptor in the immunoglobulin superfamily, functions as a signal-transducing cell surface acceptor for amyloid-beta peptide (Abeta). In view of increased neuronal expression of RAGE in Alzheimer's disease, a murine model was developed to assess the impact of RAGE in an Abeta-rich environment, employing transgenics (Tgs) with targeted neuronal overexpression of RAGE and mutant amyloid precursor protein (APP). Double Tgs (mutant APP (mAPP)/RAGE) displayed early abnormalities in spatial learning/memory, accompanied by altered activation of markers of synaptic plasticity and exaggerated neuropathologic findings, before such changes were found in mAPP mice. In contrast, Tg mice bearing a dominant-negative RAGE construct targeted to neurons crossed with mAPP animals displayed preservation of spatial learning/memory and diminished neuropathologic changes. These data indicate that RAGE is a cofactor for Abeta-induced neuronal perturbation in a model of Alzheimer's-type pathology, and suggest its potential as a therapeutic target to ameliorate cellular dysfunction.

Alzheimer Disease↗
PubMed2006

Hexameric calgranulin C (S100A12) binds to the receptor for advanced glycated end products (RAGE) using symmetric hydrophobic target-binding patches.

Calgranulin C (S100A12) is a member of the S100 family of proteins that undergoes a conformational change upon calcium binding allowing them to interact with target molecules and initiate biological responses; one such target is the receptor for advanced glycation products (RAGE). The RAGE-calgranulin C interaction mediates a pro-inflammatory response to cellular stress and can contribute to the pathogenesis of inflammatory lesions. The soluble extracellular part of RAGE (sRAGE) was shown to decrease the inflammation response possibly by scavenging RAGE-activating ligands. Here, by using high resolution NMR spectroscopy, we identified the sRAGE-calgranulin C interaction surface. Ca2+ binding creates two symmetric hydrophobic surfaces on Ca2+-calgranulin C that allow calgranulin C to bind to the C-type immunoglobulin domain of RAGE. Apo-calgranulin C also binds to sRAGE using a completely different surface and with substantially lower affinity, thus underscoring the role of Ca2+ binding to S100 proteins as a molecular switch. By using native gel electrophoresis, chromatography, and fluorescence spectroscopy, we established that sRAGE forms tetramers that bind to hexamers of Ca2+-calgranulin C. This arrangement creates a large platform for effectively transmitting RAGE-dependent signals from extracellular S100 proteins to the cytoplasmic signaling complexes.

Amino Acid Sequence↗
PubMed2005

Haplotype analysis of the RAGE gene: identification of a haplotype marker for diabetic nephropathy in type 2 diabetes mellitus.

BACKGROUND: Diabetic nephropathy (DN) represents a devastating complication of diabetes. Family clustering, heterogeneity in the onset and progression and results of segregation studies indicate that susceptibility to DN is a complex trait. METHODS: Common single nucleotide polymorphisms in the RAGE (receptor of advanced glycation end-products) gene (-429T/C, -374T/A, G82S, 1704G/T, 2184A/G and 2245G/A) were studied in the association study comprising 605 Caucasian subjects by means of haplotype analysis in order to identify an eventual haplotype marker for DN in type 2 diabetes. Haplotypes were constructed computationally; frequencies were compared among groups of subjects with type 2 diabetes (DM) and DN, diabetics without DN and non-diabetics. Survival analysis was carried out to ascertain whether certain RAGE haplotypes influence onset of DN in type 2 diabetics. RESULTS: Significant differences in haplotype frequencies among DM + DN vs DM non-DN and non-DM groups were found (P = 0.0007 and 0.0013, respectively; permutation test). Frequency of the RAGE(2) haplotype containing minor alleles in positions -429 and 2184 (CTGGGG) in the DN group was significantly higher than in the two control groups (21.7% vs 12.8% and 13.8%, both P(corr)<0.003; two-tail Fisher exact test); odds ratios 1.65 [95% confidence interval (CI): 1.08-2.50; P = 0.020] and 1.79 (95% CI: 1.22-2.62; P = 0.003), respectively. In survival analysis, duration of diabetes until the onset of DN (e.g. appearance of persistent proteinuria) was significantly different among RAGE(2) diplotype groups (P<0.05); median DN-free interval was 9.6 years in RAGE(2) +/+ homozygotes, 15.2 years in +/- heterozygotes and 17.0 years in the -/- combination. CONCLUSIONS: The RAGE(2) haplotype is associated with DN in type 2 diabetics and with earlier DN onset and, thus, can be regarded a marker for DN.

