Sulforaphane Induces Transient Reactive Oxygen Species-Mediated DNA Damage in HeLa Cells.

Sulforaphane (SFN), an isothiocyanate found in plants of the Brassicaceae family, possesses antioxidant, apoptosis-inducing, and radiosensitizing effects. As one of the mechanisms of cytotoxicity by SFN, SFN has been suggested to be involved in the induction of DNA damage and inhibition of DNA repair. Recently, we reported on the potency of SFN in inducing single-ended double-strand breaks (DSBs) that are caused by the collision of replication forks with single-strand breaks (SSBs).

Anthocyanins as potent inhibitors of pentosidine synthesis: Antioxidant-mediated effects.

Pentosidine (PEN), an advanced glycation end product (AGE), is associated with various age-related diseases and schizophrenia. This study aimed to identify the natural compounds that inhibit PEN synthesis from glucuronic acid using an in vitro system. A screening of 93 natural compounds revealed 47 that reduced PEN synthesis by > 50 %, with eight inhibiting it by > 80 %.

The origin of esterase activity of Parkinson's disease causative factor DJ-1 implied by evolutionary trace analysis of its prokaryotic homolog HchA.

DJ-1, a causative gene for hereditary recessive Parkinsonism, is evolutionarily conserved across eukaryotes and prokaryotes. Structural analyses of DJ-1 and its homologs suggested the 106th Cys is a nucleophilic cysteine functioning as the catalytic center of hydratase or hydrolase activity. Indeed, DJ-1 and its homologs can convert highly electrophilic α-oxoaldehydes such as methylglyoxal into α-hydroxy acids as hydratase in vitro, and oxidation-dependent ester hydrolase (esterase) activity has also been reported for DJ-1.

Association of homocysteine with white matter dysconnectivity in schizophrenia.

Several studies have shown white matter (WM) dysconnectivity in people with schizophrenia (SZ). However, the underlying mechanism remains unclear. We investigated the relationship between plasma homocysteine (Hcy) levels and WM microstructure in people with SZ using diffusion tensor imaging (DTI).

Glucuronic acid is a novel source of pentosidine, associated with schizophrenia.

Pentosidine (PEN) is an advanced glycation end-product (AGEs), where a fluorescent cross-link is formed between lysine and arginine residues in proteins. Accumulation of PEN is associated with aging and various diseases. We previously reported that a subpopulation of patients with schizophrenia showed PEN accumulation in the blood, having severe clinical features.

Urinary exosomal microRNAs as predictive biomarkers for persistent psychotic-like experiences.

Psychotic-like experiences (PLEs) occur occasionally in adolescence and mostly disappear with increasing age. Their presence, if persistent, is considered a robust risk factor for subsequent psychiatric disorders. To date, only a few biological markers have been investigated for persistent PLE prediction.

A Cell System-Assisted Strategy for Evaluating the Natural Antioxidant-Induced Double-Stranded DNA Break (DSB) Style.

Natural antioxidants derived from plants exert various physiological effects, including antitumor effects. However, the molecular mechanisms of each natural antioxidant have not yet been fully elucidated. Identifying the targets of natural antioxidants with antitumor properties in vitro is costly and time-consuming, and the results thus obtained may not reliably reflect in vivo conditions.

Hair zinc levels and psychosis risk among adolescents.

Recent meta-analyses have shown lower zinc and higher copper levels in the serum of people with schizophrenia than in healthy controls. However, the relationship between trace elements (TEs) and the pathophysiology of psychosis, including schizophrenia, remains unclear due to the antipsychotic effects on mineral levels. In this study, we aimed to determine the relationship between zinc and copper levels in hair and psychosis risk among drug-naïve adolescents.

Role of advanced glycation end products in the longitudinal association between muscular strength and psychotic symptoms among adolescents.

Muscular strength, assessed by handgrip, is a risk indicator for psychiatric disorders, including psychosis. However, the biological mechanisms underlying this association remain unclear. Since advanced glycation end products (AGEs) play a key role in skeletal muscle underdevelopment and psychosis, we examined the role of AGEs in the longitudinal association between muscular strength and psychotic symptoms among adolescents.

Exonic deletions in IMMP2L in schizophrenia with enhanced glycation stress subtype.

We previously identified a subtype of schizophrenia (SCZ) characterized by increased plasma pentosidine, a marker of glycation and oxidative stress (PEN-SCZ). However, the genetic factors associated with PEN-SCZ have not been fully clarified. We performed a genome-wide copy number variation (CNV) analysis to identify CNVs associated with PEN-SCZ to provide an insight into the novel therapeutic targets for PEN-SCZ.

Role of glyoxalase 1 in methylglyoxal detoxification-the broad player of psychiatric disorders.

