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PubMed2001

[Clinical epidemiology].

Although the exact incidence of chronic myeloid leukemia(CML) in Japan is obscure, the occurrence rate of CML is approximately 15% of all leukemia patients in Japan, and thus about 5/100,000 cases appeared per year. This incidence of CML seems to be lower that that of Caucasian, but the incidence of CML patients in Japan may increase gradually. Molecular investigation in CML disclosed the exact mechanism of t(9; 22) anomaly, thus providing appropriate classification for chronic myeloid leukemia. From the etiological aspect, it is well documented that exposure to atomic bomb at Nagasaki and Hiroshima actually induced CML, however, factors other than irradiation are still obscure. Recent spread of annual examination pick up some CML patients at the early phase and the disease severity might be thus different from those of previous CML patients. For example, currently diagnosed CML patients usually lack palpable splenomegaly and some of them had normal karyotypes in addition to Ph-cells in the bone marrow at the time of CML diagnosis. These findings indicate that epidemiological aspect in CML patients might be changing.

Adult↗

PubMed1990

Anti-leukemia potential of interleukin-2 activated natural killer cells after bone marrow transplantation for chronic myelogenous leukemia.

The anti-leukemia potential of natural killer (NK) cells has been evaluated in 40 patients transplanted for chronic myelogenous leukemia (CML) to determine whether differences in NK cell function were correlated with subsequent leukemic relapse. Cells from patients and their donors were tested in 51Cr release assays against fully allogeneic CML targets and against cultured K562 targets; cells from 26 patients were tested against host-derived CML targets that were cryopreserved before transplantation. Cultured CML targets (K562) were highly susceptible to lysis by freshly isolated peripheral blood lymphocytes (PBL) and to a greater degree by PBL cultured in medium containing interleukin-2 (IL-2) in all assays performed. In contrast, noncultured CML targets were lysed only by IL-2-activated cells from a subset of patients. When present, lytic activity to CML targets was detectable as early as 3 weeks after bone marrow transplantation, and remained positive throughout the posttransplant period. Optimal lytic activity developed within the first week of culture and required greater than or equal to 250 U/mL of IL-2 in the culture medium. Lytic activity to fully allogeneic and host-derived CML targets appeared to be mediated by CD16+ and CD56+ cells but not by CD3+ cells. Lysis of allogeneic CML targets was variable, but patients could be divided into two groups: those with and those without lytic activity to the majority of targets tested. The basis for the differences in lytic activity could not be ascribed to target susceptibility to lysis, the proportion of NK cells in the cultures, or to the phenotype of the NK cell subsets in the cultures. When tested in parallel, the lytic activity of donor and recipient cultures against host-derived CML targets was highly correlated, suggesting that there may be inherent differences in the ability of NK cells to recognize CML targets. The risk of relapse for patients who failed to generate lytic activity against host-derived CML targets was significantly increased over that for patients with lytic activity against host leukemia. These data indicate that posttransplant immunotherapy with IL-2 designed to activate NK cells will likely augment the graft-versus-leukemia potential of the graft.

Adolescent↗

PubMed1989

[Changes in serum RNase activities in chronic phase and acute crisis of chronic myelocytic leukemia].

We investigated serum acid and alkaline RNase activities in 16 cases of acute crisis of chronic myelocytic leukemia (CML), 21 cases of untreated CML, and 13 cases of treated CML, to clarify clinical significance of the determination of RNase activities in acute crisis of CML. We obtained results as follows; the ratio of acid to alkaline Rnase activities (Ac/Al ratio) of chronic phase of CML was 1.64 +/- 0.47 (mean +/- SD) in the untreated cases, and was 1.32 +/- 0.16 in the treated cases. The Ac/Al ratio always indicated over 1.0 in the chronic phase of CML without any relationship to treatments. On the other hand, in the cases of acute crisis, the Ac/Al ratio was significantly lowered (0.94 +/- 0.22) as compared to the chronic phase of CML (p less than 0.001), and was similar to that of acute leukemia. The acid and alkaline RNase activities of the blast from the patients with acute crisis of CML showed remarkably lower value than those of leukemic cells from patients with chronic phase of CML. Therefore, it was Suggested that the return to normal range of Ac/Al ratio in acute crisis of CML depended on marked decrease of RNase activities of blasts. Thus, serial determinations of the enzyme activities are considered to be one of useful tools for prediction of acute crisis of CML.