Biomarkers↗
PubMed2007

Association of RAGE gene polymorphisms with coronary artery disease in the Korean population.

BACKGROUND AND OBJECTIVES: AGEs (advanced glycation end products)-RAGE (receptor for advanced glycation end products) interaction in vessel wall may lead to inflammation, smooth muscle cell proliferation and extracellular matrix production, culminating in exaggerated intimal hyperplasia and restenosis. We focused on the putative association of five candidate RAGE gene polymorphisms on the risk of coronary artery disease in the Korean population. METHODS: A total of 1555 male patients who underwent coronary angiography were enrolled in the study; 805 patients (mean age: 53.18+/-9.74 years) had normal coronary artery and 750 patients (mean age: 55.73+/-8.31 years) had significant coronary artery disease. Among the coronary artery disease patients, 269 had single-vessel disease (35.87%), 242 had two-vessel disease (32.27%) and 239 had three-vessel disease (31.87%). The genotypes of RAGE were determined by the methods of single base extension with amplifying primers and probes for TaqMan. Genotype analysis was performed on five single nucleotide polymorphisms of the RAGE gene, namely -443T>C, -388T>A, -257G>A, +557G>A and +1704G>T. Analysis for the association with coronary artery disease was performed. RESULTS: Analysis of four single nucleotide polymorphisms, except +557G>A (G82S), with regard to the association with coronary artery disease was not significant. Only the +557 gene allele (G/A) showed significant association with coronary artery disease (coronary artery disease vs. normal; G allele: 0.87 vs. 0.84, A allele: 0.13 vs. 0.16, P=0.0326). The +557G>A (G82S) showed strong tendency of association with coronary artery disease (coronary artery disease vs. normal; GG: 75.2 vs. 69.8%, GA: 23.2 vs. 28.6%, AA: 1.6 vs. 1.6%, P=0.0524). The presence of AA or GA genotype, assuming codominant effect of the A allele, was independently associated with decreased risk of coronary artery disease when controlled for age, body mass index, smoking and diabetes mellitus [odds ratio=0.749 (95% confidence interval, 0.579-0.969), P=0.0280]. Subgroup analysis demonstrated the significant protective effect of AA or GA genotype in nondiabetic patients as well [odds ratio=0.741 (0.570-0.962), P=0.0244]. CONCLUSIONS: The results of this large population study demonstrate that the AA/GA genotypes of the RAGE +557G>A polymorphism are associated with a significantly decreased risk of significant coronary artery disease. Other polymorphisms of RAGE were not significantly associated with the risk of coronary artery disease in this study population.

Asian People↗
PubMed2007

RAGE-NF-kappaB pathway activation in response to oxidative stress in facioscapulohumeral muscular dystrophy.

OBJECTIVES: An increased expression of adenine nucleotide translocator (ANT1), found in facioscapulohumeral muscular dystrophy (FSHD), is known to lead to a decrease in nuclear factor-kappaB (NF-kappaB) DNA binding and to sensitize muscle cells to oxidative stress and apoptosis. Receptor for advanced glycation end products (RAGE) mediated by NF-kappaB activation is involved in proinflammatory pathomechanism and in muscle fiber regeneration in inflammatory myopathies and in limb girdle muscular dystrophy. Oxidative stress can stimulate RAGE- NF-kappaB pathway. Our purpose was to verify if oxidative stress may induce RAGE- NF-kappaB pathway activation in FSHD, contributing to the pathogenesis of such a disease. MATERIALS AND METHODS: On muscle samples of eight patients with FSHD, eight patients with Duchenne muscular dystrophy and eight normal controls the following studies were carried out: immunocytochemistry for activated NF-kappaB; electrophoretic mobility shift assay of NF-kappaB DNA binding activity; Western blot studies of RAGE and ANT1; hydrogen peroxide (HP), peroxidase and glutathione peroxidase (GPx) assays. RESULTS: An increased RAGE and ANT1 expression in FSHD with moderate increase of NF-kappaB DNA binding activity was found together with an increased production of HP and a reduced activity of peroxidase and GPx. CONCLUSIONS: Our data confirm that response to oxidative stress and ANT1 increased activity are early events in FSHD muscle. The study also reveals that the RAGE- NF-kappaB pathway, induced by oxidative stress, is activated independently of the presence of a clear histochemical evidence of muscle damage in FSHD.

