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Bipolar disorder is a mental illness that causes extreme mood swings and has a chronic course. However, the mechanism by which mood episodes with completely opposite characteristics appear repeatedly, or a mixture of symptoms appears, in patients with bipolar disorder remains unknown. Therefore, mood stabilizers are indicated only for single mood episodes, such as manic episodes and depressive episodes, and no true mood-stabilizing drugs effective for treating both manic and depressive episodes currently exist. Therefore, in this review, therapeutic targets that facilitate the development of mood stabilizers were examined by reviewing the current understanding of the neuromolecular etiology of bipolar disorder.

Caudal-type homeobox 2 (CDX2), special AT-rich sequence-binding protein 2 (SATB2), and keratin 20 (KRT20) are frequently used as intestinal epithelium-specific markers in immunohistochemical studies. However, subsets of colorectal carcinomas (CRCs) show loss of these markers. We analyzed The Cancer Genome Atlas data to explore molecular correlates of CDX2, SATB2, and KRT20 genes in 390 CRCs. The decreased mRNA expression of each of the three genes commonly correlated with microsatellite instability-high (MSI-H), CpG island methylator phenotype-high (CIMP-H), BRAF/RNF43 mutations, consensus molecular subtype 1, and high tumor mutational burden. The downregulation of CDX2 or SATB2 was dependent on both MSI-H and CIMP-H, whereas that of KRT20 was more dependent on MSI-H than on CIMP-H. Next, we evaluated the immunohistochemical expression of CDX2, SATB2, and KRT20 in 436 primary CRCs. In contrast to RNA-level expression, decreased expression of CDX2 and SATB2 was more dependent on CIMP-H than on MSI-H. However, consistent with RNA-level expression, decreased expression of KRT20 was more dependent on MSI-H than on CIMP-H. CIMP-H and lymphatic invasion were consistently associated with both CDX2 loss and SATB2 loss in CRCs, regardless of MSI status. In microsatellite stable CRCs, CDX2 loss correlated with BRAF mutation, whereas SATB2 loss was associated with KRAS mutations and decreased T-cell infiltration. Cases with concurrent loss of all three markers were found exclusively in MLH1-methylated MSI-H/CIMP-H CRCs. In conclusion, MSI-H and/or CIMP-H are major common correlates of decreased CDX2/SATB2/KRT20 expression in CRCs, but the specific features associated with the loss of each marker are different in CRCs.

Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent cause of familial Parkinson’s disease (PD). The increase in LRRK2 kinase activity observed in the pathogenic G2019S mutation is important for PD development. Several studies have reported that increased LRRK2 kinase activity and treatment with LRRK2 kinase inhibitors decreased and increased ciliogenesis, respectively, in mouse embryonic fibroblasts (MEFs) and retinal pigment epithelium (RPE) cells. In contrast, treatment of SH-SY5Y dopaminergic neuronal cells with PD-causing chemicals increased ciliogenesis. Because these reports were somewhat contradictory, we tested the effect of LRRK2 kinase activity on ciliogenesis in neurons. In SH-SY5Y cells, LRRK2 inhibitor treatment slightly increased ciliogenesis, but serum starvation showed no increase. In rat primary neurons, LRRK2 inhibitor treatment repeatedly showed no significant change. Little difference was observed between primary cortical neurons prepared from wild-type (WT) and G2019S+/- mice. However, a significant increase in ciliogenesis was observed in G2019S+/- compared to WT human fibroblasts, and this pattern was maintained in neural stem cells (NSCs) differentiated from the induced pluripotent stem cells (iPSCs) prepared from the same WT/G2019S fibroblast pair. NSCs differentiated from G2019S and its gene-corrected WT counterpart iPSCs were also used to test ciliogenesis in an isogenic background. The results showed no significant difference between WT and G2019S regardless of kinase inhibitor treatment and B27-deprivation-mimicking serum starvation. These results suggest that LRRK2 kinase activity may be not a direct regulator of ciliogenesis and ciliogenesis varies depending upon the cell type or genetic background.

