Microglia sense and suppress epileptic neuronal hyperexcitability.

Microglia are the resident immune cells of the central nervous system, undertaking surveillance role and reacting to brain homeostasis and neurological diseases. Recent studies indicate that microglia modulate epilepsy-induced neuronal activities, however, the mechanisms underlying microglia-neuron communication in epilepsy are still unclear. Here we report that epileptic neuronal hyperexcitability activates microglia and drives microglial ATP/ADP hydrolyzing ectoenzyme CD39 (encoded by Entpd1) expression via recruiting the cAMP responsive element binding protein (CREB)-regulated transcription coactivator-1 (CRTC1) from cytoplasm to the nucleus and binding to CREB. Activated microglia in turn suppress epileptic neuronal hyperexcitability in a CD39 dependent manner. Disrupting microglial CREB/CRTC1 signaling, however, decreases CD39 expression and diminishes the inhibitory effect of microglia on epileptic neuronal hyperexcitability. Overall, our findings reveal CD39-dependent control of epileptic neuronal hyperexcitability by microglia is through an excitation-transcription coupling mechanism.

[Retracted] MicroRNA­454 inhibits non­small cell lung cancer cells growth and metastasis via targeting signal transducer and activator of transcription­3.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the cell migration and invasion assay data shown in Figs. 2C and 4D were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 3979­3986, 2018; DOI: 10.3892/mmr.2017.8350].

Roles of the m6A Modification of RNA in the Glioblastoma Microenvironment as Revealed by Single-Cell Analyses.

Purpose: Glioblastoma multiforme (GBM) is a common and aggressive form of brain tumor. The N6-methyladenosine (m6A) mRNA modification plays multiple roles in many biological processes and disease states. However, the relationship between m6A modifications and the tumor microenvironment in GBM remains unclear, especially at the single-cell level. Experimental Design: Single-cell and bulk RNA-sequencing data were acquired from the GEO and TCGA databases, respectively. We used bioinformatics and statistical tools to analyze associations between m6A regulators and multiple factors. Results: HNRNPA2B1 and HNRNPC were extensively expressed in the GBM microenvironment. m6A regulators promoted the stemness state in GBM cancer cells. Immune-related BP terms were enriched in modules of m6A-related genes. Cell communication analysis identified genes in the GALECTIN signaling network in GBM samples, and expression of these genes (LGALS9, CD44, CD45, and HAVCR2) correlated with that of m6A regulators. Validation experiments revealed that MDK in MK signaling network promoted migration and immunosuppressive polarization of macrophage. Expression of m6A regulators correlated with ICPs in GBM cancer cells, M2 macrophages and T/NK cells. Bulk RNA-seq analysis identified two expression patterns (low m6A/high ICP and high m6A/low ICP) with different predicted immune infiltration and responses to ICP inhibitors. A predictive nomogram model to distinguish these 2 clusters was constructed and validated with excellent performance. Conclusion: At the single-cell level, m6A modification facilitates the stemness state in GBM cancer cells and promotes an immunosuppressive microenvironment through ICPs and the GALECTIN signaling pathway network. And we also identified two m6A-ICP expression patterns. These findings could lead to novel treatment strategies for GBM patients.

MicroRNA-320a Promotes Epithelial Ovarian Cancer Cell Proliferation and Invasion by Targeting RASSF8.

MicroRNAs (miRNAs) play important roles in tumorigenesis by controlling target gene expression. With opposing roles as a tumor suppressor or oncogene, microRNA-320a (miR-320a) was found to participate in tumor genesis and progression and also identified as a potentially useful marker in cancer diagnosis, treatment, and prognosis. To better understand the role of miR-320a in ovarian cancer, we investigated miR-320a expression in epithelial ovarian cancer (EOC) specimens as well as EOC cell lines and analyzed correlations between miR-320a expression and processes associated with EOC progression. The miR-320a level in EOC specimens was found to be associated with ovarian cancer progression and infiltration. Through in vitro and in vivo studies, we found that miR-320a significantly promoted the proliferation, migration, and invasion of EOC cells, and we identified RASSF8 as a target gene of miR-320a that was downregulated in EOC tissues and cell lines. In vitro downregulation of RASSF8 promoted the growth, migration, and invasion of EOC cells. Together these findings indicate that RASSF8 is a direct target of miR-320a, through which miR-320a promotes the progression of EOC.