Adenine Nucleotide Translocator 1↗
PubMed2002

RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice.

BACKGROUND: Previous studies suggested that blockade of RAGE in diabetic apolipoprotein (apo) E-null mice suppressed early acceleration of atherosclerosis. A critical test of the potential applicability of RAGE blockade to clinical settings was its ability to impact established vascular disease. In this study, we tested the hypothesis that RAGE contributed to lesion progression in established atherosclerosis in diabetic apoE-null mice. METHODS AND RESULTS: Male apoE-null mice, age 6 weeks, were rendered diabetic with streptozotocin or treated with citrate buffer. At age 14 weeks, certain mice were killed or treated with once-daily murine soluble RAGE or albumin; all mice were killed at age 20 weeks. Compared with diabetic mice at age 14 weeks, albumin-treated animals displayed increased atherosclerotic lesion area and complexity. In diabetic mice treated with sRAGE from age 14 to 20 weeks, lesion area and complexity were significantly reduced and not statistically different from those observed in diabetic mice at age 14 weeks. In parallel, decreased parameters of inflammation and mononuclear phagocyte and smooth muscle cell activation were observed. CONCLUSIONS: RAGE contributes not only to accelerated lesion formation in diabetic apoE-null mice but also to lesion progression. Blockade of RAGE may be a novel strategy to stabilize atherosclerosis and vascular inflammation in established diabetes.

Animals↗
PubMed2003

The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control.

BACKGROUND: RAGE (receptor for advanced glycation end products [AGEs]) plays a role in diabetic atherosclerosis. Recently, we have demonstrated enhanced expression of cyclooxygenase-2 and PGE synthase-1 (COX-2/mPGES-1) in human symptomatic plaques, and provided evidence that it is associated with metalloproteinase (MMP)-induced plaque rupture. However, the specific transmembrane signaling pathway(s) influencing plaque COX-2/mPGES-1 expression is unknown. The aim of this study was to characterize RAGE expression in human plaques and to correlate it with the inflammatory infiltration, COX-2/mPGES-1 and MMP expression, and with clinical evidence of diabetes. METHODS AND RESULTS: Plaques obtained from 60 patients undergoing carotid endarterectomy were divided into diabetic and nondiabetic according to clinical evidence of type 2 diabetes. Plaques were subjected to analysis of RAGE, NF-kappaB, COX-2/mPGES-1, MMP-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, and collagen content by immunohistochemistry and Western blot, whereas zymography was used to detect MMP activity. Immunohistochemistry was used to identify CD68+ macrophages, CD3+ T-lymphocytes, smooth muscle cells (SMCs), and HLA-DR+ inflammatory cells. Diabetic plaques had more (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells, more (P<0.0001) immunoreactivity for RAGE, activated NF-kappaB, COX-2/mPGES-1, and MMPs, increased (P<0.0001) gelatinolytic activity, reduced (P<0.0001) collagen content, and increased (P<0.0001) lipid and oxLDL content. Interestingly, RAGE, COX-2/mPGES-1, and MMP expression was linearly correlated with plasma level of HbA1c. CONCLUSIONS: In conclusion, this study demonstrates in humans that RAGE overexpression is associated with enhanced inflammatory reaction and COX-2/mPGES-1 expression in diabetic plaque macrophages, and this effect may contribute to plaque destabilization by inducing culprit metalloproteinase expression.

Aged↗
PubMed2002

Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses.

