Alzheimer’s disease (AD), a progressive neurodegenerative disease characterized by impairments of cognitive function as a result of synaptic deficits and neuronal loss, is associated with inflammation. Apelin-13, a predominant neuropeptide with inhibiting effect on inflammation, has beneficial effects on cognition memory and neuronal damage. However, whether apelin-13 can protect neurons to ameliorate cognitive deficits in AD by inhibiting the inflammatory response remains largely unknown. To test this hypothesis, rats were intracerebroventricularly (ICV) injected with streptozotocin (3 mg/kg) alone or in combination with apelin-13 (2 μg). And tyrosine receptor kinase B (TrkB) blocker K252a (200 nM) was administrated 10 min before apelin injection. Furthermore, cognitive performance was assessed by new object recognition (NOR) and Y-maze tests. Protein expression of apelin, APJ, microglial marker (IBA1), astroglia marker (GFAP), interleukin 1 beta (IL-1β), tumor necrosis factor-α (TNF-α), synaptophysin (SYP), brain-derived neurotrophic factor (BDNF), TrkB, phospho-TrkB (p-TrkB) in the hippocampus were examined by western blotting or immunohistochemistry. And the gene expression of IBA1, GFAP, IL-1β, TNF-α, and SYP were detected by real-time quantitative polymerase chain reaction (PCR). Inflammatory disorder in the hippocampus was tested by hematoxylin and eosin (H&E) staining. The enzyme-linked immunosorbent assay (ELISA) was used to study the expression level of acetylcholine. And the activity of acetylcholinesterase was detected by Acetylcholinesterase Assay Kit. We observed that apelin/APJ signaling was downregulated in the hippocampus of rats administrated with STZ. Apelin-13 was found to significantly ameliorate STZ-induced AD-like phenotypes including congnitive deficit, cholinergic disfunction and the damage of neuron and synaptic plasticity. Moreover, apelin-13 inhibited microglia and astrocyte activation, reduced IL-1β and TNF-α expression and hippocampal BDNF/TrkB expression deficit in AD rats. Finally, apelin-13-mediated effects were blocked by TrkB receptor antagonist K252a. These results suggest that apelin-13 upregulates BDNF/TrkB pathway against cognitive deficit in a STZ-induced rat model of sporadic AD by attenuating inflammation.

Coronary artery disease (CAD) and ischemic stroke (IS) are manifestations of atherosclerosis, with a high death rate. miR-146a is a microRNA that participates in the progress of CAD and IS. A single nucleotide polymorphism (SNP) in the precursor of miR-146a, rs2910164, was found to be associated with the risks of CAD and IS. However, the results were inconsistent and inconclusive. A meta-analysis was performed to assess the relationship of rs2910164 and CAD as well as IS susceptibility. The database Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM) were searched for related studies. Crude odds ratios with 95% confidence intervals were used to investigate the strength of the association by random- or fixed-effect model. A total of eight studies, with 3138 cases and 3097 controls were identified for the meta-analysis. The results shows that rs2910164 is associated with the risk of CAD significantly in allelic model (OR = 0.86), homozygous model (OR = 0.70), heterozygous model (OR = 0.80) and dominant model (OR = 0.76). The subjects carrying the GG genotype, GG + GC genotype or G allele are at lower risks of CAD. For the susceptibility of IS, there are no significant associations between rs2910164 and total studies. However, in subgroup analysis by sample size and ethnicity, the GG, GG + GC and G allele of rs2910164 are found to be associated with higher risks of IS in large sample size group and in Koreans, under homozygous and dominant models. In conclusion, the current meta-analysis suggests lower risks of CAD for GG, GG + GC genotype and G allele of rs2910164, while rs2910164 is not associated with the risk of IS. Thus rs2910164 might be recommended as a predictor for susceptibility of CAD, but not IS.

In this work, a novel type of pH-sensitive multifunctional envelope-type mesoporous silica nanocontainers (SBDAPF) was constructed for targeted drug delivery to cancer cells. Poly(N-succinimidyl acrylate) was coated on the mesoporous silica nanoparticles surface via an acid-labile acetal linker to obtain the SBA particles for pH-triggered drug release. A model drug doxorubicin (DOX)-loaded SBA system (SBDA) showed low premature drug release at neutral pH and effective stimuli-responsive release under the acidic conditions. To provide the colloidal stability and avoid nonspecific uptake of normal or healthy cells, the SBDA nanocontainers were modified with a poly(ethylene glycol) (PEG) polymer to form a protection layer. Furthermore, folic acid was introduced as a targeting component and anchored on the PEG outer layer to achieve the cancer-targeting ability. In vitro study demonstrated that SBDAPF could selectively adhere to the surface of cancer cells through the specific binding with folate receptor and be internalized into cells, subsequently releasing the entrapped DOX with high efficiency in slightly acidic intracellular microenvironment to finally kill cancer cells. Such a versatile drug delivery system as SBDAPF should have a potential application in cancer therapy.

