Biomedical subjects

Min Lu

Publications and source records attributed to Min Lu.

At least 19 recordsLinked to original sources

PubMed2026

FANCM is required for the PAX3::FOXO1-driven oncogenic program in rhabdomyosarcoma.

Many cancers are driven by mutationally altered transcription factors (TFs) that rewire cells to an oncogenic state. Cells must activate specific mechanisms to tolerate the burden of oncogenic TF activity. To define such mechanisms, we focused on a canonical oncogenic fusion protein-driven cancer, alveolar rhabdomyosarcoma (ARMS), where the PAX3::FOXO1 fusion protein hyperactivates and mislocalizes PAX3 and FOXO1 TF functions. Employing sequential functional genomic CRISPR-Cas9 screens, we identified FANCM, a DNA translocase in the Fanconi anemia pathway, as a selective dependency in PAX3::FOXO1+ ARMS. FANCM loss reduces fusion protein levels, induces myogenic differentiation, and disrupts the PAX3::FOXO1 transcriptional program, thereby halting oncogenic proliferation. Mechanistically, FANCM depletion exacerbates replication stress (RS) and DNA damage signaling, with chromatin-associated RS enriched at PAX3::FOXO1 target gene loci, resulting in selective downregulation of the oncogenic program. CRISPR exon-tiling screens prioritized FANCM's helicase and DNA-binding domains as essential for this dependency, linking FANCM-mediated replication fork binding to sustained oncogenesis.

ARMS↗

PubMed2026

The RrWRKY75-mediated activation of ascorbate synthesis in Rosa roxburghii Tratt contributes to salt stress tolerance.

L-Ascorbic acid (AsA) is a key antioxidant that alleviates oxidative stress in plants. Previous yeast one-hybrid (Y1H) screening identified RrWRKY75 as a transcription factor capable of binding to the promoter of RrGGP2 (GDP-L-galactose pyrophosphatase 2), a key structural gene responsible for massive AsA accumulation in Rosa roxburghii fruit. The function of RrWRKY75 in plant stress responses remains unclear. Here, RrWRKY75 is verified to specifically bind to the RrGGP2 promoter and activate its transcription. This positive regulatory effect on RrGGP2 transcript levels and AsA accumulation is further confirmed through overexpression or silencing of RrWRKY75 in R. roxburghii fruit or callus. Among various abiotic stress conditions, RrWRKY75 expression is significantly induced by salt stress. Upon its overexpression in callus or Arabidopsis thaliana, elevated AsA levels and antioxidant capacity are observed, thereby enhancing salt tolerance. Interestingly, RrWRKY75 also binds to the promoter of RrUNE12, a salt-responsive factor in R. roxburghii, and activates its expression. Moreover, yeast two-hybrid and bimolecular fluorescence complementation (BiFC) assays confirm the physical interaction between RrWRKY75 and RrUNE12, which jointly upregulates RrGGP2 expression and AsA production. Collectively, RrWRKY75 boosts AsA biosynthesis and salt tolerance both by directly trans-activating RrGGP2 and by synergizing with RrUNE12 through transcriptional activation and protein complex formation. These findings provide insights into the regulatory role of RrWRKY75 in abiotic stress tolerance and offer valuable genetic resources for R. roxburghii germplasm improvement.

Rosa↗

PubMed2005

Synthesis and anticancer activity of 2-alkylaminomethyl-5-diaryl-methylenecyclopentanone hydrochlorides and related compounds.