MiR34a Regulates Neuronal MHC Class I Molecules and Promotes Primary Hippocampal Neuron Dendritic Growth and Branching.

In the immune system, Major Histocompatibility Complex class I (MHC-I) molecules are located on the surface of most nucleated cells in vertebrates where they mediate immune responses. Accumulating evidence indicates that MHC-I molecules are also expressed in the central nervous system (CNS) where they play important roles that are significantly different from their immune functions. Classical MHC-I molecules are temporally and spatially expressed in the developing and adult CNS, where they participate in the synaptic formation, remodeling and plasticity. Therefore, clarifying the regulation of MHC-I expression is necessary to develop an accurate understanding of its function in the CNS. Here, we show that microRNA 34a (miR34a), a brain enriched noncoding RNA, is temporally expressed in developing hippocampal neurons, and its expression is significantly increased after MHC-I protein abundance is decreased in the hippocampus. Computational algorithms identify putative miR34a target sites in the 3'UTR of MHC-I mRNA, and here we demonstrate direct targeting of miR34a to MHC-I mRNA using a dual-luciferase reporter assay system. MiR34a targeting can decrease constitutive MHC-I expression in both Neuro-2a neuroblastoma cells and primary hippocampal neurons. Finally, miR34a mediated reduction of MHC-I results in increased dendritic growth and branching in cultured hippocampal neurons. Taken together, our findings identify miR34a as a novel regulator of MHC-I for shaping neural morphology in developing hippocampal neurons.

Safety and efficacy of remote ischemic postconditioning after thrombolysis in patients with stroke.

OBJECTIVE: To determine the effect of remote ischemic postconditioning (RIPC) on patients with acute ischemic stroke (AIS) undergoing IV thrombolysis (IVT). METHODS: A single-center randomized controlled trial was performed with patients with AIS receiving IVT. Patients in the RIPC group were administered RIPC treatment (after IVT) during hospitalization. The primary endpoint was a score of 0 or 1 on the modified Rankin scale (mRS) at day 90. The safety, tolerability, and neuroprotection biomarkers associated with RIPC were also evaluated. RESULTS: We collected data from both the RIPC group (n = 34) and the control group (n = 34). The average duration of hospitalization was 11.2 days. There was no significant difference between 2 groups at admission for the NIH Stroke Scale score (p = 0.364) or occur-to-treatment time (p = 0.889). Favorable recovery (mRS score 0-1) at 3 months was obtained in 71.9% of patients in the RIPC group vs 50.0% in the control group (adjusted odds ratio 9.85, 95% confidence interval 1.54-63.16; p = 0.016). We further found significantly lower plasma S100-ß (p = 0.007) and higher vascular endothelial growth factor (p = 0.003) levels in the RIPC group than in the control group. CONCLUSIONS: Repeated RIPC combined with IVT can significantly facilitate recovery of nerve function and improve clinical prognosis of patients with AIS. CLINICALTRIALSGOV IDENTIFIER: NCT03218293. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that RIPC after tissue plasminogen activator treatment of AIS significantly increases the proportion of patients with an MRS score of 0 or 1 at 90 days.

Targeted NIRF/MR dual-mode imaging of breast cancer brain metastasis using BRBP1-functionalized ultra-small iron oxide nanoparticles.

Tumor metastasis to brain is the main clinical manifestation of patients with advanced breast cancer, leading to poor survival prognosis. In order to detect the early incidence of brain metastasis, it is urgent to develop hypersensitive contrast agents for multimode imaging. In this study, PEG-phospholipids coated, a phage play derived peptide, BRBP1 peptide modified ultra-small iron oxide nanoparticles were prepared for targeted NIRF and MR imaging of breast cancer brain metastasis. The nanoparticles showed 10 nm core-shell, high relaxivity values and photon emission efficiency in vitro. The nanoparticles offered a T2 contrast imaging effect and near-infrared fluorescent signal enhancement. Compared with control peptide modified nanoparticles, the MR/NIRF imaging signal of BRBP1-modified nanoparticles in tumor tissue was significantly enhanced, which should be induced by the targeting ability of BRBP1 peptide. These results indicated that BRBP1-SPIO@mPEG (DiR) nanoparticles could be applied as an effective targeted delivery system for diagnosis of breast cancer brain metastasis.