Methylglyoxal (MG) is a highly reactive α-ketoaldehyde formed endogenously as a byproduct of the glycolytic pathway. To remove MG, various detoxification systems work together in vivo, including the glyoxalase system, which enzymatically degrades MG using glyoxalase 1 (GLO1) and GLO2. Recently, numerous reports have shown that GLO1 expression and MG accumulation in the brain are involved in the pathogenesis of psychiatric disorders, such as anxiety disorder, depression, autism, and schizophrenia.

High-sucrose diets contribute to brain angiopathy with impaired glucose uptake and psychosis-related higher brain dysfunctions in mice.

Metabolic dysfunction is thought to contribute to the severity of psychiatric disorders; however, it has been unclear whether current high–simple sugar diets contribute to pathogenesis of these diseases. Here, we demonstrate that a high-sucrose diet during adolescence induces psychosis-related behavioral endophenotypes, including hyperactivity, poor working memory, impaired sensory gating, and disrupted interneuron function in mice deficient for glyoxalase-1 (GLO1), an enzyme involved in detoxification of sucrose metabolites. Furthermore, the high-sucrose diet induced microcapillary impairments and reduced brain glucose uptake in brains of -deficient mice.

Fingertip advanced glycation end products and psychotic symptoms among adolescents.

Case control studies have suggested that advanced glycation end products play a key role in the pathophysiology of chronic schizophrenia. However, the longitudinal association between advanced glycation end products and psychotic symptoms among drug-naïve adolescents remains unclear. This study examined whether advanced glycation end products could predict the trajectory of psychotic symptoms in drug-naive adolescents using data from prospective population-based biomarker subsample study of the Tokyo Teen Cohort.

Combined glyoxalase 1 dysfunction and vitamin B6 deficiency in a schizophrenia model system causes mitochondrial dysfunction in the prefrontal cortex.

Methylglyoxal (MG) is a reactive and cytotoxic α-dicarbonyl byproduct of glycolysis. Our bodies have several bio-defense systems to detoxify MG, including an enzymatic system by glyoxalase (GLO) 1 and GLO2. We identified a subtype of schizophrenia patients with novel mutations in the GLO1 gene that results in reductions of enzymatic activity.

Dysregulation of post-transcriptional modification by copy number variable microRNAs in schizophrenia with enhanced glycation stress.

Previously, we identified a subpopulation of schizophrenia (SCZ) showing increased levels of plasma pentosidine, a marker of glycation and oxidative stress. However, its causative genetic factors remain largely unknown. Recently, it has been suggested that dysregulated posttranslational modification by copy number variable microRNAs (CNV-miRNAs) may contribute to the etiology of SCZ.

Advanced glycation end products and cognitive impairment in schizophrenia.

Advanced glycation end products play a key role in the pathophysiology of schizophrenia. Cognitive impairment is one of the central features of schizophrenia; however, the association between advanced glycation end products and cognitive impairment remains unknown. This study investigated whether advanced glycation end products affect the cognitive domain in patients with schizophrenia.

Vitamin B6 deficiency hyperactivates the noradrenergic system, leading to social deficits and cognitive impairment.

We have reported that a subpopulation of patients with schizophrenia have lower levels of vitamin B (VB6) in peripheral blood than do healthy controls. In a previous study, we found that VB6 level was inversely proportional to the patient's positive and negative symptom scale (PANSS) score for measuring symptom severity, suggesting that the loss of VB6 might contribute to the development of schizophrenia symptoms. In the present study, to clarify the relationship between VB6 deficiency and schizophrenia, we generated VB6-deficient (VB6(-)) mice through feeding with a VB6-lacking diet as a mouse model for the subpopulation of schizophrenia patients with VB6 deficiency.

Accumulation of Carbonyl Proteins in the Brain of Mouse Model for Methylglyoxal Detoxification Deficits.

Recent studies have shown that carbonyl stress is a causative factor of schizophrenia, categorized as carbonyl stress-related schizophrenia (CS-SCZ). However, the correlation between carbonyl stress and the pathogenesis of this disease is not well established. In this study, glyoxalase 1(Glo1)-knockout and vitamin B6-deficient mice (KO/VB6 (-) mice), which are susceptible to methylglyoxal (MGO)-induced oxidative damages, were used as a CS-SCZ model to analyze MGO-modified protein and the carbonyl stress status in the brain.

Evolution of DNA methylation in the human brain.

DNA methylation is a critical regulatory mechanism implicated in development, learning, memory, and disease in the human brain. Here we have elucidated DNA methylation changes during recent human brain evolution. We demonstrate dynamic evolutionary trajectories of DNA methylation in cell-type and cytosine-context specific manner.