We investigated the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, on a depression-like phenotype in mice exposed to chronic unpredictable stress (CUS). Learning and memory were also assessed using the Morris water maze (MWM) test.Liraglutide (0.3 mg/kg/day for 21 days) was administered to mice with or without exposure to CUS. After 21 days of CUS, the forced swim test (FST) was performed to assess its antidepressant effect. To evaluate cognitive function, liraglutide was administered to mice under stress-free conditions for 21 days, and then the MWM test was performed on 6 consecutive days.Chronic liraglutide treatment reduced FST immobility in mice with and without CUS. In the probe trial of the Morris water maze test, the search error rate was reduced and the time spent and path length in the target quadrant and the number of platform crossings were increased.Additional animal model experiments and molecular level studies are needed to support the results obtained in this study.Liraglutide appears to exert antidepressant effects and could improve cognitive function. Based on these results, GLP-1 agonists could have potential as novel antidepressants.

Background: Detecting microsatellite instability (MSI) in colorectal cancers (CRCs) is essential since it is therapeutic strategy determinant feature, including immunotherapy and chemotherapy. Yet, no attempt has been made to exploit transcriptomic profile and tumor microenvironment (TME) of it to unveil MSI status in CRC. Methods: Hence, we developed a novel TME-aware, single-transcriptome predictor of MSI for CRC, called MAP (Microsatellite instability Absolute single sample Predictor). MAP was developed utilizing recursive feature elimination-random forest with 466 CRC samples from The Cancer Genome Atlas, and its performance was validated in independent cohorts, including 1118 samples. Results: MAP showed robustness and predictive power in predicting MSI status in CRC. Additional advantages for MAP were demonstrated through comparative analysis with existing MSI classifier and other cancer types. Conclusions: Our novel approach will provide access to untouched vast amounts of publicly available transcriptomic data and widen the door for MSI CRC research and be useful for gaining insights to help with translational medicine.

Detecting microsatellite instability (MSI) in colorectal cancers (CRCs) is essential since it is therapeutic strategy determinant feature, including immunotherapy and chemotherapy. Yet, no attempt has been made to exploit transcriptomic profile and tumor microenvironment (TME) of it to unveil MSI status in CRC. Hence, we developed a novel TME-aware, single-transcriptome predictor of MSI for CRC, called MAP (Microsatellite instability Absolute single sample Predictor). MAP was developed utilizing recursive feature elimination-random forest with 466 CRC samples from The Cancer Genome Atlas, and its performance was validated in independent cohorts, including 1118 samples. MAP showed robustness and predictive power in predicting MSI status in CRC. Additional advantages for MAP were demonstrated through comparative analysis with existing MSI classifier and other cancer types. Our novel approach will provide access to untouched vast amounts of publicly available transcriptomic data and widen the door for MSI CRC research and be useful for gaining insights to help with translational medicine.

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Background: Characterising the tumor microenvironment (TME) and immune landscape of cancer has been a promising step towards discovering new therapeutic biomarkers and guiding precision medicine; however, its application in salivary mucoepidermoid carcinoma (MEC) has been sparse. Here, we conducted a comprehensive transcriptomic study to understand the properties of the TME and immune profiles of MEC.Methods: Molecular features in heterogeneous immunophenotypic subgroups of MEC and their intrinsic characteristics were determined by applying bioinformatic and immunoinformatic analyses on 20 matched primary MEC RNA-seq data.Results: In this study, distinct two immunophenotypic subgroups, hot and cold MECs, were uncovered with their distinct molecular features, and potential immune-oncologic therapeutic options for each subgroup were suggested. In search for immunophenotype defining molecular features, tumor mutational burden, CRTC1-MAML2 fusion status, and its fusion neoantigen were not discriminable factors. However, we demonstrate that a significant inverse correlation between lipid metabolism activity and immunogenic state, and lipid metabolic regulators, such as MLXIPL and FASN, which are associated suppression of immune activity, were under-expressed in the immune-hot subgroup, contributing significant role in high immunity of immune active subgroup.Conclusions: Our study has shown heterogeneous immunophenotypic MEC subgroups with their distinctive molecular characteristics and provided potential treatment options tailored to the immune context, which yields, for the first time, new insights into TME of MEC and may help the next step to studying this uncharted cancer.