Prognostic Potential of Electrocardiographic Parameters in Patients with Multiple Myeloma: A Retrospective Analysis of the Multiple Myeloma Population.

INTRODUCTION: Patients with multiple myeloma (MM) can develop cardiac abnormalities, predisposing them to the development of heart failure, arrhythmias, or infarction with poor prognosis. The purpose of this study is to evaluate the prognostic potential of electrocardiographic (ECG) parameters in patients with MM. METHODS: This study retrospectively included patients with MM from January 2010 to December 2018 in the First Affiliated Hospital of Xi'an Jiao Tong University. Univariate and multivariate Cox proportional hazard models were conducted to evaluate the relationship between ECG parameters and all-cause mortality in patients with MM. RESULTS: A total of 409 patients were included (mean age 61.3 ± 9.7 years, 59.2% male). The relationship between ECG parameters (including PR interval, voltage, QRS axis, QRS duration, and QTc interval) and all-cause mortality in patients with MM was evaluated. Overall, patients with QTc interval ≥ 400 ms have a significantly higher all-cause mortality compared to those with QTc interval < 400 ms (P < 0.001). When stratified by the International Staging System (ISS), this relationship was true for stages II and III (P < 0.01), but not stage I (P > 0.05). Patients with MM and QRS duration ≥ 120 ms had a higher all-cause mortality compared to those with QRS duration < 120 ms for women (P < 0.01) but not for men (P > 0.05). PR interval, voltage, and QRS axis did not predict mortality. CONCLUSION: QTc interval was independently associated with all-cause mortality in patients with MM, especially when QTc interval was more than 400 ms in more advanced stages II and III. ECG parameters may provide prognostic potential in patients with MM and aid risk stratification of these patients.

Neuronal NLRC5 regulates MHC class I expression in Neuro-2a cells and also during hippocampal development.

Major histocompatibility Complex class I (MHC I) molecules are ubiquitously expressed, being found in most nucleated cells, where they are central mediators of both the adaptive and innate immune responses. Recent studies have shown that MHC I are also expressed in the developing brain where they participate in synapse elimination and plasticity. Up-regulation of MHC I within the developing brain has been reported, however, the mechanism(s) regulating this developmental up-regulation of neuronal MHC I remains unknown. Here, we show NLR family CARD domain containing 5 (NLRC5), a newly identified member of the NLR family, is widely expressed in hippocampal neurons, and the expression pattern of NLRC5 coincides with increased MHC I mRNA in the developing hippocampus. Using a luciferase assay in Neuro-2a cells we demonstrate that NLRC5 can induce the activation of MHC I and this induction requires the W/S-X-Y motif. Further studies show that transcription factors regulatory factor X (RFX) and CREB1, which bind to X1 and X2 box, are crucial for NLRC5-mediated induction. Moreover immunoprecipitation experiments reveal that NLRC5 interacts with RFX subunits RFX5 and RFXANK. Knockout of Nlrc5 dramatically impairs basal expression of MHC I in mouse hippocampus. Taken together, our findings identify NLRC5 as a key regulator of MHC I up-regulation in the developing hippocampus and suggest an important role for NLRC5 in neurons. Cover Image for this issue: doi: 10.1111/jnc.14729.

MicroRNA-23a contributes to hippocampal neuronal injuries and spatial memory impairment in an experimental model of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common form of epilepsy characterized by spontaneous recurrent seizures. It has been widely accepted that individuals with TLE tend to have neuronal injuries and memory impairment. However, little is known about the underlying molecular mechanisms. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of target genes at the posttranscriptional level. An increasing body of evidence suggests that miRNAs play pivotal roles in the pathogenesis of epilepsy. Here, we sought to determine the role of miR-23a, one of the most common miRNAs involved in various cancer types, in hippocampal neuronal injuries and spatial memory impairment in an experimental model of TLE. We found that miR-23a is upregulated in the hippocampus after status epilepticus (SE) in kanic acid (KA)-induced TLE mice. Furthermore, the upregulation of miR-23a is accompanied by hippocampal oxidative damage, neuronal injuries and spatial memory impairment in TLE mice. Inhibition of miR-23a expression by miR-23a antagomirs reduced hippocampal oxidative stress, neuronal injuries and improved spatial memory, while an increase in miR-23a expression by miR-23a agomir exacerbated hippocampal oxidative stress, neuronal injuries and spatial memory impairment in TLE mice. Our findings suggest that miR-23a contributes to hippocampal oxidative damage and neuronal injuries, which may consequently contribute to spatial memory impairment in TLE mice. Thus, targeting miR-23a in the epileptic brain may provide a novel strategy for protecting against hippocampal neuronal injuries and improving spatial memory in TLE patients.