Synthetic DNA machines that operate on the nanoscale three-dimensional (3D) track have attracted rapidly increasing interest because of their potential in biocomputing, drug delivery, and biosensing applications. Current nanoscale 3D DNA tracks are typically created by self-assembling thiolated oligonucleotides at gold nanoparticle (AuNP) surfaces via the strong Au–S chemistry. However, it remains challenging to accurately control the conformation and orientation of the 3D DNA track on AuNP surfaces and finely adjust the hybridization ability of the 3D track. Herein, we describe for the first time a polyadenine (polyA)-based, spatially isolated 3D DNA track, on which a target-initiated DNAzyme walker moves by a burnt-bridge mechanism with improved efficiency and processivity. PolyA serves as an anchoring block for preferential binding with the AuNP surface, and the appended substrate block adopts an upright conformation that favors the hybridization and subsequent DNAzyme-mediated cleavage. The operation of this target-initiated DNAzyme walker was monitored in real time and at a single-particle level. We tested the cleavage efficiency of 3D substrates with various polyA block lengths, which displayed that the DNAzyme activity was remarkably improved as compared with a thiol-based 3D track. We also explored bioanalytical applications of this DNAzyme nanomachine by movement-triggered cascade signal amplification.

Objective. The present study was performed to investigate the effects and mechanisms of miR-99a on LPS-induced endothelial cell inflammation, as well as the regulation of NF-κB on miR-99a production. Methods and Results. ELISA showed that LPS treatment significantly promoted the secretion of inflammatory factors (TNF-α, IL-6, IL-1β, and MCP-1). LPS treatment also inhibited miR-99a production and promoted mTOR expression and NF-κB nuclear translocation. Overexpression of miR-99a suppressed the LPS-induced TNF-α, IL-6, IL-1β, and MCP-1 overproduction, mTOR upregulation, and NF-κB nuclear translocation. The PROMO software analysis indicated NF-κB binding site in the −1643 to −1652 region of miR-99a promoter. Dual luciferase reporter analysis, electrophoretic mobility shift assays (EMSA), and chromosome immunoprecipitation (ChIP) assays demonstrated that NF-κB promoted the transcription of miR-99a by binding to the −1643 to −1652 region of miR-99a promoter. Further studies on HUVECs verified the regulatory effects of NF-κB on miR-99a production. Conclusion. MiR-99a inhibited the LPS-induced HUVECs inflammation via inhibition of the mTOR/NF-κB signal. NF-κB promoted miR-99a production by binding to the −1643 to −1652 region of miR-99a promoter. Considering the importance of endothelial inflammation on cardiovascular diseases, such as atherosclerosis, our results may provide a new insight into the pathogenesis and therapy of atherosclerosis.

BackgroundThe aim of the study was to determine whether polymorphisms in toll-like receptor 4 (TLR4) confer susceptibility to rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) in a central south Chinese Han population.MethodsGenotyping for six well studied polymorphisms (rs4986790, rs4986791, rs10759932, rs41426344, rs11536889 and rs7873784) in TLR4 gene were conducted in 1074 unrelated patients with RA and 1692 healthy control subjects, as well as in 217 unrelated patients with JIA and 378 healthy control subjects using direct sequencing technique. Comparisons between cases and controls in alleles, genotypes and haplotypes were carried out using Fisher’s exact test.ResultsSignificant genetic associations were detected between the 3’UTR rs41426344C and RA (p < 0.001, p adj < 0.001, OR = 2.24) and JIA (p < 0.001, p adj < 0.001, OR = 2.05). In addition, rs4986790G was found to be significantly associated with the susceptibility for RA (p = 0.005, p adj = 0.03, OR = 3.43), but not for JIA (p = 0.06, p adj = 0.36, OR = 2.65). Furthermore, significant increasing in the distributions of haplotypes H4 and H10 in RA (H4: p = 0.001, OR = 1.13; H10: p = 0.001, OR = 1.15) and JIA (H4: p = 0.04, OR = 2.06; H10: p = 0.02, OR = 2.47) were also found. Moreover, the frequency of rs41426344C significantly increased in RF-positive and anti-CCP positive subjects both in RA (RF+: p <0.0001, OR = 2.33; anti-CCP+: p =0.008, OR = 2.79) and JIA (RF+: p =0.02, OR = 2.91; anti-CCP+: p = 0.02, OR = 2.78).ConclusionsOur study suggested that rs41426344 and rs4986790 of TLR4 might contribute to RA, and rs41426344 might contribute to JIA pathogenesis in central south Chinese Han population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12969-017-0137-5) contains supplementary material, which is available to authorized users.

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Sequencing-based identification of tumor tissue-of-origin (TOO) is critical for patients with cancer of unknown primary lesions. Even if the TOO of a tumor can be diagnosed by clinicopathological observation, reevaluations by computational methods can help avoid misdiagnosis. In this study, we developed a neural network (NN) framework using the expression of a 150-gene panel to infer the tumor TOO for 15 common solid tumor cancer types, including lung, breast, liver, colorectal, gastroesophageal, ovarian, cervical, endometrial, pancreatic, bladder, head and neck, thyroid, prostate, kidney, and brain cancers. To begin with, we downloaded the RNA-Seq data of 7,460 primary tumor samples across the above mentioned 15 cancer types, with each type of cancer having between 142 and 1,052 samples, from the cancer genome atlas. Then, we performed feature selection by the Pearson correlation method and performed a 150-gene panel analysis; the genes were significantly enriched in the GO:2001242 Regulation of intrinsic apoptotic signaling pathway and the GO:0009755 Hormonemediated signaling pathway and other similar functions. Next, we developed a novel NN model using the 150 genes to predict tumor TOO for the 15 cancer types. The average prediction sensitivity and precision of the framework are 93.36 and 94.07%, respectively, for the 7,460 tumor samples based on the 10-fold cross-validation; however, the prediction sensitivity and precision for a few specific cancers, like prostate cancer, reached 100%. We also tested the trained model on a 20-sample independent dataset with metastatic tumor, and achieved an 80% accuracy. In summary, we present here a highly accurate method to infer tumor TOO, which has potential clinical implementation.