Alpha-synuclein (αSyn) is a major component of Lewy bodies, which are a known pathogenic marker of Parkinson's disease (PD). The dysfunction of protein degradation machinery causes αSyn accumulation. The reinforcement of αSyn degradation is a potential therapeutic target for PD because accumulated αSyn is responsible for the pathogenesis of PD. Nucleolin (NCL) is essential in the formation of the nucleolar structure. The function of NCL is correlated with oxidative stress-mediated cell death. A previous study demonstrated that NCL overexpression alleviated rotenone-induced neurotoxic effects, whereas knockdown of NCL had the opposite effect. These results suggest that NCL malfunction would exacerbate PD pathology. Thus, it was hypothesized that the introduction of ectopic NCL could rescue α-synucleinopathy in PD. This study investigated whether the ectopic expression of NCL facilitates αSyn clearance. Ectopic expression of NCL was accomplished via the transfection of green fluorescent protein (GFP) or GFP-NCL in mouse embryonic fibroblasts (MEF) or transduction of GFP or GFP-NCL using lentivirus in rat primary cortical neurons and mouse substantia nigra. NCL overexpression enhanced the clearance of accumulated or aggregated αSyn in MEFs and rat primary cortical neurons. The activity of the autophagy-lysosome pathway was enhanced by NCL expression. NCL transduction in the substantia nigra, which was co-injected with αSyn fibrils, rescued PD manifestation. The elevation of NCL levels may reflect a therapeutic strategy for α-synucleinopathy in PD.

BackgroundNTRK fusions are emerging tissue-agnostic drug targets in malignancies including colorectal cancers (CRCs), but their detailed landscape in the context of various colorectal carcinogenesis pathways remains to be investigated.MethodsPan-TRK expression was assessed by immunohistochemistry in retrospectively collected colorectal epithelial tumor tissues, including 441 CRCs (133 microsatellite instability-high (MSI-high) and 308 microsatellite stable (MSS)) and 565 premalignant colorectal lesions (300 serrated lesions and 265 conventional adenomas). TRK-positive cases were subjected to next-generation sequencing and/or fluorescence in situ hybridization to confirm NTRK rearrangements.ResultsTRK positivity was not observed in any of the MSS CRCs, conventional adenomas, traditional serrated adenomas, or hyperplastic polyps, whereas TRK positivity was observed in 11 of 58 (19%) sporadic MSI-high CRCs, 4 of 23 (17%) sessile serrated lesions with dysplasia (SSLDs), and 5 of 132 (4%) SSLs. The 11 TRK-positive MSI-high CRCs commonly harbored CpG island methylator phenotype-high (CIMP-high), MLH1 methylation, KRAS/BRAF wild-type, and NTRK1 or NTRK3 fusion (TPM3-NTRK1, TPR-NTRK1, LMNA-NTRK1, SFPQ-NTRK1, ETV6-NTRK3, or EML4-NTRK3). Both NTRK1 or NTRK3 rearrangement and KRAS/BRAF wild-type were detected in all nine TRK-positive SSL(D)s, seven of which demonstrated MSS and/or CIMP-low. TRK overexpression and early dysplastic changes are occasionally co-localized in the crypt base area of SSLs. Age-related occurrence patterns suggest that the progression interval from NTRK-rearranged SSLs to CRCs may be shorter than from BRAF-mutated SSLs to CRCs.ConclusionNTRK-rearranged colorectal tumors develop exclusively through the serrated neoplasia pathway and can be initiated from non-dysplastic SSLs without KRAS/BRAF mutations prior to full occurrence of MSI-high/CIMP-high.

Background. Leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the pathogenesis of Parkinson’s disease (PD). Aging is the most critical risk factor for the progression of PD. The correlation between aging and cellular senescence has been established. Cellular senescence is correlated with the dysregulation of the proteolytic pathway and mitochondrial dysfunction, which are also associated with the aggregation of α-synuclein (α-syn). Methods. Human dopaminergic neuron-like cells (differentiated SH-SY5Y cells) were treated with rotenone in the presence or absence of the LRRK2 kinase inhibitor GSK2578215A (GSK-KI) for 48 h. The markers of cellular senescence, including p53, p21Waf1/Cip1 (p21), β-galactosidase (β-gal), Rb phosphorylation, senescence-associated (SA) β-gal activity, and lysosomal activity, were examined. The dSH cells and rat primary cortical neurons were treated with α-syn fibrils 30 min before treatment with rotenone in the presence or absence of GSK-KI for 48 h. Mice were intraperitoneally injected with rotenone and MLi-2 (LRRK2 kinase inhibitor) once every two days for two weeks. Results. Rotenone upregulated LRRK2 phosphorylation and β-gal levels through the activation of the p53-p21 signaling axis and downregulated Rb phosphorylation. Additionally, rotenone upregulated SA β-gal activity, reactive oxygen species levels, and LRRK2 phosphorylation and inhibited lysosome activity. Rotenone-induced LRRK2 upregulation impaired the clearance of α-syn fibrils. Treatment with LRRK2 inhibitor mitigated rotenone-induced cellular senescence and α-syn accumulation. Conclusions. Rotenone-induced upregulation of LRRK2 kinase activity promoted cellular senescence, which enhanced α-syn accumulation. However, the administration of an LRRK2 kinase inhibitor rejuvenated rotenone-induced cellular senescence.

