AIMS:The present study aimed to investigate how Schizophrenia (SCZ)-specific long non-coding RNAs (lncRNAs) served as competing endogenous RNAs (ceRNAs) to modulate the biological functions and pathways involved in the pathogenesis of SCZ.MAIN METHODS:Microarray dataset (GSE54913) was obtained from Gene Expression Omnibus (GEO) database. Differently expressed (DE) lncRNAs and mRNAs were identified by "limma" package. The binding miRNAs of lncRNAs and target mRNAs of shared miRNAs were predicted by miRcode, miRDB, miRTarbase and targetscan databases. Following the ceRNAs theory, interaction network was established and visualized with the cytoscape. Functional enrichment analysis uncovered the concentrated functions and signaling pathways that may be associated with SCZ progression. Protein-protein interaction (PPI) analysis was utilized to determine hub genes. Quantitative real-time PCR (qRT-PCR) and receiver operating characteristic curve (ROC) were performed to evaluate the expression and diagnostic value of ceRNAs members, respectively.KEY FINDINGS:DElncRNAs and DEmRNAs were initially screened from GSE54913 to construct the SCZ-related ceRNAs network with 42 nodes and 53 edges. Functional enrichment analysis revealed that ceRNAs members appeared to be highly correlated with transcription factor activation, cell replication and tumor-related pathways. Once validated, a significant ceRNAs subnetwork was proposed as being implicated in the pathogenesis of SCZ. ROC analysis indicated that SCZ-related ceRNAs members may be sensitive diagnostic biomarkers for SCZ.SIGNIFICANCE:The significant SCZ-related ceRNAs subnetworks (lncRNA-C2orf48A/hsa-miR-20b-5p,-17-5p/KIF23, FOXJ2) may represent promising predictive and diagnostic biomarkers and provide novel insights into the mechanism by which lncRNAs act as microRNA sponges and contribute to the pathogenesis of SCZ.

The lack of biomarkers greatly limits the diagnosis and treatment of major depressive disorder (MDD). Endogenous L-carnitine (LC) and its derivative acetyl-L-carnitine (ALC) play antidepressant roles by improving brain energy metabolism, regulating neurotransmitters and neural plasticity. The levels of ALC in people and rodents with depression are significantly reduced. It is necessary to determine whether serum LC and ALC might be used as novel biomarkers for the diagnosis of MDD. Here, ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the concentration of LC and ALC in the serum of healthy controls and patients with MDD; among the latter, in patients who were responsive (effective group) and non-responsive (ineffective group) after 2 weeks of treatment. The diagnostic value of serum LC and ALC for MDD was assessed. Compared with healthy controls, the serum LC and ALC concentrations in patients with MDD were significantly decreased (P < 0.001). Pearson correlation analysis shows that the HDRS-24 score was negatively associated with serum ALC (r = −0.325, P = 0.007). Receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.801 with 83.1% sensitivity and 66.3% specificity for LC, and an AUC of 0.898 with 88.8% sensitivity and 76.4% specificity for ALC, differentiating patients with MDD from healthy controls. Furthermore, the concentration of LC and ALC in patients with depression was significantly increased in the effective treatment group, and no significant change was observed in the ineffective treatment group. These results suggest that serum LC and ALC may be novel biomarkers for the diagnosis of MDD.

Telomeres, protective DNA-protein complexes at the end of eukaryotic linear chromosomes, play pivotal roles in the maintenance of genomic stability during cell division. When telomeres are severely shortened, cells stop dividing and die, consequently leading to tissues degeneration. Concretely, replicative senescence and genomic damage are generally accompanied with telomere shortening, which may be a potential contributor in the pathogenesis of neurological disorders. Regardless of occasional negative findings, accelerated telomere erosion is routinely found in neurodegenerative diseases and has been believed to be positively correlated with the severity of neurodegenerative diseases. As considerable knowledge of telomeres and telomerase continues to accumulate, telomerase is increasingly being recognized as a promising therapeutic target for neurodegenerative disease. Until now, strong evidence has accumulated that activated telomerase is responsible for telomere elongation that may be sufficient to prevent “mother cells” from replicative aging, and besides, telomerase activators exhibit remarkable neuroprotective effects through the prolongation of telomere length and the promotion of neuronal survival as well as proliferation. Therefore, a consensus is emerging that the activation of telomerase, promoted by peptides, natural herbal extracts, small molecules compounds and others, represents a novel promising treatment strategy for neurodegenerative diseases.

