Rhein promotes TRAIL-induced apoptosis in bladder cancer cells by up-regulating DR5 expression.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) combined with sensitizer is a potential method to reverse TRAIL-resistance in tumor cells. Rhein (RH) is a monomer extracted from Chinese herbs that has been reported to show anti-tumor effects in a variety of tumor cells, but the role of RH in TRAIL-induced anti-tumor effects in bladder cancer cells has not been reported. In this study, we found that the combined treatment of a non-toxic concentration of RH with TRAIL significantly inhibited the proliferation and induced apoptosis in both TRAIL sensitive and resistant bladder cancer cell lines. Furthermore, we found that RH promoted bladder cancer cell apoptosis by up-regulating DR5 expression. Our findings provide potential value in the clinical treatment of bladder cancer.

Downregulation of CRTC1 Is Involved in CUMS-Induced Depression-Like Behavior in the Hippocampus and Its RNA Sequencing Analysis.

Chronic stress is an important risk factor for mood disorders including depression. The decreased level of CREB (cAMP-responsive element binding)-regulated transcription coactivator 1 (CRTC1) expression in hippocampus may be involved in depression-like behavior in some stress-induced depression models. But the mechanism of CRTC1 in mediating depression-like behavior remains unknown. In this study, chronic unpredictable mild stress (CUMS)-treated mice showed depression-like behavior accompanied by the downregulation of CRTC1 in the hippocampus. Adeno-associated virus (AAV)-CRTC1-mediated overexpression of CRTC1 in the hippocampus by stereotactic brain injection could significantly prevent depression-like behavior in CUMS-treated mice. The above data reveal that the downregulation of hippocampal CRTC1 expression participates in CUMS-induced depression-like behavior. In order to explore the key targets regulated by CRTC1, AAV-mediated CRTC1 short hairpin (shRNA) was constructed to achieve knockdown of CRTC1 in the hippocampus, and then the hippocampi were collected for RNA-sequencing (RNA-seq). The RNA-seq data show that upregulated genes were enriched in stress and immune system-associated GO terms and pathways such as response to stress and external stimulus and regulation of immune response and that downregulated genes were enriched in neural activity such as synaptic transmission and cognitive behavior. We further provided RT-qPCR data that the inflammation-related factors including Gpr84, Tlr2, Lyz2, and Icam1 were significantly upregulated in the hippocampus of both CUMS- and CRTC1 shRNA-induced models, some of them were also validated in protein levels by Western blotting. We propose a hypothesis that CUMS induces downregulation of CRTC1, which might lead to depression-like behavior via neuroinflammation pathway. This study provides new explanation for the inflammatory hypothesis of depression and some clues for exploring the molecular mechanism of CRTC1 regulation.

Construction of an algorithm based on oncosis-related LncRNAs comprising the molecular subtypes and a risk assessment model in lung adenocarcinoma.

BACKGROUND: As an important non-apoptotic cell death method, oncosis has been reported to be closely associated with tumors in recent years. However, few research reported the relationship between oncosis and lung cancer. METHODS: In this study, we established an oncosis-based algorithm comprised of cluster grouping and a risk assessment model to predict the survival outcomes and related tumor immunity of patients with lung adenocarcinomas (LUAD). We selected 11 oncosis-related lncRNAs associated with the prognosis (CARD8-AS1, LINC00941, LINC01137, LINC01116, AC010980.2, LINC00324, AL365203.2, AL606489.1, AC004687.1, HLA-DQB1-AS1, and AL590226.1) to divide the LUAD patients into different clusters and different risk groups. Compared with patients in clsuter1, patients in cluster2 had a survival advantage and had a relatively more active tumor immunity. Subsequently, we constructed a risk assessment model to distinguish between patients into different risk groups, in which low-risk patients tend to have a better prognosis. GO enrichment analysis revealed that the risk assessment model was closely related to immune activities. In addition, low-risk patients tended to have a higher content of immune cells and stromal cells in tumor microenvironment, higher expression of PD-1, CTLA-4, HAVCR2, and were more sensitive to immune checkpoint inhibitors (ICIs), including PD-1/CTLA-4 inhibitors. The risk score had a significantly positive correlation with tumor mutation burden (TMB). The survival curve of the novel oncosis-based algorithm suggested that low-risk patients in cluster2 have the most obvious survival advantage. CONCLUSION: The novel oncosis-based algorithm investigated the prognosis and the related tumor immunity of patients with LUAD, which could provide theoretical support for customized individual treatment for LUAD patients.

Identification of an Autophagy-Related lncRNA Prognostic Signature and Related Tumor Immunity Research in Lung Adenocarcinoma.

Autophagy is closely associated with the tumor immune microenvironment (TIME) and prognosis of patients with lung adenocarcinoma (LUAD). In the present study, we established a signature on the basis of long noncoding RNAs (lncRNAs) related to autophagy (ARlncRNAs) to investigate the TIME and survival of patients with LUAD. We selected ARlncRNAs associated with prognosis to construct a model and divided each sample into different groups on the basis of risk score. The ARlncRNA signature could be recognized as an independent prognostic factor for patients with LUAD, and patients in the low-risk group had a greater survival advantage. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis suggested that several immune functions and pathways were enriched in different groups. A high-risk score correlated significantly negatively with high abundance of immune cells and stromal cells around the tumor and high tumor mutational burden. Low-risk patients had a higher PD-1, CTLA-4, and HAVCR2 expression and had a better efficacy of immune checkpoint inhibitors, including PD-1/CTLA-4 inhibitor. A reliable signature on the basis of ARlncRNAs was constructed to explore the TIME and prognosis of patients with LUAD, which could provide valuable information for individualized LUAD treatment.

