Tadashi Jono

Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) serves as an endothelial receptor for advanced glycation end products (AGE)

Advanced glycation end products (AGE) are known to serve as ligands for the scavenger receptors such as SR‐A, CD36 and SR‐BI. In the current study, we examined whether AGE is recognized by lectin‐like oxidized low density lipoprotein receptor‐1 (LOX‐1). Cellular binding experiments revealed that AGE‐bovine serum albumin (AGE‐BSA) showed the specific binding to CHO cells overexpressing bovine LOX‐1 (BLOX‐1), which was effectively suppressed by an anti‐BLOX‐1 antibody. Cultured bovine aortic endothelial cells also showed the specific binding for AGE‐BSA, which was suppressed by 67% by the anti‐BLOX‐1 antibody. Thus, LOX‐1 is identified as a novel endothelial receptor for AGE.

Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation

Abstract To assess a role for oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS), we analyzed the immunohistochemical localization of 8-hydroxy-2′-deoxyguanosine (OHdG) as a nucleic acid oxidation product, acrolein-protein adduct and 4-hydroxy-2-nonenal (HNE)-protein adduct as lipid peroxidation products, Nɛ-carboxymethyl-lysine (CML) as a lipid peroxidation or protein glycoxidation product, pentosidine as a protein glycoxidation product, and imidazolone and pyrraline as nonoxidative protein glycation products in the spinal cord of three familial ALS patients with superoxide dismutase-1 (SOD1) A4V mutation, six sporadic ALS patients, and six age-matched control individuals. The spinal cord sections of the control cases did not show any distinct immunoreactivities for these examined products. In the familial ALS cases, intense immunoreactivities for pyrraline and CML were confined to the characteristic Lewy body-like hyaline inclusions, and imidazolone immunoreactivity was located in the cytoplasm of the residual motor neurons. No significant immunoreactivities for other examined products were detected in the familial ALS spinal cords. In the sporadic ALS cases, intense immunoreactivities for pentosidine, CML and HNE-protein adduct were seen in the cytoplasm of the degenerated motor neurons, and OHdG immunoreactivity was located in the cell nuclei of the residual neurons and glial cells. The present results indicate that oxidative reactions are involved in the disease processes of sporadic ALS, while there is no evidence for increased oxidative damage except for CML deposition in the familial ALS spinal cords. Furthermore, it is likely that the accumulation of pyrraline and imidazolone supports a nonoxidative mechanism in SOD1-related motor neuron degeneration.

Glycoxidation and lipid peroxidation of low-density lipoprotein can synergistically enhance atherogenesis

OBJECTIVE The purpose of this study was to clarify the role of glycoxidation and lipid peroxidation of low-density lipoprotein (LDL) in atherogenesis. METHODS AND RESULTS We examined the formation of N(epsilon)-(carboxymethyl) lysine (CML), a glycoxidation product, and malondialdehyde (MDA), a lipid peroxidation product, in vitro and their co-localization in human atherosclerotic lesions. Immunochemical analysis revealed that CML was formed in a time-dependent manner by human LDL incubated with copper ions and glucose, i.e. an in vitro model of glycoxidation of LDL. When LDL was exposed to copper ions alone, a small amount of CML was formed, however this was significantly less in oxidized LDL than glycoxidative LDL. In contrast, MDA formation was observed in both oxidation and glycoxidation of LDL, but not in glycation of LDL. Hexitol-lysine (HL), an Amadori product, was formed by both glycation and glycoxidation of LDL, but not by oxidation of LDL. Immunohistochemical analysis showed that CML and MDA accumulated mainly in macrophage/foam cells, while pyrraline, a non-oxidative product of glycation, and apolipoprotein B were localized in the extracellular matrix in atherosclerotic lesions. Atheromas were positive for CML and MDA, but negative for pyrraline. Macrophage/foam cells in atherosclerotic lesions exhibited co-localization of macrophage scavenger receptor-A with CML and MDA, but not with pyrraline. CONCLUSION Our results suggest that glycoxidation and lipid peroxidation of LDL synergistically promote the development of atherosclerotic lesions through interaction with macrophage scavenger receptor-A.