Eleven new diaryl-methylenecyclopentanone Mannich hydrochlorides and related compounds were synthesized with different modification on Mannich base and alpha,beta-unsaturated bonds. The glutathione-binding ability, glutathione-s-transferase pi (GSTpi) inhibition and antitumor effect of these compounds were compared. Compounds containing both Mannich base and alpha-unsaturated bond have GSH binding ability, GSTpi inhibitory activity and antitumor effect. Compounds without Mannich base or having a alpha-saturated bond lose GSH binding ability and the antitumor effect. Converting of Mannich base from dimethylaminomethyl group to morpholino, pyrrolidino, or piperidino-methyl groups do not evidently change the antitumor effect. However replacement of phenyl group with methylphenyl group on beta-chain significantly increases cytotoxic effect in breast cancer cells but not in immortalized mammary epithelial cells. Our data suggest that diaryl-methylenecyclopentanones represent a new category of compounds which might inhibit tumor growth through binding to glutathione or thiol proteins.

Antineoplastic Agents↗

PubMed2005

Severe acute respiratory syndrome associated coronavirus is detected in intestinal tissues of fatal cases.

OBJECTIVES: A significant percentage of confirmed severe acute respiratory syndrome (SARS) patients experienced gastrointestinal symptoms, and the viral sequence was detectable in the stool of most patients. At present, the knowledge of the pathology of the digestive system in SARS patients is limited. Because a resurgence of the SARS epidemic is constantly possible, there is an urgent need to understand the involvement of the digestive system in this new disease. METHODS: We performed seven SARS autopsies in which samples of alimentary tract and digestive glands were examined with routine pathology, electron microscopy (EM), in situ hybridization (ISH), immunohistochemistry, and real-time polymerase chain reaction (PCR). RESULTS: The main histopathological finding was atrophy of the mucosal lymphoid tissue. A few mucosal epithelial cells and lymphocytes in the intestine were positively stained for coronavirus with ISH. SARS-coronavirus (CoV)-like particles were found in the mucosal epithelial cells under EM and mild focal inflammation was detected in the alimentary tract. One patient who experienced severe diarrhea had pseudomembranous enteritis of the ileum. Fatty degeneration and central lobular necrosis were observed in the liver. No evidence of direct viral infection was found in the esophagus, the stomach, the salivary gland, the liver, or the pancreas. CONCLUSIONS: In addition to the lungs, the gastrointestinal tract is another target of SARS-CoV infection, as the intestinal epithelial cells and mucosal lymphoid tissue are infected. The findings provide possible explanations for the gastrointestinal symptoms and the presence of virus in the stool of SARS patients.

Adult↗

PubMed2005

The cytoplasmic tail slows the folding of human immunodeficiency virus type 1 Env from a late prebundle configuration into the six-helix bundle.

Effects of the cytoplasmic tail (CT) of human immunodeficiency virus type 1 Env on the process of membrane fusion were investigated. Full-length Env (wild type [WT]) and Env with its CT truncated (DeltaCT) were expressed on cell surfaces, these cells were fused to target cells, and the inhibition of fusion by peptides that prevent Env from folding into a six-helix bundle conformation was measured. For both X4-tropic and R5-tropic Env proteins, DeltaCT induced faster fusion kinetics than did the WT, and peptides were less effective at inhibiting DeltaCT-induced fusion. We tested the hypothesis that the inhibitory peptides were less effective at inhibiting DeltaCT-induced fusion because DeltaCT folds more quickly into a six-helix bundle. Early and late intermediates of WT- and DeltaCT-induced fusion were captured, and the ability of peptides to block fusion when added at the intermediate stages was quantified. When added at the early intermediate, the peptides were still less effective at inhibiting DeltaCT-induced fusion but they were equally effective at preventing WT- and DeltaCT-induced fusion when added at the late intermediate. We conclude that for both X4-tropic and R5-tropic Env proteins, the CT facilitates conformational changes that allow the trimeric coiled coil of prebundles to become optimally exposed. But once Env does favorably expose its coiled coil to inhibitory peptides, the CT hinders subsequent folding into a six-helix bundle. Because of this facilitation of maximal exposure and hindrance of bundle formation, the coiled coil is optimally exposed for a longer time for WT than for DeltaCT. This accounts for the greater peptide inhibition of WT-induced fusion.