BACKGROUND: The products of nonenzymatic glycation and oxidation of proteins, the advanced glycation end products (AGEs), form under diverse circumstances such as aging, diabetes, and kidney failure. Recent studies suggested that AGEs may form in inflamed foci, driven by oxidation or the myeloperoxidase pathway. A principal means by which AGEs alter cellular properties is through interaction with their signal-transduction receptor RAGE. We tested the hypothesis that interaction of AGEs with RAGE on endothelial cells enhances vascular activation. METHODS AND RESULTS: AGEs, RAGE, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin are expressed in an overlapping manner in human inflamed rheumatoid synovia, especially within the endothelium. In primary cultures of human saphenous vein endothelial cells, engagement of RAGE by heterogeneous AGEs or Nepsilon(carboxymethyl)lysine-modified adducts enhanced levels of mRNA and antigen for vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin. AGEs increased adhesion of polymorphonuclear leukocytes to stimulated endothelial cells in a manner reduced on blockade of RAGE. CONCLUSIONS: AGEs, through RAGE, may prime proinflammatory mechanisms in endothelial cells, thereby amplifying proinflammatory mechanisms in atherogenesis and chronic inflammatory disorders.

Arthritis, Rheumatoid↗
PubMed1997

MRI of inner ear and facial nerve pathology using 3D MP-RAGE and 3D CISS sequences.

The aim of this study was to evaluate 3D CISS, unenhanced 3D MP-RAGE and contrast enhanced 3D MP-RAGE for the diagnosis of neoplastic, vascular and inflammatory lesions of the cerebellopontine angle, the inner auditory canal, the labyrinth and the facial nerve 42 MR examinations were performed on a total of 38 patients (25 males, 13 females; aged 1-77 years, mean age 43 +/- 20 years) using a 1.5 T MR unit. A T2* weighted 3D CISS sequence (TR 14.65 ms, TE 21 ms, flip angle 65 degrees, voxel size 0.7 x 0.7 x 0.7 mm3) and a T1 weighted 3D MP-RAGE sequence (TR 12.5 ms, TE 5 ms, T1 300 ms, flip angle 15 degrees, voxel size 1.0 x 0.9 x 0.9 mm3) with and without contrast medium (gadolinium-DTPA, 0.1 mmol kg-1 body weight) were used. Results of contrast enhanced 3D MP-RAGE-pathological enhancement was found in the following lesions: schwannomas of the cerebellopontine angle (CPA) and the internal auditory canal (IAC), 4; schwannomas of the IAC, 7 and labyrinthine tumours, 3; posterior fossa lymphoma, 1; meatal meningioma, 1; acute labyrinthitis, 15 and neuritis of the seventh cranial nerve, 10. Results of 3D CISS-filling defects were found with the following lesions: schwannomas of the CPA, the IAC or labyrinth, 14; lymphoma, 1; meningioma, 1; labyrinthine fibrosis, 13 and scar in the IAC, 4. These results suggest that unenhanced and contrast enhanced 3D MP-RAGE and 3D CISS are complementary MR imaging modalities. T1 weighted 3D MP-RAGE is preferred to T1 weighted 2D (turbo) spin echo sequences because of the multiplanar reconstruction possibilities of 3D sequences, which are very useful in the case of the inner ear and facial nerve.

Acute Disease↗
PubMed2003

Inhibition of the interaction of AGE-RAGE prevents hyperglycemia-induced fibrosis of the peritoneal membrane.

The peritoneal membrane of long-term peritoneal dialysis patients is characterized by a loss of ultrafiltration capacity, associated morphologically with submesothelial fibrosis and neoangiogenesis. Exposure to high glucose concentrations in peritoneal dialysate and the resultant advanced glycation end-products (AGE) accumulation have been implicated in the development of these changes, but their exact pathophysiological role is unknown. We examined the effect of the interaction of AGE with one of their receptors (i.e., RAGE) on the function and structure of the peritoneum exposed to high ambient glucose concentrations. Streptozotocin-induced diabetic rats and control rats were treated during 6 wk with either neutralizing monoclonal anti-RAGE antibodies or control antibodies. The expression of RAGE was strongly enhanced in the peritoneal membrane of the diabetic animals. The diabetic peritonea were characterized by an elevated transport of small solutes, lower ultrafiltration rates, a higher vascular density, and an upregulation of endothelial nitric oxide synthase expression. These parameters were unaffected by treatment with anti-RAGE antibodies. In contrast, anti-RAGE but not control antibodies prevented upregulation of TGF-beta, development of submesothelial fibrosis, and fibronectin accumulation in the peritoneum of diabetic animals. In conclusion, binding of AGE to RAGE increases the expression of TGF-beta and contributes to the development of submesothelial fibrosis. Neoangiogenesis and the resultant loss of ultrafiltration capacity are mediated by different pathogenetic pathways.