Prognostic Value of Long Noncoding RNA CRNDE as a Novel Biomarker in Solid Cancers: An Updated Systematic Review and Meta-Analysis.

Background: Long noncoding RNA colorectal neoplasia differentially expressed (CRNDE) has been reported to exhibit a potential oncogenic role in the development of human cancers. However, the clinical value of CRNDE expression in various cancers still remains unclear. Herein, we conducted a meta-analysis to investigate the association between CRNDE and clinical outcomes in solid cancers. Methods: A systematic search was performed though the PubMed, EMBASE, Web of Science, Ovid, Cochrane library, CNKI and WanFang databases for eligible studies on clinical values of CRNDE in solid cancers. The pooled hazard ratios (HRs) or odd ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the link between CRNDE and clinical outcomes. Results: A total of 3690 patients from 20 studies (including 2 studies have 2 cohorts, respectively) were included. The results suggested that elevated CRNDE expression predicted a poor overall survival (OS) for in 13 types of solid cancers (HR=1.46, 95% CI: 1.33-1.58, P<0.001) with no heterogeneity (I2=21.8%, P=0.19). Subgroup analysis indicated a significant association between high CRNDE expression and shorter OS in the studies with digestive system cancers (HR=1.42, 95% CI: 1.28-1.55, P<0.001), qRT-PCR method (HR=1.45, 95% CI: 1.30-1.59, P<0.001), sample size >100 (HR=1.44, 95% CI: 1.32-1.57, P<0.001), and NOS>7 (HR= 1.50, 95% CI: 1.23-1.78, P<0.001). Furthermore, the pooled results showed that CRNDE was an independent prognostic factor for OS in cancer patients (HR=1.37, 95% CI: 1.22-1.52, P<0.001). In addition, we also revealed that CRNDE was positively related to tumor size (OR=2.10, 95%CI: 1.68-2.63, P<0.001), TNM stage (OR=2.86, 95%CI: 2.29-3.56, P<0.001), lymph node metastasis (LNM) (OR=3.21, 95%CI: 2.01-5.13, P<0.001), and distant metastasis (OR=4.36, 95%CI: 2.36-8.07, P<0.001). Although the probable evidences of publication bias were found in the studies with OS, tumor size, TNM stage or LNM, the trim and fill analysis confirmed the reliability of these results was not affected. Conclusion: Elevated CRNDE expression was associated with larger tumor size, advanced TNM stage, worse LNM and distant metastasis, and shorter OS, suggesting that CRNDE may act as an independent prognostic biomarker in solid cancers.

Exosome-mediated microRNA-138 and vascular endothelial growth factor in endometriosis through inflammation and apoptosis via the nuclear factor-κB signaling pathway.

Endometriosis (Ems) is a condition that refers to the ectopic implantation and growth of endometrial tissue outside the uterine cavity. The aim of the present study was to investigate the role of microRNA­138 (miR­138) in Ems and the possible underlying mechanism. Flow cytometry was measured CD11b level, cell proliferation was measured using MTT assay and lactate dehydrogenase (LDH) assays was analyzed using LDH activity kits. Cell apoptosis was measured using Annexin V­FITC/PI double staining apoptosis detection kit and DAPI assays. ELISA assay and western blot analysis were used to measure protein expression determination. It was first observed that miR­138 expression was markedly downregulated and the CD11b level was reduced in Ems mice compared with the control group. Subsequently, miR­138 expression was downregulated in the uterine endothelial cells co­cultured with THP­1 cells, which resulted in decreased apoptosis and increased inflammation in the uterine endothelial cells. By contrast, upregulation of miR­138 by mimic transfection increased the proliferation and reduced inflammation in uterine endothelial cells. In addition, in the co­culture of uterine endothelial and THP­1 cells, downregulation of miR­138 induced the expression of nuclear factor (NF)­κB and vascular endothelial growth factor (VEGF) proteins in THP­1 cells. Furthermore, treatment with an NF­κB inhibitor and downregulation of miR­138 in the co­culture of uterine endothelial and THP­1 cells reduced inflammation. VEGF inhibitor treatment and downregulation of miR­138 in this cell co­culture promoted the proliferation of uterine endothelial cells. These results suggested that uterine endothelial cells promoted miR­138 to induce exosome­mediated inflammation and apoptosis in Ems through the VEGF/NF­κB signaling pathway.