In several rodent models, acute administration of the metabotropic glutamate 2/3 (mGlu2/3) receptor antagonist LY341495 induced antidepressant-like effects via a mechanism of action similar to that of ketamine. However, the effects of chronic mGlu2/3 antagonism have not yet been explored. Therefore, we investigated the effects of chronic LY341495 treatment on the mechanistic target of rapamycin complex 1 (mTORC1) signaling and the levels of synaptic proteins in mice subjected to chronic unpredictable stress (CUS). LY341495 (1 mg/kg) was administered daily for 4 weeks to mice with and without CUS exposure. After the final treatment, the forced swimming test (FST) was used to assess antidepressant-like effects. The hippocampal levels of mTORC1-related proteins were derived by Western blotting. Chronic LY341495 treatment reversed the CUS-induced behavioral effects of FST. CUS significantly reduced the phosphorylation of mTORC1 and downstream effectors [eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP-1) and small ribosomal protein 6 (S6)], as well as the expression of synaptic proteins postsynaptic density-95 (PSD-95) and AMPA receptor subunit GluR1 (GluA1) in the hippocampus. However, chronic LY341495 treatment rescued these deficits. Our results suggest that the activation of hippocampal mTORC1 signaling is related to the antidepressant effect of chronic LY341495 treatment in an animal model of CUS-induced depression.

Early life stress (ELS) causes long-lasting changes in depression-like behaviors through epigenetic mechanisms. However, little is known about the effects of ELS in adulthood, specifically across different age groups. In this study, the epigenetic modifications of p11 expression in adult mice subjected to ELS were investigated in different stages of adulthood. Pups experienced maternal separation (MS) for 3 h daily from postnatal day 1 to 21. At young and middle adulthood, behavior phenotypes, hippocampal p11 expression levels, and levels of histone acetylation and methylation and DNA methylation at the hippocampal p11 promoter were measured. Middle-aged, but not young adult, MS mice exhibited depression-like behavior in the forced swimming test. Concurrent with reduced hippocampal p11 levels, mice in both age groups showed decreases in histone acetylation and activating histone methylation as well as increases in repressive histone methylation at the p11 promoter. The extent of the reduction in gene expression and histone acetylation was much higher in middle than in young adulthood. Moreover, DNA methylation analysis of the p11 promoter revealed increased CpG methylation in middle-aged MS mice only. The results highlight the age-dependent deleterious effects of ELS on depression-like behavior and on the epigenetic modifications of p11 transcription.

Bipolar disorder (BPD) is a severe mental illness characterized by episodes of depression and mania. To investigate the molecular mechanisms underlying the pathophysiology of bipolar disorder, we performed transcriptome studies using RNA-seq data from the prefrontal cortex (PFC) of individuals with BPD and matched controls, as well as data from cell culture and animal model studies. We found 879 differentially expressed genes that were also replicated in an independent cohort of post-mortem samples. Genes involving the mechanistic target of rapamycine (mTOR) pathway were down-regulated, while genes interrelated with the mTOR pathway such as Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway were up-regulated. Gene co-expression network analyses identified a module related to the mTOR pathway that was up-regulated in BPD and also enriched for markers of endothelial cells. We also found a down-regulated co-expression module enriched for genes involved in mTOR signalling and in mTOR related pathways and enriched with neuronal markers. The mTOR related modules were also replicated in the independent cohort of samples. To investigate whether the expression of the modules related to mTOR signalling pathway could be differentially regulated in different cell types we performed comparative network analyses in experimental models. We found both up-regulated modules in the PFC significantly overlapped with an up-regulated module in the brain endothelial cells from mice treated with lipopolysaccharides (LPS) and mTOR related pathways such as JAK-STAT, PI3K-Akt and ribosome were enriched in the common genes. In addition, the down-regulated module in the PFC significantly overlapped with a down-regulated module from neurons treated with the mTOR inhibitor, Torin1 and mTOR signalling, autophagy, and synaptic vesicle cycles were significantly enriched in the common genes. These results suggest that co-expression networks related to mTOR signalling pathways may be up- or down-regulated in different cell types in the PFC of BPD. These results provide novel insights into the molecular mechanisms underlying the pathophysiology of BPD.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Simple Summary A platform and normalization bias agnostic single sample classifier (SSC) is needed. A random forest SSC (MiniABS) utilizing 11 genes was developed and validated. MiniABS surpassed previous classifiers and can be applied on multiple platforms. MiniABS may provide a cost-effective strategy for the diagnosis of breast cancer. Abstract While intrinsic molecular subtypes provide important biological classification of breast cancer, the subtype assignment of individuals is influenced by assay technology and study cohort composition. We sought to develop a platform-independent absolute single-sample subtype classifier based on a minimal number of genes. Pairwise ratios for subtype-specific differentially expressed genes from un-normalized expression data from 432 breast cancer (BC) samples of The Cancer Genome Atlas (TCGA) were used as inputs for machine learning. The subtype classifier with the fewest number of genes and maximal classification power was selected during cross-validation. The final model was evaluated on 5816 samples from 10 independent studies profiled with four different assay platforms. Upon cross-validation within the TCGA cohort, a random forest classifier (MiniABS) with 11 genes achieved the best accuracy of 88.2%. Applying MiniABS to five validation sets of RNA-seq and microarray data showed an average accuracy of 85.15% (vs. 77.72% for Absolute Intrinsic Molecular Subtype (AIMS)). Only MiniABS could be applied to five low-throughput datasets, showing an average accuracy of 87.93%. The MiniABS can absolutely subtype BC using the raw expression levels of only 11 genes, regardless of assay platform, with higher accuracy than existing methods.