Albumins↗
PubMed2005

Receptor for advanced glycation end product (RAGE) upregulation in human gingival fibroblasts incubated with nornicotine.

BACKGROUND: Clinical and epidemiological data strongly support a link between smoking and periodontal disease. The mechanism by which smoking contributes to the destruction of periodontal tissue is not clear and cannot be attributed solely to the vasoconstrictive effects of nicotine. Our hypothesis is that nornicotine, a metabolite of nicotine, upregulates the expression of the receptor for the advanced glycation end products (RAGE) in the gingiva of smokers and triggers the proinflammatory effects of AGE by stimulating the secretion of cytokines and reactive oxygen species which directly cause destruction of the periodontal apparatus. METHODS: Human gingival cells grown in tissue culture were exposed to 1 microM nornicotine for 72 hours. Following the nornicotine pretreatment, some of the cells were also treated with AGE that was generated with nornicotine for 48 hours and another group was continued on nornicotine only for 48 hours. Control cells that were not exposed to either nornicotine or AGE were also cultured. The cells were harvested and RNA was extracted for reverse transcription-polymerase chain reaction (RT-PCR) and RAGE mRNA was amplified. RESULTS: The nornicotine-treated cells increased their expression of RAGE by approximately 4-fold (P <0.05, Student t test). These data suggest that nornicotine, a byproduct of cigarette smoke, can induce RAGE expression in gingival tissues. Therefore, our data support the hypothesis that RAGE potentially plays a significant role in the progression of periodontal disease exacerbated by smoking. CONCLUSION: Nornicotine, AGE, and upregulation of RAGE may be involved in the pathogenesis of periodontal disease associated with smoking.

Cell Line↗
PubMed2006

Autoimmunity in Alzheimer's disease as evidenced by plasma immunoreactivity against RAGE and Abeta42: complication of diabetes.

Features of autoimmunity have been associated with both Alzheimer's disease (AD) and with diabetes. In both diseases high levels of advanced glycation end products (AGEs) and their receptor (RAGE) have been detected in tissues and in the circulation. In addition high titers of antibodies directed against a RAGE-like peptide occur in the circulation. In this study we report the presence of auto-antibodies directed against RAGE and the cytotoxic amyloid peptide Abeta42 in plasma samples derived from four study groups. Anti-RAGE IgG titers were greatest in the AD-diabetic cohort. They were followed in decreasing order by the AD-non-diabetic cohort, the elderly diabetic cohort, and lastly by the control non-diabetic elderly cohort. The same profile of IgG differences was evident for the anti-Abeta42 titers. When all of the data were combined, there was a strong linear correlation between the RAGE and Abeta42 titers suggesting that the two peptides exist as a tight complex in plasma. Plasma IgG titers were not correlated with cognitive status except that AD and AD-diabetic participants were significantly cognitively impaired relative to the two non-AD groups. There also was no significant correlation between IgG titers and subject age, except that there was a trend for a negative slope for the AD participants and a positive slope for the control participants. In keeping with the human data, we also report that chemically-induced diabetes in rats was associated with high levels of AGEs, anti-RAGE-like IgGs, and anti-Abeta42-like IgGs. For non-diabetic rats, there was a clear age-dependency regarding the magnitude of the IgG levels. These data support the concept of an interrelationship between diabetes and AD. For both diseases one underlying contributing factor to cytotoxicity could be the development of an autoimmune response triggered by the presence of AGEs and amyloid peptides.

Aged↗
PubMed2001

Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion.