Adult↗

PubMed1993

Characterization of lineage-negative blast subpopulations derived from normal and chronic myelogenous leukemia bone marrows and determination of their responsiveness to human c-kit ligand.

Lineage-negative (lin-) normal and chronic myelogenous leukemia (CML) marrow blast populations were obtained by negative selection and subsequently separated on the basis of size by velocity sedimentation. The three subpopulations of lin- blasts obtained were enriched for F8 (the more primitive small blasts), F11 (blasts intermediate in size), and F13 (the more mature large blasts). We examined the morphological and phenotypic characteristics and cell cycle status of the subpopulations and determined the responsiveness of granulocyte-monocyte progenitors (colony-forming units/granulocyte-macrophage) derived from each subpopulation to mast cell growth factor in combination with granulocyte (G-CSF) or granulocyte-macrophage (GM-CSF) colony-stimulating factors alone and in combination. Morphological assessment revealed that an increased proportion of CML lin- blasts exhibited early cytoplasmic maturation as evidenced by the appearance of azurophilic (nonspecific) granules in the cytoplasm. Although the percentages of CML and normal small blasts expressing CD34 were similar, the proportion of CML lin- blasts expressing CD34 declined in the intermediate and more mature large lin- blast subpopulations by about 50%, whereas the percentage of CD34+ normal blasts remained essentially the same, indicating an earlier loss of CD34 expression by CML lin- blasts. In addition, the percentages of CML small blasts expressing CD33 were higher than normal (26-61% versus 0-16%, respectively), indicating that a higher proportion of CML small lin- blasts had a more mature phenotype. Mast cell growth factor addition to cultures stimulated by G-CSF, GM-CSF, or G-CSF plus GM-CSF, exerted the greatest synergistic effect (increased colony number and size) in the normal small and intermediate lin- blast cultures, but mast cell growth factor had considerably less effect, or no effect, in cultures of comparable CML subpopulations, indicating that CML lin- progenitors had a somewhat lower requirement for multiple growth factors. The findings suggest that the differences observed between normal and CML marrow subpopulations are proportional differences and that a greater proportion of CML lin- blast subpopulations exhibit characteristics associated with a more advanced stage of maturation than comparable normal lin- blast subpopulations.

Bone Marrow↗

PubMed1996

Results with high-dose chemotherapy and unpurged autologous stem cell transplantation in 73 patients with chronic myelogenous leukemia: the MD Anderson experience.

The purpose of this study was to evaluate the effectiveness of unpurged autologous stem cell transplantation (ASCT) for chronic myelogenous leukemia (CML) and its impact on the survival of patients in first and late chronic phase (CML-CP) including those resistant to or unable to tolerate interferon alfa (IFN-alpha) therapy. Between 1982 and 1993, 73 patients with CML who underwent ASCT were evaluated. Twenty-eight patients had signs of transformation, 20 were in second or subsequent CP, 22 had CML-CP and had shown resistance to or were unable to tolerate IFN-alpha therapy, and there had Philadelphia (Ph) chromosome-negative CML. Survival of patients in CML-CP who underwent ASCT was compared to controls who were in first CP receiving INF-a therapy. Patients and controls were matched for age, decade of therapy, response to IFN-alpha therapy (resistance vs toxicity) and the time to ASCT (study group) vs time to resistance (control group). Nine 12% patients failed to achieve hematologic recovery, and five (7%) had early death secondary to toxicity. Twenty-seven (58%) patients who received transplants in advanced-stage CML and 18 (82%) transplanted in CML-CP achieved complete hematologic remission (CHR). The incidence of complete cytogenetic response was 10 and 14%, respectively. The median survival of these two groups of patients was 5 and 34 months, respectively (P < 0.001). However, the survival of patients in CML-CP was not significantly different from controls (34 vs 49 months; P = 0.17). We conclude that unpurged ASCT does not prolong the survival of patients in CML-CP who are resistant to IFN-alpha therapy. Progress in autotransplantation in CML might require innovative approaches to eradicate the leukemic cells from the autologous stem cells prior to transplants.