CD4 Antigens↗

PubMed2004

Kinetics and thermodynamics of the unfolding and refolding of the three-stranded alpha-helical coiled coil, Lpp-56.

Temperature-induced reversible unfolding and refolding of the three-stranded alpha-helical coiled coil, Lpp-56, were studied by kinetic and thermodynamic methods, using CD spectroscopy, dynamic light scattering, and scanning calorimetry. It was found that both unfolding and refolding reactions of this protein in neutral solution in the presence of 100 mM NaCl are characterized by unusually slow kinetics, which permits detailed investigation of the mechanism of these reactions. Kinetic analyses show that the unfolding of this coiled coil represents a single-stage first-order reaction, while the refolding represents a single-stage third-order reaction. The activation enthalpy and entropy for unfolding do not depend noticeably on temperature and are both significantly greater than those for the folding reaction, which show a significant dependence on temperature. The activation heat capacity change for the unfolding reaction is close to zero, while it is quite significant for the folding reaction. The correlation between the activation and structural parameters obtained for the Lpp-56 coiled coil suggests that interhelical van der Waals interactions are disrupted in the transition state, which is nevertheless still compact, and water has not yet penetrated into the interface; the transition from the transient state to the unfolded state results in hydration of exposed apolar groups of the interface and the disruption of helices. The low propensity for the Lpp-56 strands to fold and associate is caused by the high number of charged groups at neutral pH. On one hand, these charges give rise to considerable repulsive forces destabilizing the helical conformation of the strands. On the other hand, they align the folded helices in parallel and in register so that the apolar sides face each other, and the oppositely charged groups may form salt links, which are important for the formation of the trimeric coiled coil. A decrease in pH, which eliminates the salt links, dramatically decreases the stability of Lpp-56; its structure becomes less rigid and unfolds much faster.

Amino Acid Sequence↗

PubMed2004

The ARE-dependent mRNA-destabilizing activity of BRF1 is regulated by protein kinase B.

Butyrate response factor (BRF1) belongs to the Tis11 family of CCCH zinc-finger proteins, which bind to mRNAs containing an AU-rich element (ARE) in their 3' untranslated region and promote their deadenylation and rapid degradation. Independent signal transduction pathways have been reported to stabilize ARE-containing transcripts by a process thought to involve phosphorylation of ARE-binding proteins. Here we report that protein kinase B (PKB/Akt) stabilizes ARE transcripts by phosphorylating BRF1 at serine 92 (S92). Recombinant BRF1 promoted in vitro decay of ARE-containing mRNA (ARE-mRNA), yet phosphorylation by PKB impaired this activity. S92 phosphorylation of BRF1 did not impair ARE binding, but induced complex formation with the scaffold protein 14-3-3. In vivo and in vitro data support a model where PKB causes ARE-mRNA stabilization by inactivating BRF1 through binding to 14-3-3.

14-3-3 Proteins↗

PubMed2004

Atomic structure of a tryptophan-zipper pentamer.

Coiled-coil motifs are ubiquitous mediators of specific protein-protein interactions through the formation of interlocking hydrophobic seams between alpha-helical chains. Residues that form these seams occur at the first (a) and fourth (d) positions of a characteristic 7-aa repeat and are primarily aliphatic. The potential of aromatic residues to promote helix association in a coiled coil was explored by engineering a "Trp-zipper" protein with Trp residues at all 14 a and d positions. The protein forms a discrete, stable, alpha-helical pentamer in water at physiological pH. Its 1.45-A crystal structure reveals a parallel, five-stranded coiled coil, a previously uncharacterized type of "knobs-into-holes" packing interaction between interfacial Trp side chains, and an unusual approximately 8-A-diameter axial channel lined with indole rings that is filled with polyethylene glycol 400 and water and sulfate ion molecules. The engineered Trp-zipper pentamer enlarges current views of coiled-coil assembly, molecular recognition, and protein engineering, and may serve as a soluble model for membrane ion channels.