Advanced glycation end product (AGE) activation of the signal-transducing receptor for AGE (RAGE) has been linked to a proinflammatory phenotypic change within cells. However, the precise intracellular signaling pathways involved have not been elucidated. We demonstrate here that human serum albumin modified with N(epsilon)-(carboxymethyl)lysine (CML), a major AGE adduct that progressively accumulates with aging, diabetes, and renal failure, induced nuclear factor (NF)-kappaB-driven reporter gene expression in human monocytic THP-1 cells. The NF-kappaB response was blocked with a synthetic peptide corresponding to the putative ligand-binding domain of RAGE, with anti-RAGE antiserum, and by coexpression of truncated receptors lacking the intracellular domain. Signal transduction from RAGE to NF-kappaB involved the generation of reactive oxygen species, since reporter gene expression was blocked with the antioxidant N-acetyl-L-cysteine. CML-modified albumin produced rapid transient activation of tyrosine phosphorylation, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinase (MAPK), but not c-Jun NH(2)-terminal kinase. RAGE-mediated NF-kappaB activation was suppressed by the selective p38 MAPK inhibitor SB203580 and by coexpression of a kinase-dead p38 dominant-negative mutant. Activation of NF-kappaB by CML-modified albumin increased secretion of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1) severalfold, and inhibition of p38 MAPK blocked these increases. These results indicate that p38 MAPK activation mediates RAGE-induced NF-kappaB-dependent secretion of proinflammatory cytokines and suggest that accelerated inflammation may be a consequence of cellular activation induced by this receptor.

Cell Line↗
PubMed2004

Possible pathologic involvement of receptor for advanced glycation end products (RAGE) for development of encapsulating peritoneal sclerosis in Japanese CAPD patients.

Encapsulating peritoneal sclerosis (EPS) is a serious complication of PD. The cause(s) of EPS are unknown but may include peritonitis and long duration of PD treatment. However, EPS may also develop in some patients without a history of peritonitis or with rather short duration of PD therapy. It has been suggested that an increasing peritoneal solute transport rate (PSTR) as a function of time on PD treatment is a risk factor for EPS development after transfer to hemodialysis, and that high PSTR is associated with an increased peritoneal microvessels surface area. Other putative mechanisms might include advanced glycated end products (AGE) and their receptors, RAGE. The purpose of this study was to investigate genetic variations in PD patients developing EPS in comparison to PD patients without EPS. SNPs in genes related to angiogenesis as well as RAGE were analyzed. Twenty patients (M/F: 12/8, mean age at start of PD 42.2 years, mean duration of PD 8.4 years) who were diagnosed as EPS during the period 1982 - 2002 at Jikei University Hospital and a matched control group (n = 20) of nonEPS PD patients were studied. The following 5 SNPs were analyzed: VEGF 936 C/T, ecNOS -786 T/C, 298 Glu/Asp, and RAGE -374 T/A, and -429 T/C. The SNPs were analyzed by the pyrosequencing method. The C allele (T/C and C/C) in the RAGE -429T/C genotype was not found in any of the EPS patients (EPS, T/T: 20/20 (100%), nonEPS, T/T: 15/20 (75%), T/C: 4/20 (20%), C/C: 1/2 0(5%), nonC allele vs C allele, p = 0.013), although every allele was found in other SNPs. We conclude that these preliminary data show that whereas genotypes directly related to angiogenesis did not differ between EPS and nonEPS patients, it is noteworthy that no patients in the EPS group had a C allele in the RAGE -429T/C genotype. This might indicate a possible genetic contribution to the development of EPS that is related to RAGE.

Adult↗
PubMedDate not supplied

Suppressive effects of tea polyphenol and conformational changes with receptor for advanced glycation end products (RAGE) expression in human hepatoma cells.

BACKGROUND/AIMS: It is reported that polyphenol is associated with low risk of hepatoma and that RAGE (receptor for advanced glycation end products) is important for cancer invasion. METHODOLOGY: Effects of teapolyphenol, EGCG (epigallocatechin-3-gallate) were studied. Proliferation of on human hepatoma cells, HLF, was measured with the use of WST-1 colorimetric assay. Cell invasion was analyzed by the Matrigel invasion assay. Morphology and immunohistological staining of expression of RAGE were also performed. RESULTS: Proliferation was inhibited with the addition of EGCG in a dose-dependent manner. EGCG (200 mumol/L) produced a profound growth suppression of HLF cells (24.5%). Cell invasion was also inhibited with preincubation of 100 mumol/L of EGCG (10.2%). In addition to the antitumor effects, neurite-like conformational changes of HLF cells were observed. Addition of EGCG (100 mumol/L) showed the expression of RAGE on cell surface in accordance to the morphological changes. CONCLUSIONS: The pathway associated to cell movement might be activated with RAGE expression. Although EGCG inhibits the growth and invasion, the cells which expressed RAGE seem to survive. Thus, the enrollment of RAGE should be analyzed to clarify the mechanisms of cancer resistance.