Adolescent↗

PubMed1989

Natural killer cell immunodeficiency in patients with chronic myelogenous leukemia. III. Defective interleukin-2 production by T-helper and natural killer cells.

Even though they possess normal to increased numbers of circulating natural killer (NK) cells, patients with chronic myelogenous leukemia (CML) have a functional NK-cell deficiency which is restorable in vitro in the presence of recombinant IL-2. We therefore measured the level of IL-2 production by both T-helper and NK cells from CML patients as compared to normal controls using PHA-stimulated peripheral blood mononuclear cells (PBMs) as well as FACS-sorted CD4+ (OKT4+) lymphoid cells and FACS-sorted CD16+ (B73.1+) lymphoid cells. Peripheral blood mononuclear cells from CML patients demonstrated markedly defective IL-2 production as compared to normal controls (4.0 +/- 1.6 and 5.9 +/- 1.4 units/ml after 24 hr of 5 and 10 micrograms/ml PHA stimulation as compared with 40.7 +/- 10.3 and 69.3 +/- 15.1 units/ml for normal subjects). In addition to the decreased relative percentage of CD4+ (OKT4+) lymphoid cells in CML patients, FACS-sorted CD4+ (OKT4+) cells also demonstrated a significant defect in IL-2 production, (10.8 +/- 3.6 units/ml as compared to 39.0 +/- 5.8 units/ml after 24 hr stimulation with 10 micrograms/ml PHA). FACS-sorted CD16+ (B73.1+) lymphoid cells from CML patients also demonstrated significantly decreased IL-2 production after 24 hr incubation with increasing concentrations of PHA or with the NK-sensitive target K562 as compared to normal controls. Defective IL-2 production by PBMs, CD4+ (OKT4+), and CD16+ (B73.1+) cells from CML patients was also evident after 48 hr of PHA stimulation. Although the percentages of both T4+2H4+ and T4+4B4+ subsets are significantly decreased in CML patients, CML patients have normal ratios of T4+4B4+/T4+2H4+ subsets as compared to normal controls. These and previous results support the hypothesis that decreased IL-2 production by both T-helper and NK cells from CML patients may be mechanistically related to the observed NK-cell immunodeficiency in CML patients.

Adult↗

PubMed1998

Mechanisms of resistance of HIV-1 primary isolates to complement-mediated lysis.

Previous studies suggested that HIV-1 primary isolates (PI) were resistant to complement-mediated lysis (CML), while virus produced in certain T cell lines and virus taken directly from the plasma of HIV+ persons were both susceptible to CML. The purpose of this study was to investigate the mechanism(s) of PI resistance. PI were resistant to CML using pooled seropositive serum as an antibody source. Additionally, PI obtained from two patients at several times over 2 years were resistant to CML using autologous antibody. PI were also resistant to CML induced by monoclonal antibodies which neutralize a broad range of PI. Resistance to CML was associated with low binding of antibody to PI but was not due to low gp120 levels. Cell-line-derived virus and PI were equally sensitive to CML induced by antibody to host-cell proteins, suggesting that PBMC do not contribute properties to virions which make them more physically resistant to CML in general but that PI resistance is restricted to CML induced by antiviral antibody. These studies show that PI are resistant to CML mediated by various antiviral antibodies and indicate that low binding of antibody to virus is an important factor contributing to resistance.

Complement System Proteins↗

PubMed1986

Different characteristics of allogeneic and trinitrophenyl-modified H-2-restricted cell-mediated lympholysis: analysis of differences in interleukin-2 dependency using an ontogenical approach.