Background Alpha-synuclein (αSyn) is a major component of Lewy bodies, which are known to be a pathogenic marker of Parkinson’s disease (PD). The accumulation of αSyn is caused by dysfunctions in protein degradation machinery. The reinforcement of αSyn degradation is a potential therapeutic target of PD since accumulated αSyn is responsible for the pathogenesis of PD. Nucleolin (NCL) is essential for forming nucleolar structure. The function of NCL is correlated with oxidative stress-mediated cell death. A previous study demonstrated that NCL was reduced in PD brains, and overexpression of NCL alleviated rotenone-induced neural toxic effects. Knockdown of NCL had the opposite effect. These results suggest that the malfunctioning of NCL would exacerbate PD pathology. Thus, we hypothesized that the introduction of ectopic NCL could rescue the α-synucleinopathy in PD. Methods We tested whether ectopic expression of NCL facilitates the clearance of αSyn. The Ectopic expression of NCL was accomplished by the transfection of GFP or GFP-NCL in mouse embryonic fibroblasts (MEF) or transduction of green fluorescent protein (GFP) or GFP-NCL using lentivirus in rat primary cortical neuron. We also investigated whether the expression of GFP or GFP-NCL in mouse substantia nigra alleviates the PD pathology derived by αSyn aggregates. Results The expression of NCL enhanced the clearance of αSyn accumulation or aggregates in MEF and rat primary cortical neurons. The activity of autophagy-lysosome pathway was enhanced by NCL expression. The transduction of NCL in the substantia nigra, which was co-injected with αSyn fibrils, rescued PD manifestations. Conclusions The elevation of NCL levels may reflect a therapeutic strategy for α-synucleinopathy in PD.

Growing evidence suggests that early life stress (ELS) has long-lasting effects on glucocorticoid receptor (GR) expression and behavior via epigenetic changes of the GR exon 17 promoter. However, it remains unclear whether ELS regulates histone modifications of the GR exon 17 promoter across the life span. We investigated the effects of maternal separation (MS) on histone acetylation and methylation of GR exon 17 promoter in the hippocampus, according to the age of adults. Depression-like behavior and epigenetic regulation of GR expression were examined at young and middle adulthood in mice subjected to MS from postnatal day 1 to 21. In the forced swimming test, young adult MS mice showed no effect on immobility time, but middle-aged MS mice significantly increased immobility time. Young adult and middle-aged MS mice showed decreased GR expression. Their two ages showed decreased histone acetylation with increased histone deacetylases (HDAC5) levels, decreased permissive methylation, and increased repressive methylation at the GR exon 17 promoter. The extent of changes in gene expression and histone modification in middle adulthood was greater than in young adulthood. These results indicate that MS in early life causes long-term negative effects on behavior via histone modification of the GR gene across the life span.