Antineoplastic Agents, Phytogenic↗
PubMedDate not supplied

Expression of receptor for advanced glycation end products (RAGE) in human biliary cancer cells.

BACKGROUND/AIMS: Amphoterin is considered as a regulator for the ability of invasion and migration in tumor cells and embryonic neurons through binding to RAGE (receptor for advanced glycation end products), a mult-iligand cell surface molecule of the immunoglobulin superfamily. METHODOLOGY: To see the involvement of RAGE in biliary cancer, three representative human biliary cancer cells (SK-ChA-1, TGBC-1 and NOZC-1) were rendered for the study. Cell invasion ability was determined using Matrigel invasion assay. The expression of RAGE protein was studied by Western blotting. RESULTS: Cell invasion assay through Matrigel showed high invasion potential in SK-ChA-1 and NOZC-1 (40.3 +/- 3.27, 48.7 +/- 4.8); low invasion potential in TGBC-1 (25.7 +/- 2.8). RAGE was strongly expressed in SK-ChA-1 and NOZC-1 that have high invasion ability. On the contrary, RAGE was faintly expressed in TGBC-1 that has low ability. CONCLUSIONS: RAGE is expressed in concordance to the invasion ability of the human biliary cancer cells. Control of this molecule could be a key to regulate the invasion ability of biliary cancers.

Bile Duct Neoplasms↗
PubMedDate not supplied

Expression of receptor for advanced glycation end products (RAGE) and MMP-9 in human pancreatic cancer cells.

BACKGROUND/AIMS: Amphoterin is considered as a regulator for the ability of invasion and migration in tumor cells and embryonic neurons through binding to receptor for advanced glycation end products (RAGE), a multiligand cell surface molecule of the immunoglobulin superfamily. As matrix metalloproteinase-9 (MMP-9, gelatinase B) has been reported to play a critical role in tumor progression and metastasis, we have examined the relation of RAGE and MMP in human pancreatic cancer. METHODOLOGY: Three representative human pancreatic carcinoma cells were rendered for the study which show different metastatic potential, PANC-1 and MIA PaCa-2 as the cells with high ability, BxPC-3 as with low. The expression of RAGE was examined by RT-PCR. The expression of MMP-9 protein was examined by Western blotting. RESULTS: RAGE was strongly expressed in MIA PaCa-2 and PANC-1 that have high metastatic ability. On the contrary, RAGE was expressed little in BxPC-3 that has low ability. Similarly, expression of MMP-9 showed almost the same tendency. RAGE and MMP-9 are expressed concordant with the metastatic ability of the human pancreatic cancer cells. CONCLUSIONS: Control of these molecules could be a key to regulating the metastatic ability of pancreatic cancer and this may be exploited in targeted therapy of this cancer.

Blotting, Western↗
PubMed2006

RAGE in inflammation: a new therapeutic target?

High-molecular group box 1-protein, S100/calgranulins, advanced glycation end products (AGEs), amyloid-beta peptides and the family of beta-sheet fibrils contribute to a number of inflammatory conditions by promoting cellular dysfunction and breaking immune tolerance. The receptor of AGE (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules that acts as a pattern recognition receptor. Besides binding ligands actively participating in inflammation and immune responses, RAGE serves as an endothelial adhesion receptor for leukocyte integrins and promotes leukocyte recruitment and extravasation of infiltrating cells. Engagement of RAGE subsequently converts transient cellular stimulation into sustained cellular dysfunction driven by long-term activation of the proinflammatory nuclear factor-kappaB. Deletion of RAGE and pharmacological interventions targeting interruption of RAGE-ligand interaction suppresses inflammation and dampens tissue damage in experimental models of inflammatory disorders, thus delineating RAGE as a potential therapeutic target in inflammation.

Animals↗