Ontogenical development of in vitro allogeneic cell-mediated lympholysis (CML) and in vitro trinitrophenyl (TNP)-modified CML was studied mainly in correlation with helper cell activity, using C3H/HeN and C57BL/6 mice. Allogeneic and TNP-modified CML were not detected in the spleen of these mice at 1 week after birth. Allogeneic CML was detectable, in parallel with increases in age. This activity in 5-week-old mice was much the same as in the 8-week-old mice but the TNP-modified CML did not appear until 8 weeks after birth. Exogenous interleukin-2 (IL-2) induced sufficient activity of TNP-modified CML, even in spleen cells from 1-week-old mice, while the same treatment had a weak but significant effect on the induction of allogeneic CML in these same cells. Experiments on the mixed lymphocyte reaction (MLR) in the presence of exogenous IL-2 showed that lymphocyte proliferation in response to TNP-modified cells was higher than that in response to allogeneic cells. These results suggest different dependencies on IL-2 between allogeneic and TNP-modified killer precursor cells. Endogenous IL-2 production and proliferative response in MLR showed that helper cells contributing to the TNP-modified CML matured later, compared to allogeneic CML. Different sensitivities to IL-2 in two types of CML, in addition to different ontogenical developments, suggest that cytotoxic T lymphocytes to allogeneic cells differ quantitatively and qualitatively from TNP-modified H-2-restricted killer cells.

Aging↗

PubMed2004

Donor chimerism does not predict response to donor lymphocyte infusion for relapsed chronic myelogenous leukemia after allogeneic hematopoietic cell transplantation.

We studied the effect of donor chimerism level on the outcome of donor lymphocyte infusion (DLI) therapy in 42 patients with persistent or relapsed hematologic malignancies after non-T cell-depleted allogeneic hematopoietic cell transplantation. Seventy-five percent of chronic myelogenous leukemia (CML) and 39% of non-CML patients entered remission after DLI therapy. Remission and survival rates were similar for CML patients irrespective of their pre-DLI donor chimerism levels; however, remission occurred sooner in patients with > or =10% pre-DLI donor chimerism. None of the non-CML patients with <10% pre-DLI donor chimerism and 47% of those with > or =10% pre-DLI donor chimerism attained remission. The 2-year survival rates after DLI were 75% for CML and 17% for non-CML patients. We conclude that a low level of donor marrow chimerism is not an adverse prognostic factor for response to DLI in CML patients, but for non-CML patients it may confer worse outcomes. Better methods to augment the response to DLI for patients with hematologic malignancies other than CML that recur after allogeneic hematopoietic cell transplantation are needed, whereas for relapsed CML patients, combination therapies including imatinib mesylate or other promising antileukemic agents may provide outcomes superior to those with DLI alone.

Adolescent↗

PubMed2003

Increased level of glycoxidation product N(epsilon)-(carboxymethyl)lysine in rat serum and urine proteins with aging: link with glycoxidative damage accumulation in kidney.

Accumulation of carboxymethylated proteins (CML-proteins) is taken as a biomarker of glycoxidative stress which is thought to contribute to the age-related impairment in tissue and cell function. To investigate the occurrence and extent of glycoxidative damage with aging in rat kidney, serum and urine, we have prepared a polyclonal antibody against CML-modified bovine serum albumin. We subsequently used it for immunolocalization and in enzyme-linked immunosorbent assays to evaluate CML-protein content. In the serum, CML-protein level was 1.43+/-0.14 pmol CML/micrograms protein at 3 months and significantly increased by 50% from 10 to 27 months (1.50+/-0.14 pmol CML/micrograms protein vs 2.27+/-0.26 pmol CML/micrograms protein), albumin and transferrin being the main modified proteins. In the urine, CML-protein level was 2.50+/-0.14 pmol CML/micrograms protein at 3 months and markedly increased from 10 months (2.99+/-0.24 pmol CML/micrograms protein) to 27 months (3.76+/-0.25 pmol CML/micrograms protein), with albumin as the main excreted modified protein. Immunolocalization of CML-proteins in kidney provided evidence for an age-dependent increased accumulation in extracellular matrices. Intense staining of the glomerular basement membrane (GBM), Bowman's capsule, and the tubular basement membrane was found. Additionally, the CML content for collagen from GBM was 195.85+/-28.95 pmol CML/microgrms OHPro at 3 months and significantly increased from 10 months (187.61+/-21.99 pmol CML/micrograms OHPro) to 27 months (334.55+/-62.21 pmol CML/micrograms OHPro). These data show that circulating CML-protein level in serum and urine and CML accumulation in nephron extracellular matrices with aging are increasing in parallel. The CML-protein measurement in serum and urine may thus be used as an index for the assessment of age-associated glycoxidative kidney damage.