Metalloprotease Adam10 suppresses epilepsy through repression of hippocampal neuroinflammation.

BACKGROUND: Mice with pilocarpine-induced temporal lobe epilepsy (TLE) are characterized by intense hippocampal neuroinflammation, a prominent pathological hallmark of TLE that is known to contribute to neuronal hyperexcitability. Recent studies indicate that Adam10, a member of a disintegrin and metalloproteinase domain-containing protein (Adam) family, has been involved in the neuroinflammation response. However, it remains unclear whether and how Adam10 modulates neuroinflammation responses in the context of an epileptic brain or whether Adam10 affects epileptogenesis via the neuroinflammation pathway. METHODS: Adult male C57BL/6J mice were subjected to intraperitoneal injection of pilocarpine to induce TLE. Adeno-associated viral (AAV) vectors carrying Adam10 (AAV-Adam10) or lentiviral vectors carrying short hairpin RNA, which is specific to the mouse Adam10 mRNA (shRNA-Adam10), were bilaterally injected into the hippocampus to induce overexpression or knockdown of Adam10, respectively. The specific anti-inflammatory agent minocycline was administered following status epilepticus (SE) to block hippocampal neuroinflammation. Continuous video EEG recording was performed to analyze epileptic behavior. Western blot, immunofluorescence staining, and ELISA were performed to determine Adam10 expression as well as hippocampal neuroinflammation. RESULTS: In this study, we demonstrate that overexpression of Adam10 in the hippocampus suppresses neuroinflammation and reduces seizure activity in TLE mice, whereas knockdown of Adam10 exacerbates hippocampal neuroinflammation and increases seizure activity. Furthermore, increased seizure activity in Adam10 knockdown TLE mice is dependent on hippocampal neuroinflammation. CONCLUSION: These results suggest that Adam10 suppresses epilepsy through repression of hippocampal neuroinflammation. Our findings provide new insights into the Adam10 regulation of development of epilepsy via the neuroinflammation pathway and identify a potential therapeutic target for epilepsy.

The kinematic recovery process of rhesus monkeys after spinal cord injury.

After incomplete spinal cord injury (SCI), neural circuits may be plastically reconstructed to some degree, resulting in extensive functional locomotor recovery. The present study aimed to observe the post-SCI locomotor recovery of rhesus monkey hindlimbs and compare the recovery degrees of different hindlimb parts, thus revealing the recovery process of locomotor function. Four rhesus monkeys were chosen for thoracic hemisection injury. The hindlimb locomotor performance of these animals was recorded before surgery, as well as 6 and 12 weeks post-lesion. Via principal component analysis, the relevant parameters of the limb endpoint, pelvis, hindlimb segments, and joints were processed and analyzed. Twelve weeks after surgery, partial kinematic recovery was observed at the limb endpoint, shank, foot, and knee joints, and the locomotor performance of the ankle joint even recovered to the pre-lesion level; the elevation angle of the thigh and hip joints showed no obvious recovery. Generally, different parts of a monkey hindlimb had different spontaneous recovery processes; specifically, the closer the part was to the distal end, the more extensive was the locomotor function recovery. Therefore, we speculate that locomotor recovery may be attributed to plastic reconstruction of the motor circuits that are mainly composed of corticospinal tract. This would help to further understand the plasticity of motor circuits after spinal cord injury.

DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer.