Accumulation of imidazolone, pentosidine and Nε-(carboxymethyl)lysine in hippocampal CA4 pyramidal neurons of aged human brain

Previous studies from our laboratory demonstrated that Nɛ‐(carboxymethyl)lysine (CML), one of the major advanced glycation end products (AGE), was accumulated in human pyramidal neurons in the hippocampus in an age‐dependent manner. This suggests a potential link between AGE‐accumulation and the aging process in neurons. The purpose of the present study was to examine whether this notion could be extended to other AGE structures, such as imidazolone and pentosidine. This was done using 19 human brains that were not affected by dementia. The immunohistochemical survey on distribution in brain tissues of imidazolone and pentosidine was carried out with monoclonal antibodies specific for imidazolone and pentosidine. A parallel control experiment was carried out with anti‐CML antibody. The results showed that pentosidine and imidazolone were localized in neurons in different areas of human brain tissue, especially in neurons of CA4 in the hippocampus. The characteristic distribution of pentosidine and imidazolone is very similar to that of CML. Furthermore, when the accumulation of these AGE structures was compared with the age of individual brains it was found that accumulation of imidazolone, pentosidine and CML in the CA4 region increased with age. These findings taken together support the notion that the accumulation of AGE structures in the CA4 region might be closely related to the aging process in neurons.

Association between depression, examination-related stressors, and sense of coherence: The ronin-sei study

In the Japanese education system, students who fail university entrance exam often go to special preparatory schools to prepare for the following years exam. These students are called ronin‐sei. The purpose of this study was to clarify: (i) depression and somatic complaints in ronin‐sei; and (ii) the association between depression, examination‐related stressors, and sense of coherence (SOC).

Detection of 3-deoxyglucosone-derived AGE structures in vitro

Abstract In the Maillard reaction, 3-deoxyglucosone (3-DG) was known to generate from Amadori product and contribute to further AGE formation such as I a -(carboxymethyl)lysine (CML), 3-DG-derived imidazolone (3-DG-imidazolone) and pyrraline. However, main AGE structures generated from 3-DG modification have not yet been elucidated. To solve this issue, we set up the detection system for AGE by immunochemical analysis as well as high-performance liquid chromatography (HPLC) and determined them in 3-DG-modified bovine serum albumin (BSA). When BSA was incubated at 37 °C for up to 4 weeks with 3-DG, the reactivity of antibodies against CML and 3-DG-imidazolone increased steeply with incubation time, whereas the reactivity of antibodies against pyrraline was increased slightly. In contrast, in addition to CML and 3-DG-imidazolone, significant amount of pyrraline was observed when AGE formation was enhanced by high temperature at 60 °C. In HPLC analysis, CML (1.10 mol/mol of BSA), 3-DG-imidazolone (0.84 mol/mol of BSA) and pyrraline (0.33 mol/mol of BSA) were detected in BSA incubated with 3-DG at 37 °C for 4 weeks. Taken together, our analyses clarified that formation of CML and 3-DG-imidazolone is higher than that of pyrraline during the incubation of protein with 3-DG.

Effect of lamotrigine in the treatment of bipolar depression with psychotic features: a case report

BackgroundMajor depressive episodes with psychotic features are more common in bipolar disorder than in major depressive disorder; however, there is little information on the optimal treatment for bipolar depression with psychotic features.Case presentationThe patient was a 69-year-old man. At the age of 66, he was admitted to the hospital for the treatment of bipolar depression with psychotic features. He was treated with a combination therapy of antipsychotics and antidepressants during long-term hospitalization. At the age of 69, he relapsed and was admitted to the hospital again. He was initially treated with olanzapine and lithium for the treatment of bipolar depression with psychotic features. He partially responded to the combination therapy, and psychomotor retardation and delusion of guilt disappeared; however, he developed psychomotor agitation and delusion of persecution, which was a mood-incongruent psychotic feature. Finally, he fully recovered with an additional dosage of lamotrigine, and had no experience of relapse after discontinuation of olanzapine.ConclusionsThis case report implicates the utility of lamotrigine for bipolar depression with psychotic features, and further studies are needed to establish the optimal treatment.