Aging↗

PubMed2002

Peripheral blood leucocytes ornithine decarboxylase activity in chronic myeloid leukemia patients: prognostic and therapeutic implications.

Leukocytes ornithine decarboxylase (ODC) activity was measured in normal individuals and in patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP) as well as in accelerated phase (CML-AP), with an aim to examine the role of ODC activity in prognostic evaluation of CML patients. Our results showed that ODC activity was significantly higher in CML-CP (41.02+/-25.57nmol/h per 10(7) cells, P<0.005) and CML-AP (67.71+/-44.42nmol/h per 10(7) cells, P<0.001) patients than in normal subjects (3.12+/-1.34nmol/h per 10(7) cells). Furthermore, patients with CML-AP showed higher ODC activity than CML-CP patients (P<0.005). Patients with CML-CP who converted to accelerated phase within 24 months had higher ODC activity (84.58+/-12.81nmol/h per 10(7) cells) than patients who did not convert to accelerated phase (31.13+/-18.24nmol/h per 10(7) cells). The high value of ODC activity was also associated with less clinico-hematological response. We suggest that ODC activity reflects the neoplastic proliferative activity in CML patients and may serve as an additional prognostic marker.

Adolescent↗

PubMed1990

Reaction of ascorbate with lysine and protein under autoxidizing conditions: formation of N epsilon-(carboxymethyl)lysine by reaction between lysine and products of autoxidation of ascorbate.

N epsilon-(Carboxymethyl)lysine (CML) has been identified as a product of oxidation of glucose adducts to protein in vitro and has been detected in human tissue proteins and urine [Ahmed, M. U., Thorpe, S. R., & Baynes, J. W. (1986) J. Biol. Chem. 261, 4889-4894; Dunn, J. A., Patrick, J. S., Thorpe, S. R., & Baynes, J. W. (1989) Biochemistry 28, 9464-9468]. In the present study we show that CML is also formed in reactions between ascorbate and lysine residues in model compounds and protein in vitro. The formation of CML from ascorbate and lysine proceeds spontaneously at physiological pH and temperature under air. Kinetic studies indicate that oxidation of ascorbic acid to dehydroascorbate is required. Threose and N epsilon-threuloselysine, the Amadori adduct of threose to lysine, were identified in the ascorbate reaction mixtures, suggesting that CML was formed by oxidative cleavage of N epsilon-threuloselysine. Support for this mechanism was obtained by identifying CML as a product of reaction between threose and lysine and by analysis of the relative rates of formation of threuloselysine and CML in reactions of ascorbate or threose with lysine. The detection of CML as a product of reaction of ascorbate and threose with lysine suggests that other sugars, in addition to glucose, may be sources of CML in proteins in vivo. The proposed mechanism for formation of CML from ascorbate is an example of autoxidative glycosylation of protein and suggests that CML may also be an indicator of autoxidative glycosylation of proteins in vivo.

Ascorbic Acid↗

PubMed2001

Allosterically controllable maxizyme-mediated suppression of progression of leukemia in mice.

Chronic myelogenous leukemia (CML) is a hematopoietic malignant disease associated with expression of a chimeric BCR-ABL gene. We recently succeeded in designing a novel allosterically controllable ribozyme, the maxizyme (Tanabe et al. Biomacromolecules 2000, 1, 108-117; Kuwabara et al. Biomacromolecules 2001, 2, 788-799), that not only specifically cleaves BCR-ABL mRNA and induces apoptosis in cultured CML cells but also shows significant inhibition against the growth of an established BV173 cell line in a mouse model (Tanabe et al. Nature 2000, 406, 473-474). As an extension of our studies, we tested the maxizyme against primary CML cells in the same mouse model. The maxizyme under the control of a tRNA(Val) promoter showed significant inhibition against the growth of the primary bone marrow cells from a Japanese patient with CML. Specifically, to examine the applicability of the maxizyme in the treatment of CML, we assessed the antitumor effect of the maxizyme in murine models of CML. Fourteen weeks after the injection of primary CML cells into a NOD-SCID mouse, the bone marrow of the mouse was filled with primary CML cells as a result of diffuse leukemia. In marked contrast, when maxizyme-expressing primary CML cells were injected, the mouse remained disease-free. These results further strengthen our earlier suggestion that the maxizyme technology might provide a useful approach to the treatment of CML.

