Schizophrenia (SZ) is characterized by a high morbidity and disability rate and has gradually increased in rate and caused much burden. However, the pathogenesis of SZ is elusive and may include changes in the biological molecules in exosomes. In this study, we first compared the alterations of plasma exosomal circular RNAs (exo-circRNAs) from SZ patients and matched health controls by high-throughput sequencing. We further explored whether plasma exo-circRNAs can be estimable targets for researching the pathogenesis, potential diagnostic biomarkers, and therapeutic strategy of SZ. A total of 44 plasma exo-circRNAs were differentially expressed between SZ patients and matched Health Controls, including 38 upregulated circRNAs and six downregulated circRNAs (fold change ≥2; p < .05). Eight differentially expressed circRNAs were verified by quantitative real-time polymerase chain reaction, and four out of eight circRNAs were positively confirmed and contained binding sites to many microRNAs. Bioinformatics analysis, including Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis, showed that these differentially expressed circRNAs played potential roles in pathogenesis, especially regarding the metabolic process, stress response, and histone ubiquitination. In conclusion, this study supplies a new window for understanding the pathogenesis of SZ at molecular levels, and serves as a tool for better exploring potential diagnostic biomarkers and the therapeutic strategy for SZ. K E Y W O R D S circular RNA, high-throughput sequencing, pathogenesis, plasma exosomes, schizophrenia 1 | INTRODUCTION With the development of modern society and emergence of a fastpaced life, the incidence of psychiatric disorders has gradually increased, and causes much burden. Schizophrenia (SZ), a psychiatric disorder, affects approximately 1% of population globally, but the disability rate of over 83% causes a heavy burden to patients, families, and society (Z. Wang et al., 2015). SZ is a disabling mental disorder featured by severe disturbances in thought, behavior, and emotion, including psychotic symptoms (positive or negative) and cognitive impairment (Alonso et al., 2011). Management of SZ, including prevention, diagnosis, and therapy, has become of increasingly central interest among physicians. Therefore, it makes sense to concentrate on the early precise diagnosis of SZ and improve the prognosis of SZ in medicine and healthcare by the neuroscience community. We know that both genetic and environmental factors are involved in the pathogenesis of SZ. Among genetic factors, SZ is Guifeng Tan and Limin Wang are joint first authors.

Background: Additional mechanisms of temozolomide (TMZ) resistance in gliomas remain uncertain.The aim of this study was to identify another DNA repair mechanism involving forkhead box O1 (FoxO1) and replicator C2 (RFC2) in gliomas. Methods:We established glioma cells against TMZ, U87R, by exposure to TMZ. Proliferation rate Cell counting kit-8 (CCK8) was used, and epithelial-mesenchymal transition (EMT)-related markers were detected by western blot. The association between FoxO1 and RFC2 was analyzed by heat maps and scatter plot, and Real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were used to detect the effect of FoxO1 on the expression of RFC2. The regulation effect of FoxO1 on RFC2 expression was analyzed by luciferase reporter gene assay. Knockdown of FoxO1/RFC2 was achieved via short hairpin RNA (shRNA), the effect of knockdown on the proliferation was determined by CCK8 assay and colony formation assay, and apoptosis was examined by flow cytometry and immunoblotting. Results:The TMZ-resistant glioma cell line, U87R, was established. The FoxO1 and RFC2 proteins increased significantly in U87R. The expression of FoxO1 and RFC2 were positively related in glioma tissues. We found that FoxO1 contributes to TMZ resistance and cell survival via regulating the expression of RFC2. Moreover, FoxO1 functions as a transcriptional activator to RFC2 by binding to the promoter of RFC2. Furthermore, knockdown of FoxO1/RFC2 suppressed cell proliferation, TMZ resistance, and induced apoptosis in U87R. Conclusions:The FoxO1/RFC2 signaling pathway promotes glioma cell proliferation and TMZ resistance, suggesting that the FoxO1/RFC2 pathway may be a potential target for TMZ-resistant glioma therapy.

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