Recent studies have demonstrated that antipsychotic drugs may activate mammalian target of rapamycin complex 1 (mTORC1) signaling in neurons. However, the relationship between mTORC1 signaling activation and currently prescribed antipsychotic drugs remains incompletely understood. The purpose of this study was to determine whether alterations in the level of mTORC1 signaling occur after rat primary hippocampal neurons are treated with olanzapine and haloperidol under toxic conditions. Additionally, we investigated whether these drugs affect dendritic outgrowth and synaptic protein expression through the mTORC1 signaling pathway. We measured changes in mTORC1-mediated and synaptic proteins by Western blotting assay under toxic conditions induced by B27 deprivation. Dendritic outgrowth was determined by a neurite assay. Olanzapine significantly increased the phosphorylated levels of mTORC1, its downstream effectors, and its upstream activators. The increased mTORC1 phosphorylation induced by olanzapine was significantly blocked by specific PI3K, MEK, or mTORC1 inhibitors. Olanzapine also increased dendritic outgrowth and synaptic proteins levels; all of these effects were blocked by rapamycin. However, haloperidol had none of these effects. We demonstrated that olanzapine, but not haloperidol, activated the mTORC1 signaling pathway and increased dendritic outgrowth and synaptic proteins by activating mTORC1 signaling in rat primary hippocampal neurons. These findings suggest that olanzapine affects neuroplasticity by activating mTORC1 signaling.

BackgroundColorectal cancers (CRCs) with microsatellite instability-high (MSI-H) are hypermutated tumors and are generally regarded as immunogenic. However, their heterogeneous immune responses and underlying molecular characteristics remain largely unexplained.MethodsWe conducted a retrospective analysis of 73 primary MSI-H CRC tissues to characterize heterogeneous immune subgroups. Based on combined tumor-infiltrating lymphocyte (TIL) immunoscore and tertiary lymphoid structure (TLS) activity, MSI-H CRCs were classified into immune-high, immune-intermediate, and immune-low subgroups. Of these, the immune-high and immune-low subgroups were further analyzed using whole-exome and transcriptome sequencing.ResultsWe found considerable variations in immune parameters between MSI-H CRCs, and immune subgrouping of MSI-H CRCs was performed accordingly. The TIL densities and TLS activities of immune-low MSI-H CRCs were comparable to those of an immune-low or immune-intermediate subgroup of microsatellite-stable CRCs. There were remarkable differences between immune-high and immune-low MSI-H CRCs, including their pathological features (medullary vs mucinous), genomic alterations (tyrosine kinase fusions vs KRAS mutations), and activated signaling pathways (immune-related vs Wnt and Notch signaling), whereas no significant differences were found in tumor mutational burden (TMB) and neoantigen load. The immune-low MSI-H CRCs were subdivided by the consensus molecular subtype (CMS1 vs CMS3) with different gene expression signatures (mesenchymal/stem-like vs epithelial/goblet-like), suggesting distinct immune evasion mechanisms. Angiogenesis and CD200 were identified as potential therapeutic targets in immune-low CMS1 and CMS3 MSI-H CRCs, respectively.ConclusionsMSI-H CRCs are immunologically heterogeneous, regardless of TMB. The unusual immune-low MSI-H CRCs are characterized by mucinous histology, KRAS mutations, and Wnt/Notch activation, and can be further divided into distinct gene expression subtypes, including CMS4-like CMS1 and CMS3. Our data provide novel insights into precise immunotherapeutic strategies for subtypes of MSI-H tumors.

Objective In the current study, we investigated whether there are relations among depressive symptoms, cognitive performance and serum BDNF levels in the patients with chronic kidney disease (CKD). Methods Sixty patients with CKD and 65 healthy controls participated. Depressive symptoms were evaluated with Beck depression inventory (BDI) and Hamilton Depression Rating Scale (HDRS). Mini-Mental State Examination included in the Korean version of the Consortium to Establish a Registry for Alzheimer's disease (MMSE-KC) assessment packet was used for the evaluation of overall cognitive function. To assess memory function, the Korean version of the Hopkins Verbal Learning Test (K-HVLT) was used. BDNF levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit. Results The CKD patients showed more depressive symptoms when compared with controls. The depressive symptoms and cognitive function were not associated with serum BDNF levels in the CKD patients. Conclusion In the current study, CKD patients had more depressive symptoms when compared controls. However, the serum BDNF levels of CKD patients were not associated with depressive symptoms and cognitive functions. These findings suggested that the serum BDNF levels may not be reflect the cognitive function and depressive mood state in the CKD patients.