Allosteric Regulation↗

PubMed2006

Concentrations of Nepsilon-carboxymethyllysine in human breast milk, infant formulas, and urine of infants.

Maillard products, such as Nepsilon-carboxymethyllysine (CML), are readily formed during the manufacturing of infant formulas. Little has been known, however, about the presence of CML in human breast milk and about the uptake of CML by infants. In this study, CML was measured in the serum and breast milk of 32 healthy mothers by ELISA. CML concentrations in breast milk (137 +/- 82.7 ng/mL) were significantly lower than in the serum (399 +/- 67.8 ng/mL, p < 0.001) and on average 35-fold lower than in infant formulas (4754 +/- 4299.5 ng/mL). CML was also measured in the urine of 21 infants, which were fed with breast milk or formulas. Although there was a tendency toward higher urinary CML excretion in infants fed with hypoallergenic formulas compared to breast-fed ones, the differences were not significant. Neonates that were delivered by vaginal birth had significantly higher concentrations of CML compared to those delivered by caesarean section (1306 +/- 653 vs 601 +/- 220 ng/mL, p = 0.012). It is concluded that CML passes from the serum into the breast milk, but the levels are by far lower than in infant formulas. In very young neonates (< or =3 days), the mode of delivery has a greater influence on urinary CML excretion than the nutrition.

Breast Feeding↗

PubMed1998

Chronic myelogenous leukaemia CD34+ cells exit G0/G1 phases of cell cycle more rapidly than normal marrow CD34+ cells.

To investigate the mechanisms behind the leukaemic expansion of chronic myelogenous leukaemia (CML), we examined the cell cycle status and activation kinetics of purified subpopulations of CD34+ cells from normal and CML bone marrow (BM). Propidium iodide staining was used to assess cell cycle status of fresh cells or those stimulated with cytokines. Although the cell cycle status of fresh low-density cells from CML and normal BM was similar, a larger percentage of CML CD34+ cells were cycling than those from normal BM. The HLA-DR compartment of CML CD34+ cells, a fraction enriched for normal, non-leukaemic progenitors, contained a higher percentage of quiescent cells than the CD34+ HLA-DR+ fraction. When the activation of CD34+ cells was examined in response to SCF or IL-3 alone, or SCF+IL-3+IL-6, CML CD34+ cells exited GO/G1 more rapidly than normal CD34+ cells. Interestingly, although normal BM CD34+ cells failed to cycle in response to IL-6 alone, or in the absence of exogenous cytokines, 30% of CML cells cycled under these conditions. No differences in the degree of apoptosis were documented among CML and normal CD34+ cells in these cultures. These data suggest that enhanced cell cycle activation of CML CD34+ cells, by either autocrine stimuli or via enhanced sensitivity to exogenous stimuli, may be partially responsible for the pronounced cellular expansion characteristic of CML.

Adult↗

PubMed2001

Abnormal growth factor modulation of beta1-integrin-mediated adhesion in chronic myelogenous leukaemia haematopoietic progenitors.

