Previous studies have shown glutamatergic dysfunction and γ-aminobutyric acid (GABA)-ergic dysfunction in schizophrenia. Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) dysfunction and GABA-ergic dysfunction interact with each other and lead to alterations in excitatory/inhibitory balance. The NMDAR and GABAergic-interneuron functions may be indexed by mismatch negativity (MMN) and auditory steady-state gamma-band response (ASSR), respectively. However, no previous studies have tested the hypothesis of an abnormal association between MMN and gamma-band ASSR in the same patients to identify the in vivo evidence of NMDAR-GABA association during the early stages of psychosis. Participants were individuals with recent-onset schizophrenia (ROSZ; N = 21), ultra-high risk (UHR; N = 27), and healthy controls (HCs; N = 24). The MMN amplitude was significantly impaired in ROSZ (p = 0.001, d = 1.20) and UHR (p = 0.003, d = 1.01) compared with HCs. The intertrial phase coherence (ITC) index of gamma-band ASSR was significantly reduced in ROSZ compared with HCs (p < 0.001, d = –1.27) and UHR (p = 0.032, d = –0.75). The event-related spectral perturbation (ERSP) index of gamma-band ASSR was significantly smaller in ROSZ compared with HCs (p < 0.001, d = −1.21). The MMN amplitude was significantly correlated with the ITC in ROSZ (r = −0.69, p < 0.001). These findings provide the first in vivo evidence that an abnormal association of the electrophysiological indices of NMDAR and GABA dysfunctions may be present in recent-onset schizophrenia.

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Previous studies have revealed several genes involved in the carcinogenesis of oral cancer. However, the detailed mechanisms underlying this process are poorly understood. Previously, we established a database cataloging the transcriptional progression profile of oral carcinogenesis and identified several candidate genes with continuously increasing or decreasing expression, which specifically promote the transition of oral premalignant lesions to invasive carcinomas. In this study, using our microarray database, we attempted to determine significant genes that may contribute to metabolic alterations during oral carcinogenesis. After performing a literature survey, we focused on 15 candidate genes associated with glucose metabolism changes, particularly the tri-carboxylic acid cycle, and investigated the mRNA-expression status of these genes with our database. Only the solute carrier family 2 member 1 gene (also known as GLUT1), showed significantly increased mRNA expression during oral tumorigenesis. Immunohistochemical analysis confirmed that GLUT1 protein expression significantly increased during oral carcinogenesis. In addition, tumors with high expression of this protein significantly correlated with nodal status (P=0.002). Kaplan-Meier survival curves clearly demonstrated the adverse impact of high GLUT1 protein expression on disease-free survival (P=0.004). GLUT1 mRNA and protein expression increased in the order of normal mucosal tissues, epithelial dysplastic lesions and invasive carcinomas. Therefore, metabolic alterations, especially in glucose metabolism, occurred at the very early stage of development of oral malignancies. In addition, GLUT1 played a significant role in oral cancer, acquiring a malignant phenotype.

Bone metabolism is strictly regulated, and impaired regulation caused by hormonal imbalances induces systemic bone loss. Local bone loss caused by tumor invasion into bone is suggested to be induced by the generation of cytokines, which affect bone metabolism, by tumor cells. The major cause of systemic and local bone losses is excess bone resorption by osteoclasts, which differentiate from macrophages by receptor activator of nuclear factor kappa-B ligand (RANKL) or tumor necrosis factor-alpha (TNF-α). We previously found a novel pathway for tumor-induced osteoclastogenesis targeting osteoclast precursor cells (OPCs). Tumor-induced osteoclastogenesis was resistant to RANKL and TNF-α inhibitors. In the present study, we confirmed that exosomes derived from oral squamous cell carcinoma (OSCC) cells induced osteoclasts from OPCs. We also showed that the depletion of exosomes from culture supernatants of OSCC cells partially interfered with osteoclastogenesis, and cannabidiol, an innoxious cannabinoid without psychotropic effects, almost completely suppressed tumor-induced osteoclastogenesis. Osteoclastogenesis and its interference by cannabidiol were independent of the expression of nuclear factor of T cell c1 (NFATc1). These results show that osteoclastogenesis induced by OSCC cells targeting OPCs is a novel osteoclastogenic pathway independent of NFATc1 expression that is partially caused by tumor-derived exosomes and suppressed by cannabidiol.