Four series of total 35 new pyrazolo[4,3-d]pyrimidine compounds were designed, synthesized and evaluated for their inhibitory activity against LPS-induced NO production in RAW264.7 macrophages. Among them, compound 4e was found to be the most potent inhibitor, which decreased the production of cytokines in vitro, such as NO, IL-6 and TNF-α, with IC50 values of 2.64, 4.38 and 5.63 μM, respectively. Further studies showed that compound 4e inhibited cytokines secretion of macrophages through suppressing TLR4/p38 signaling pathway. Additionally, compound 4e showed in vivo anti-inflammatory activity in LPS-induced model of acute lung injury. These data suggested that compound 4e may be a promising lead structure for the treatment of ALI.

In order to discover novel anti-inflammatory agents for treatment of arthritis and based on preliminary structure-activity relationships, four series (A-D) of total 90 new pyrazolo[4,3- d]pyrimidine compounds were designed and synthesized. All the compounds have been tested for their anti-inflammatory activities by inhibiting of LPS-induced NO production. A clear structure-activity relationship has been concluded step by step, and finally 3,4,5-trimethoxystyryl-1 H-pyrazolo[4,3- d]pyrimidine was found to be the most active scaffold. Among them, compound D27 was discovered as the most potent anti-inflammatory agent (IC50 = 3.17 μM) with low toxicity and strong inhibitory of NO release (IR = 90.4% at 10 μM). This compound also showed potent inhibition of iNOS with IC50 value of 1.12 μM. Preliminary mechanism studies indicated that it could interfere with the stability and formation of active dimeric iNOS. The anti-inflammatory effect of this compound was determined by adjuvant-induced arthritis in rat model. We believe these findings would further support the study of rational design of more efficient iNOS inhibitors in the future.

目的 对一系列吡唑并[4,3-d]嘧啶衍生物进行抗肿瘤活性评价,选取显著抑制神经胶质瘤U87-MG细胞增殖的化合物9,研究其体外对U87-MG细胞的抗肿瘤活性及机制.方法 采用MTT比色法观察化合物1-10对四种肿瘤细胞(人肝癌SMMC-7721细胞、人胃癌SGC-7901细胞、人胃癌MGC-803细胞和人神经胶质瘤U87-MG细胞)增殖的影响.采用流式细胞仪检测化合物9诱导的U87-MG细胞凋亡率,以及Western blot法检测细胞凋亡相关蛋白Bcl-2和Bax的表达和相关通路蛋白p-Akt、Akt、p-mTOR和mTOR的表达情况.结果 MTT结果显示,化合物4、5、8和9对四种肿瘤细胞株的增殖均具有一定抑制作用,其中,化合物9抑制神经胶质瘤U87-MG细胞增殖的能力最强;化合物9体外抑制U87-MG细胞增殖的作用具有时间-剂量依赖性;流式细胞仪检测结果显示,U87-MG细胞凋亡率随着化合物9浓度增加而升高,呈剂量依赖性.Western blot结果显示,随着化合物9浓度增加,Bcl-2蛋白表达下调,Bax蛋白表达上调;同时,Akt和mTOR蛋白表达量基本不变,p-Akt和p-mTOR蛋白表达均下调.结论 毗唑并[4,3-d]嘧啶衍生物9明显抑制神经胶质瘤U87-MG细胞增殖,并且诱导细胞凋亡,其诱导凋亡可能机制为通过抑制PI3 K/Akt/mTOR通路达到的.