Amino Acid Motifs↗

PubMed2004

Endoplasmic reticulum degradation impedes olfactory G-protein coupled receptor functional expression.

BACKGROUND: Research on olfactory G-protein coupled receptors (GPCRs) has been severely impeded by poor functional expression in heterologous systems. Previously, we demonstrated that inefficient olfactory receptor (OR) expression at the plasma membrane is attributable, in part, to degradation of endoplasmic reticulum (ER)-retained ORs by the ubiquitin-proteasome system and sequestration of ORs in ER aggregates that are degraded by autophagy. Thus, experiments were performed to test the hypothesis that attenuation of ER degradation improves OR functional expression in heterologous cells. RESULTS: To develop means to increase the functional expression of ORs, we devised an approach to measure activation of the mOREG OR (Unigene # Mm.196680; Olfr73) through coupling to an olfactory cyclic nucleotide-gated cation channel (CNG). This system, which utilizes signal transduction machinery coupled to OR activation in native olfactory sensory neurons, was used to demonstrate that degradation, both by the ubiquitin-proteasome system and autophagy, limits mOREG functional expression. The stimulatory effects of proteasome and autophagy inhibitors on mOREG function required export from the ER and trafficking through the biosynthetic pathway. CONCLUSIONS: These findings demonstrate that poor functional expression of mOREG in heterologous cells is improved by blocking proteolysis. Inhibition of ER degradation may improve the function of other ORs and assist future efforts to elucidate the molecular basis of odor discrimination.

Animals↗

PubMed2004

A preliminary study on DNA detection based on relative magnetic permeability measurements and histone H1 conjugated superparamagnetic nanoparticles as magnetic tracers.

Histone H1 conjugated superparamagnetic nanoparticles were assessed for their ability to work as magnetic tracers in conjunction with the relative magnetic permeability metre (MPM-100) for the detection and quantification of DNA (deoxyribonucleic acid). The method employed was based on the electrostatic adsorption of DNA (analyte) to amino group derivatised silica (carrier) and subsequent binding of histone H1 conjugated superparamagnetic nanoparticles (magnetic tracer). The sandwich complexes formed were separated from the medium by sedimentation and the relative magnetic permeability of the sediments were measured with the MPM-100. Investigations were made with both calf thymus DNA and plasmid DNA in aqueous buffered solution as well as in a lysed cell culture with high protein content. For the quantification of calf thymus DNA, a linear relationship between the DNA concentration in the sample and the relative magnetic permeability of the pellet was found for DNA concentrations up to 67 microg/ml in buffered solutions as well as in a lysed cell culture. The limits of detection were determined to 12 and 31 microg/ml, respectively. For the quantification of plasmid DNA in buffered solution a linear range was established for concentrations in up to 150 microg/ml and the limit of detection was determined to 52 microg/ml.

Animals↗

PubMed2004

Dual effects of glutathione-S-transferase pi on As2O3 action in prostate cancer cells: enhancement of growth inhibition and inhibition of apoptosis.

To determine the effects of glutathione-S-transferase pi (GSTpi) on the actions of As2O3, As2O3-induced growth inhibition and apoptosis was studied in three prostate cancer cell lines: DU-145, PC-3 and LNCaP cells. As2O3 inhibited cell proliferation of DU-145 and PC-3 cells (both cells express GSTpi), but not of LNCaP cells (which lack GSTpi expression) at concentrations below 1 microM. LNCaP cells stably transfected and expressed GSTpi (LNCaP/GSTpi) became sensitive to As2O3 growth inhibition. As2O3 arrested cell growth of DU-145, PC-3 and LNCaP/GSTpi cells in the G2/M phase of the cell cycle at low concentrations (<2 microM), but did not induce apoptosis. At higher concentrations (10-20 microM), As2O3 induced apoptosis in LNCaP cells, but not in DU-145 or PC-3 cells. The apoptosis induction due to As2O3 treatment of LNCaP cell correlated with the activation of JNK and p38 and induction of p53 protein. LNCaP/GSTpi cells became insensitive to As2O3-induced apoptosis with reduced JNK activition. These data indicate that GSTpi increases growth inhibition due to As2O3 treatment and prevents As2O3-induced apoptosis in prostate cancer cells. Therefore, it appears that As2O3 inhibits cell growth and induces apoptosis through different mechanisms.