Aim Early life stress can induce epigenetic changes through genetic and environmental interactions and is a risk factor for depression. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and antidepressant drug action. We investigated epigenetic changes at the BDNF exon I promoter in the hippocampus of adult rats subjected to maternal separation (MS) during early life and treated with an antidepressant drug as adults. Methods Rat pups were subjected to MS from postnatal day 1 to 21 and received chronic escitalopram (ESC) as adults. We assessed the effects of MS and ESC on BDNF exon I and DNA methyltransferases (DNMTs) mRNA levels (quantitative reverse-transcription polymerase chain reaction [qRT-PCR]), acetylated histone H3 and MeCP2 binding to the BDNF promoter I (chromatin immunoprecipitation followed by real-time PCR), and BDNF protein levels (enzyme-linked immunosorbent assay). Results The levels of BDNF protein, exon I mRNA, histone H3 acetylation, and DNMT1 and DNMT3a mRNA were altered in the MS group compared with the control group. Significant decreases were observed in the BDNF protein, exon I mRNA, and histone H3 acetylation levels and significant increases in DNMT1 and DNMT3a mRNA levels. The comparison between the MS + ESC and MS groups revealed significant increases in BDNF protein, exon I mRNA, and histone H3 acetylation levels and significant decreases in MeCP2 and DNMT1 and DNMT3a mRNA levels. Conclusion These findings indicate that MS induced epigenetic changes at the BDNF exon I promoter and these changes were prevented by antidepressant drug treatment during adulthood.

Glucocorticoid receptor (GR) promoter I7 is susceptible to epigenetic changes induced by environmental influences. Early life stress (ELS) has a persistent impact on GR expression, as well as behavior, in adult rodents via epigenetic changes of GR promoter I7. Moreover, various stressors can induce histone modifications in this region during adulthood. Thus, the present study aimed to investigate whether maternally separated (MS) rats exposed to chronic restraint stress (RS) would exhibit histone modifications of GR promoter I7 in the hippocampus. Rats were subjected to MS (3h per day) on postnatal days (PND) 1-21. Then, during adulthood (PND 56-77), the rats were exposed to RS (2h per day) followed by treatment with escitalopram (10mg/kg). The MS and RS groups exhibited significant decreases in total and exon I7 GR mRNA levels and the combination of MS and RS exerted a greater effect on these mRNA levels than either MS or RS alone. Additionally, both the MS and RS groups showed significant reductions in histone H3 acetylation at GR promoter I7 and the combination of MS and RS had a greater effect than did either MS or RS alone. Chronic escitalopram treatment ameliorated these changes. The present results indicate that postnatal MS and adult RS influence GR expression through histone modification at GR promoter I7, and that the combination of the two stressors potentiates these changes. Furthermore, epigenetic mechanisms are involved in escitalopram action.

The group II metabotropic glutamate 2/3 (mGlu2/3) receptor antagonist LY341495 produces antidepressant-like effects by acting on mammalian target of rapamycin complex 1 (mTORC1) signaling and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors in rodent. We investigated whether LY341495 affects neuroplasticity via these mechanisms in rat primary hippocampal cultures under conditions of dexamethasone (DEX)-induced neurotoxicity. Ketamine was used for comparison. Hippocampal cultures were treated with LY341495 under conditions of DEX-induced toxicity. Changes in mTORC1-mediated proteins were determined by Western blotting analyses. Changes in dendritic outgrowth and spine density were evaluated via immunostaining. LY341495 significantly prevented DEX-induced decreases in the levels of mTORC1, 4E-BP1, and p70S6K phosphorylation as well as the levels of the synaptic proteins. These effects were blocked by pretreatment with the AMPA receptor inhibitor 2,3-dihydroxy-6-nitro-7sulfamoyl-benzo(f)quinoxaline (NBQX) and the mTORC1 inhibitor rapamycin. LY341495 significantly attenuated DEX-induced decreases in dendritic outgrowth and spine density. Pretreatment with rapamycin and NBQX blocked these effects of LY341495. Further analyses indicted that induction of BDNF expression produced by LY341495 was blocked by pretreatment with NBQX and rapamycin. LY341495 has neuroplastic effects by acting on AMPA receptor-mTORC1 signaling under neurotoxic conditions. Therefore, activation of AMPA receptor and mTORC1 signaling, which enhance neuroplasticity, may be novel targets for new antidepressants.