Construction of an immune-related lncRNA signature as a novel prognosis biomarker for LUAD.

The tumor immune microenvironment of lung cancer is associated with prognosis and immunotherapy efficacy. Long noncoding RNAs are identified as prognostic biomarkers associated with immune functions. We constructed a signature comprising differentially expressed immune-related lncRNAs to predict the prognosis of patients with lung adenocarcinoma. We established the immune-related lncRNA signature by pairing immune-related lncRNAs regardless of expression level and lung adenocarcinoma patients were divided into high- and low-risk groups. The prognosis of patients in the two groups was significantly different; The immune-related lncRNA signature could serve as an independent lung adenocarcinoma prognostic indicator. The signature correlated negatively with B cell, CD4+ T cell, M2 macrophage, neutrophil, and monocyte immune infiltration. Patients with low risk scores had a higher abundance of immune cells and stromal cells around the tumor. Gene set enrichment analysis showed that samples from low-risk group were more active in the IgA production in intestinal immune network and the T and B cell receptor signaling pathway. High-risk groups had significant involvement of the cell cycle, DNA replication, adherens junction, actin cytoskeleton regulation, pathways in cancer, and TGF-ß signaling pathways. High risk scores correlated significantly negatively with high CTLA-4 and HAVCR2 expression and higher median inhibitory concentration of common anti-tumor chemotherapeutics (e.g., cisplatin, paclitaxel, gemcitabine) and targeted therapy (e.g., erlotinib and gefitinib). We identified a reliable immune-related lncRNA lung adenocarcinoma prognosis model, and the immune-related lncRNA signature showed promising clinical prediction value.

Dysregulated CRTC1-BDNF signaling pathway in the hippocampus contributes to Aß oligomer-induced long-term synaptic plasticity and memory impairment.

Expression of CREB-regulated transcription coactivator 1 (CRTC1) in the hippocampus is impaired in Alzheimer's disease (AD). However, CRTC1 related mechanisms associated with long-term synaptic plasticity impairment and cognitive decline in the onset of AD are unknown. In this study, electrophysiological recordings indicated that lentivirus-mediated CRTC1 overexpression effectively ameliorates suppression of late-phase long-term potentiation (L-LTP) in rat hippocampal slices treated with oligomeric amyloid ß(1-42) peptides (oAß42) (200 nM). In addition, application of oAß42 and genetic knockdown of CRTC1 by lentivirus-mediated CRTC1-shRNA inhibit L-LTP, whereas their combination does not further impair L-LTP. Brain-derived neurotrophic factor (BDNF), an important downstream protein confers protection of CRTC1 overexpression against oAß42-induced L-LTP impairment as shown by administration of K252a (200 nM) and TrkB-FC (20 µg/ml). Furthermore, behavioral and western blotting analyses showed that CRTC1 overexpression reverses oAß42-induced hippocampal-dependent cognitive deficits, downregulation of CRTC1 and BDNF expression. Notably, CRTC1-shRNA directly elicits cognitive deficits. In summary, these findings show that hippocampal CRTC1 signaling is affected by soluble oAß, and CRTC1-BDNF pathway is involved in hippocampal L-LTP impairment and memory deficits induced by oAß42.

Adeno-associated virus-mediated over-expression of CREB-regulated transcription coactivator 1 in the hippocampal dentate gyrus ameliorates lipopolysaccharide-induced depression-like behaviour in mice.

Depression is a highly complex global disabling psychiatric disorder. Unfortunately, the currently available antidepressants are not effective in a significant percentage of patients. Therefore, the underlying mechanisms of depression must be explored at the molecular level to discover new candidate molecular targets for depression treatment. Behavioural and molecular depression-like endophenotypes have been observed in cyclic AMP response element-binding protein-regulated transcription coactivator 1 (Crtc1) knockout mice; however, the underlying mechanism for these endophenotypes remains unclear. This work investigated the role of hippocampal CREB-regulated transcription coactivator 1 (CRTC1) in depression using a recombinant adeno-associated virus (AAV) system to alter Crtc1 gene expression and explore its potential mechanism. We found that shRNA-mediated Crtc1 gene knockdown (AAV-shCRTC1) in the dentate gyrus regions of the ventral hippocampus directly resulted in depression-like behaviours and down-regulation of brain-derived neurotrophic factor and neuropeptide VGF levels. A widely used depression model induced by lipopolysaccharide administration (0.5 mg/kg, i.p.) was applied in our study and was validated by increased immobility time in the tail-suspension and forced swim tests and decreased sucrose consumption in the sucrose preference test. Importantly, CRTC1 over-expression mediated by AAV-CRTC1 in the ventral dentate gyrus regions prevented lipopolysaccharide-induced depressive-like behaviours, the down-regulation of brain-derived neurotrophic factor and VGF, and the accumulation of pro-inflammatory cytokines such as interleukin-6, interleukin 1-ß and tumour necrosis factor α in mice. Together, our findings indicate that CRTC1 is a key factor in depression-like behaviour and provide an important reference for finding a novel drug target in the neuroinflammatory and neurotrophic pathways for curing depressive disorders. Cover Image for this issue: doi: 10.1111/jnc.14500.