Abnormal progenitor circulation and extramedullary haematopoiesis are characteristic features of chronic myelogenous leukaemia (CML). Growth factor (GF) and beta1-integrin interactions play an important role in regulation of progenitor trafficking to and from the marrow space. CML progenitors demonstrate abnormal beta1-integrin-mediated adhesion to fibronectin (FN). In the present study we investigated whether GF modulation of beta1-integrin-mediated adhesion and migration was altered in CML progenitors. Culture with low concentrations of GF enhanced normal progenitor adhesion to FN compared with no GF, but failed to enhance CML progenitor adhesion to FN. Similarly, high concentrations of selected GF rapidly enhanced beta1-integrin-mediated adhesion of normal progenitors to FN through a phosphotidylinositol-3 (PI-3) kinase-dependent mechanism, but failed to increase CML progenitor adhesion. Exposure to a BCR-ABL tyrosine kinase inhibitor restored GF modulation of CML progenitor adhesion. CML colony-forming cells (CFC) demonstrated increased migration across FN-coated transwells compared with normal CFC in the absence of GF. The addition of stem cell factor resulted in enhanced migration of CML and normal CFC on FN. In conclusion, GF stimulation failed to enhance integrin-mediated adhesion but enhanced migration in CML progenitors on FN. BCR-ABL induced abnormalities in GF-integrin interactions could contribute to abnormal circulation and microenvironmental localization of CML progenitors.

Androstadienes↗

PubMed1995

Mechanism of protein modification by glyoxal and glycolaldehyde, reactive intermediates of the Maillard reaction.

The role of glyoxal and glycolaldehyde in protein cross-linking and N epsilon-(carboxymethyl)lysine (CML) formation during Maillard reaction under physiological conditions was investigated. Incubation of bovine serum albumin with these reagents lead to rapid formation of C-2-imine cross-links and CML. Initial CML formation rate from glyoxal was not dependent on oxidation, suggesting an intramolecular Cannizzaro reaction. CML formation from glucose/lysine or Amadori product of both was strongly dependent on oxidation. Blocking of Amadori product by boric acid totally suppressed CML formation from Amadori product, but only by 37% in the glucose/lysine system. Trapping of glyoxal with aminoguanidine hardly suppressed CML formation from Amadori product, whereas it blocked 50% of CML production in the glucose/lysine system. While these results would support a significant role for glucose autoxidation in CML formation, the addition of lysine to a glucose/aminoguanidine incubation system catalyzed glyoxal-triazine formation 7-fold, thereby strongly suggesting that glucose autoxidation is not a factor for glyoxal-mediated CML formation. Based on these results, it can be estimated that approximately 50% of the CML forming in a glucose/lysine system originates from oxidation of Amadori product, and 40-50% originates from a pre-Amadori stage largely independent from glucose autoxidation. This step may be related to the so-called Namiki pathway of the Maillard reaction.

Acetaldehyde↗

PubMed2004

Purification, characterization, and sugar binding specificity of an N-Glycolylneuraminic acid-specific lectin from the mushroom Chlorophyllum molybdites.

A carbohydrate-binding protein was isolated from the carpophores of the mushrooms and designated the Chlorophyllum molybdites lectin (CML) based on its origin. The molecular mass of CML was 32 kDa, and it was composed of two 16-kDa monomers with no disulfide bonds. Monosaccharide analysis indicated that 12% of the mass of CML was carbohydrate and consisted of GlcNAc:GalNAc:Gal:Man:l-Fuc in a molar ratio of 1.5:1.9: 4.4:4.8:1.0. In the hemagglutination inhibition assay, CML exhibited the strongest binding specificity toward N-glycolylneuraminic acid (NeuGc) among the monosaccharides tested, whereas NeuAc did not inhibit the hemagglutination at all. GalNAc and Mealpha-GalNAc were also inhibitory at much higher concentrations than NeuGc. Among the glycoproteins, asialobovine submaxillary mucin (BSM) and porcine stomach mucin (PSM) showed strong inhibitory effects. In surface plasmon resonance analysis, asialo-BSM and PSM exhibited the strongest binding affinity. After co-injection of CML and NeuGc or GalNAc onto the asialo-BSM- or PSM-immobilized chip, the dissociation of CML from the immobilized PSM was accelerated by NeuGc and GalNAc, but the dissociation of CML from the immobilized asialo-BSM was only promoted by GalNAc. These results and the other surface plasmon resonance experiments allowed us to conclude that the binding of asialo-BSM to CML was because of an interaction between the lectin and the GalNAc residues of asialo-BSM, and both the NeuGc and GalNAc residues were responsible for the binding of PSM to CML. The results also suggested that CML had two different carbohydrate binding domains, one specific for NeuGc and the other for GalNAc.

Agaricales↗