Melatonin is a hormone that is secreted by the pineal gland. To date, melatonin is known to regulate the sleep cycle by controlling the circadian rhythm. However, recent advances in neuroscience and molecular biology have led to the discovery of new actions and effects of melatonin. In recent studies, melatonin was shown to have antioxidant activity and, possibly, to affect the development of Alzheimer’s disease (AD). In addition, melatonin has neuroprotective effects and affects neuroplasticity, thus indicating potential antidepressant properties. In the present review, the new functions of melatonin are summarized and a therapeutic target for the development of new drugs based on the mechanism of action of melatonin is proposed.

Neuro-oncological ventral antigen 1 (NOVA1) is known as a neuron-specific pre-mRNA binding splicing factor. Previously, it was shown to be highly upregulated in T lymphocytes, as well as fibroblasts/stromal spindle cells, in tertiary lymphoid tissues formed by the benign immune-inflammatory process, while it was frequently downregulated in tumor cells and other cells within the tumor microenvironment. Here, we sought to identify the mechanisms of NOVA1 modulation in head and neck squamous cell carcinoma (HNSCC). NOVA1 was induced by inflammatory-immune signals within the tumor microenvironment and was suppressed by epigenetic dysregulation, such as that with miR-146. We found attenuated expression of NOVA1 to be associated with non-oropharynx sites such as oral cavity, hypopharynx, and larynx, human papilloma virus (HPV)-negative SCC defined by immunohistochemistry for p16INK4a expression, fewer tumor infiltrating lymphocytes, and poor patient outcomes. Moreover, changes were discovered in epithelial mesenchymal transition-associated markers according to NOVA1 status. This study provides some insights to the underlying mechanism of NOVA1 regulation and suggests that NOVA1 may serve as a prognostic biomarker and potential therapeutic target for HNSCC in the future.

Early life stress (ELS) exerts long-lasting epigenetic influences on the brain and makes an individual susceptible to later depression. It is poorly understood whether ELS and subsequent adult chronic stress modulate epigenetic mechanisms. We examined the epigenetic mechanisms of the BDNF gene in the hippocampus, which may underlie stress vulnerability to postnatal maternal separation (MS) and adult restraint stress (RS). Rat pups were separated from their dams (3 h/day from P1-P21). When the pups reached adulthood (8 weeks old), we introduced RS (2 h/day for 3 weeks) followed by escitalopram treatment. We showed that both the MS and RS groups expressed reduced levels of total and exon IV BDNF mRNA. Furthermore, RS potentiated MS-induced decreases in these expression levels. Similarly, both the MS and RS groups showed decreased levels of acetylated histone H3 and H4 at BDNF promoter IV, and RS exacerbated MS-induced decreases of H3 and H4 acetylation. Both the MS and RS groups had increased MeCP2 levels at BDNF promoter IV, as well as increased HDAC5 mRNA, and the combination of MS and RS exerted a greater effect on these parameters than did RS alone. In the forced swimming test, the immobility time of the MS + RS group was significantly higher than that of the RS group. Additionally, chronic escitalopram treatment recovered these alterations. Our results suggest that postnatal MS and subsequent adult RS modulate epigenetic changes in the BDNF gene, and that these changes may be related to behavioral phenotype. These epigenetic mechanisms are involved in escitalopram action.

Clinical and preclinical studies have reported that co-administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and antidepressant drugs are effective in patients with depression and in animal models of depression. However, several studies have suggested that NSAIDs inhibit the antidepressant effects of selective serotonin reuptake inhibitors in humans and mice. The present study investigated the effects of escitalopram (ESC) and ibuprofen (IBU), alone or in combination, on the stress-induced behavior and expression of brain-derived neurotrophic factor (BDNF) and p11, markers of depression and antidepressant action, in chronically stressed rats. Rats were subjected to chronic restraint stress (CRS) for 3 weeks and administered the following drugs: single administration of ESC or IBU or co-administration of ESC and IBU (ESC + IBU). Immobility time was measured by the forced swimming test (FST), and hippocampal BDNF and p11 levels were analyzed by quantitative real-time polymerase chain reaction and Western blotting. CRS increased immobility time on the FST. Administration of ESC, IBU, or ESC + IBU significantly attenuated the stress-induced increase in immobility time. CRS also significantly increased plasma corticosterone concentration by 169%. This effect was significantly recovered by administering ESC, IBU, or ESC + IBU. The levels of BDNF and p11 in the hippocampus decreased significantly in response to CRS. These decreases were prevented by administering ESC, IBU, or ESC + IBU. These findings suggest that both single and co-administration of ESC and IBU exerts antidepressant effects. These effects were associated with upregulation of BDNF and p11 expression.