Animals↗

PubMed2004

Structure and protein design of a human platelet function inhibitor.

Hematophagous arthropods secrete a salivary apyrase that inhibits platelet activation by catabolizing ADP released from damaged tissues and blood cells. We report the X-ray crystal structures of a human enzyme of the soluble apyrase family in its apo state and bound to a substrate analog. The structures reveal a nucleotide binding domain comprising a five-blade beta propeller, binding determinants of the substrate and the active site, and an unusual calcium binding site with a potential regulatory function. Using a comparative structural biology approach, we were able to redesign the human apyrase so as to enhance its ADPase activity by more than 100-fold. The engineered enzyme is a potent inhibitor of platelet aggregation and may serve as the basis for the development of a new class of antithrombotic agents.

Amino Acid Sequence↗

PubMed2004

Hemangiopoietin, a novel human growth factor for the primitive cells of both hematopoietic and endothelial cell lineages.

The cells of hematopoietic and vascular endothelial cell lineages are believed to share a common precursor, termed hemangioblast. However, the existence of a growth factor acting relatively specifically on hemangioblasts remains unclear. Here we report the identification of hemangiopoietin (HAPO), a novel growth factor acting on both hematopoietic and endothelial cell lineages. In vitro in the human system, recombinant human HAPO (rhHAPO) significantly stimulated the proliferation and hematopoietic and/or endothelial differentiation of human bone marrow mononuclear cells and of purified CD34+, CD133+, kinase domain receptor-positive (KDR+), or CD34+/KDR+ cell populations. In the murine system, rhHAPO stimulated the proliferation of long-term culture-initiating cells (LTC-ICs) as well as CD34+ and stem cell antigen-1 (Sca-1+) cell subsets. In vivo, subcutaneous injection of rhHAPO into normal mice resulted in a significant increase in bone marrow hematopoietic cells. Furthermore, irradiated mice injected with rhHAPO had an enhanced survival rate and accelerated hematopoiesis. Our data suggest that HAPO is a novel growth factor acting on the primitive cells of both hematopoietic and endothelial cell lineages and that HAPO may have a clinical potential in the treatment of various cytopenias and radiation injury and in the expansion of hematopoietic and endothelial stem/progenitor cells.

Abortion, Spontaneous↗

PubMed2004

Fast folding of the HIV-1 and SIV gp41 six-helix bundles.

Human (HIV-1) and simian (SIV) immunodeficiency virus fusion with the host cell is promoted by the receptor-triggered refolding of the gp41 envelope protein into a stable trimer-of-hairpins structure that brings viral and cellular membranes into close proximity. The core of this hairpin structure is a six-helix bundle in which an inner homotrimeric coiled coil is buttressed by three antiparallel outer HR2 helices. We have used stopped-flow circular dichroism spectroscopy to characterize the unfolding and refolding kinetics of the six-helix bundle using the HIV-1 and SIV N34(L6)C28 polypeptides. In each case, the time-course of ellipticity changes in refolding experiments is well described by a simple two-state model involving the native trimer and the unfolded monomers. The unfolding free energy of the HIV-1 and SIV trimers and their urea dependence calculated from kinetic data are in very good agreement with data measured directly by isothermal unfolding experiments. Thus, formation of the gp41 six-helix bundle structure involves no detectable population of stable, partly folded intermediates. Folding of HIV-1 N34(L6)C28 is five orders of magnitudes faster than folding of its SIV counterpart in aqueous buffer: k(on),(HIV-1)=1.3 x 10(15)M(-2)s(-1) versus k(on),(SIV)=1.1 x 10(10)M(-2)s(-1). The unfolding rates are similar: k(off),(HIV-1)=1.1 x 10(-5)s(-1) versus k(off),(SIV=)5.7 x 10(-4)s(-1). Kinetic m-values indicate that the transition state for folding of the HIV-1 protein is significantly more compact than the transition state of the SIV protein. Replacement of a single SIV threonine by isoleucine corresponding to position 573 in the HIV-1 sequence significantly stabilizes the protein and renders the folding rate close to that of the HIV-1 protein yet without making the transition state of the mutant as compact as that of the HIV-1 protein. Therefore, the overall reduction of surface exposure in the high-energy transition state seems not to account for different folding rates. While the available biological evidence suggests that refolding of the gp41 protein is slow, our study implies that structural elements outside the trimer-of-hairpins limit the rate of HIV-1 fusion kinetics.

Animals↗

PubMed2004

ATF6 modulates SREBP2-mediated lipogenesis.

Activating transcription factor 6 (ATF6) and sterol regulatory element-binding proteins (SREBPs) are activated by proteolytic cleavage. The ensuing nuclear translocation of their N-termini (i.e., ATF6(N) and SREBP(N)) activates the respective target genes involved in unfolded protein response and lipogenesis. Here, we report that glucose deprivation activated ATF6 but suppressed the SREBP2-regulated transcription. Overexpression of ATF6(N) had similar inhibitory effects on SREBP2-targeted genes. The blockade of ATF6 cleavage by BiP/grp78 reversed this inhibitory effect. GST pull-down and immunoprecipitation assays revealed that ATF6(N) bound to SREBP2(N). Deletion analysis of the various functional domains of ATF6 indicated that the interaction was through its leucine-zipper domain. Chromatin immunoprecipitation assays revealed that ATF6(N) formed a complex with the SRE-bound SREBP2(N). The attenuated transcriptional activity of SREBP2 was due, in part, to the recruitment of HDAC1 to the ATF6-SREBP2 complex. As a functional consequence, the lipogenic effect of SREBP2(N) in liver cells was suppressed by ATF6(N). Our results provide a novel mechanism by which ATF6 antagonizes SREBP2 to regulate the homeostasis of lipid and glucose.

Activating Transcription Factor 6↗

PubMed2004

Utility of serum CA19-9 in diagnosis of cholangiocarcinoma: in comparison with CEA.

AIM: The diagnosis of cholangiocarcinoma is often difficult, making management approaches problematic. A reliable serum marker for cholangiocarcinoma would be a useful diagnostic test. The aims of our study were to evaluate the usefulness of a serum CA19-9 determination in the diagnosis of cholangiocarcinoma. METHODS: We prospectively measured serum CA19-9 and CEA concentrations in patients with cholangiocarcinoma (n=35), benign biliary diseases (n=92), and healthy individuals (n=15). Serum CA19-9 and CEA concentrations were measured by an immunoradiometric assay without knowledge of the clinical diagnosis. RESULTS: The sensitivity of a CA19-9 value >37 KU/L(-1) and a CEA value >22 microg/L(-1) in diagnosing cholangiocarcinoma were 77.14% and 68.57%, respectively. When compared with the benign biliary diseases group, the true negative rates of serum CA19-9 and CEA were 84.78% and 81.52%, respectively. The false positive rates of serum CA19-9 and CEA were 15.22% and 18.48%, whereas the accuracy of serum CA19-9 and CEA were 82.68% and 77.95%, respectively. Serum CA19-9 and CEA concentrations were significantly elevated (P<0.001 and P<0.05) in patients with cholangiocarcinoma (290.31+/-5.34 KU/L(-1) and 36.46+/-18.03 microg/L(-1)) compared with patients with benign biliary diseases (13.38+/-2.59 KU/L(-1) and 13.84+/-3.85 microg/L(-1)) and healthy individuals (12.78+/-3.69 KU/L(-1) and 11.48+/-3.37 microg/L(-1)). In 15 patients undergoing curative resection of cholangiocarcinoma, the mean serum CA19-9 concentration was decreased from a preoperative level of 286.41+/-4.36 KU/L(-1) to a postoperative level of 62.01+/-17.43 KU/L(-1) (P<0.001), and the mean serum CEA concentration from 39.41+/-24.35 microg/L(-1) to 28.69+/-11.03 microg/L(-1) (P<0.05). In patients with cholangiocarcinoma, however, no correlation was found between serum CEA and CA19-9 concentrations (r=0.036). CONCLUSION: These data suggest that the serum CA19-9 determination is a useful addition to the available tests for the differential diagnosis of cholangiocarcinoma. Serum CA19-9 is an effective tumor marker in diagnosing cholangiocarcinoma, deciding whether the tumor has been radically resected and monitoring effect of treatment.

Bile Duct Neoplasms↗

PubMed2004

Conformational and enzymatic changes of 20S proteasome of rat natural killer cells induced by mono- and divalent cations.

We have been investigated the relation between activation of "neutral" and "acidic" chymotrypsin-like (ChT-L) activity and conformational changes in the 20S proteasome complex from the rat natural killer (NK) cells induced by SDS, mono- and divalent cations. The conformational changes were monitored by tryptophan fluorescence and light scattering. It was revealed that the changes in the maximum position and contribution of the short-wavelength spectral component correlated with the alteration of ChT-L activity of the proteasome. Statistical analysis was applied to assign the fluorescence components with tryptophan residues based on the classification of calculated structural parameters of the environment of tryptophan fluorophores in protein. It was proposed that the emission of W13 from alpha6-subunit located near the cluster of highly conserved proteasome residues is mostly sensitive to the activation of the enzyme. We concluded that the expression of maximal ChT-L activity of 20S proteasome is associated with the conformational changes occurs in this cluster that lead to the proteasome open conformation, allowing substrate access into the proteolytic chamber.

Animals↗

PubMed2004

Glycoxidation and inflammation in renal failure patients.

BACKGROUND: Inflammation is common in patients with chronic renal failure and has been associated with the increased risk for cardiovascular disease (CVD) in this condition. Advanced glycoxidation end products (AGEs) are among the factors implicated in the inflammatory state of chronic renal failure. METHODS: In a cross-sectional study of 189 dialysis patients, we measured circulating levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), vascular adhesion molecule-1 (VCAM-1), vascular endothelial growth factor (VEGF), and plasminogen activator inhibitor-1 (PAI-1) to test for possible relationships between them and serum AGE levels. In addition, these parameters were measured in a subgroup of 18 patients with chronic renal failure randomly assigned to a 4-week diet, either low (L-AGE) or high (H-AGE) in AGE content. AGEs were measured by means of a monoclonal antibody against epsilonN-carboxymethyllysine. RESULTS: At baseline, serum AGE levels, as well as those for CRP, TNF-alpha, VCAM-1, and VEGF, were markedly elevated, although no correlation was found between AGE levels and the other markers. Dietary AGE modulation resulted in a significant decrease in levels of serum AGEs, CRP, and PAI-1 in the L-AGE group (approximately 35%, 44%, and 17%, respectively; P < 0.03), whereas only serum AGE levels increased significantly in the H-AGE group. VCAM-1 and TNF-alpha levels, although similar at baseline, became significantly lower in patients on an L-AGE compared with H-AGE diet (P < 0.05) at the end of the study. CONCLUSION: Data from the interventional phase of the study suggest that AGEs have a role in the initiation of the inflammatory state of chronic renal failure, which eventually leads to increased CVD. This finding opens the possibility for using anti-AGE strategies in the prevention and treatment of CVD in patients with chronic renal failure.

Adult↗