DNA methyltransferase 3A (DNMT3A) has been recognised as a key element of epigenetic regulation in normal development, and the aberrant regulation of DNMT3A is implicated in multiple types of cancers, especially haematological malignancies. However, its clinical significance and detailed functional role in solid tumours remain unknown, although abnormal expression has gained widespread attention in these cancers. Here, we show that DNMT3A isoform b (DNMT3Ab), a member of the DNMT3A isoform family, is critical for directing epithelial-mesenchymal transition (EMT)-associated metastasis in gastric cancer (GC). DNMT3Ab is positively linked to tumour-node-metastasis (TNM) stage, lymph node metastasis and poor prognosis in GC patients. Overexpression of DNMT3Ab promotes GC cell migration and invasion as well as EMT through repression of E-cadherin. Meanwhile, DNMT3Ab promotes lung metastasis of GC in vivo. Mechanistic studies indicate that DNMT3Ab mediates the epigenetic inaction of the E-cadherin gene via DNA hypermethylation and histone modifications of H3K9me2 and H3K27me3. Depletion of DNMT3Ab effectively restores the expression of E-cadherin and reverses TGF-ß-induced EMT by reducing DNA methylation, H3K9me2 and H3K27me3 levels at the E-cadherin promoter. Importantly, DNMT3Ab cooperated with H3K9me2 and H3K27me3 contributes to the transcriptional regulation of E-cadherin in a Snail-dependent manner. Further, gene expression profiling analysis indicates that multiple metastasis-associated genes and oncogenic signalling pathways are regulated in response to DNMT3Ab overexpression. These results identify DNMT3Ab as a crucial regulator of metastasis-related genes in GC. Targeting the DNMT3Ab/Snail/E-cadherin axis may provide a promising therapeutic strategy in the treatment of metastatic GC with high DNMT3Ab expression.

Mutation status and prognostic values of KRAS, NRAS, BRAF and PIK3CA in 353 Chinese colorectal cancer patients.

Mutations in KRAS exon 2, BRAF and PIK3CA are commonly present in colorectal cancer (CRC) worldwide, but few data about RAS mutations outside KRAS exon 2 are available for Chinese CRCs. We, therefore, determined the mutation frequencies and prognostic values of KRAS exon 2, 3 and 4, NRAS exon 2 and 3, PIK3CA exon 9 and 20, and BRAF exon 15 by PCR and direct sequencing in 353 CRC patients from two Chinese clinical centers. KRAS exon 2, BRAF, PIK3CA mutations were identified in 42.2%, 4.5%, 12.3% of the cases, respectively. We found "rare mutations" in RAS genes in nearly 14% of CRCs-i.e., in almost a quarter (24.0%) of KRAS exon 2 wild type CRCs, including 2.3% in KRAS exon 3, 8.2% in KRAS exon 4 and 3.4% in NRAS. Stage I-III patients with PIK3CA or NRAS mutations developed more distant metastases (3-year risk in PIK3CA mutated and wild type patients: 23.3% vs 11.5%, P = 0.03; multivariate Hazard ratio (HR) = 3.129, P = 0.003; 3-year risk in NRAS mutated and wild type patients: 40.0% vs 12.2%, P = 0.012; multivariate HR = 5.152, P = 0.003). Our data emphasizes the importance of these novel molecular features in CRCs.

On-target and direct modulation of alloreactive T cells by a nanoparticle carrying MHC alloantigen, regulatory molecules and CD47 in a murine model of alloskin transplantation.

Biomimetic nanoparticles have been reported as immune modulators in autoimmune diseases and allograft rejections by numerous researchers. However, most of the therapeutics carrying antigens, toxins or cytokines underlay the mechanism of antigen presentation by cellular uptake of NPs through pinocytosis and phagocytosis. Few researches focus on the direct and antigen-specific modulation on T cells by NPs and combined use of multiple regulatory molecules. Here, polylactic-co-glycolic acid nanoparticles (PLGA-NPs) were fabricated as scaffold to cocoupling H-2Kb-Ig dimer, anti-Fas mAb, PD-L1-Fc, TGF-ß and CD47-Fc for the generation of alloantigen-presenting and tolerance-inducing NPs, termed killer NPs and followed by i.v. injection into a single MHC-mismatched murine model of alloskin transplantation. Three infusions prolonged alloskin graft survival for 45 days; depleted most of H-2Kb alloreactive CD8+ T cells in peripheral blood, spleen and local graft, in an antigen-specific manner. The killer NPs circulated throughout vasculature into various organs and local allograft, with a retention time up to 30 h. They made contacts with CD8+ T cells to facilitate vigorous apoptosis, inhibit the activation and proliferation of alloreactive CD8+ T cells and induce regulatory T cells in secondary lymphoid organs, with the greatly minimized uptake by phagocytes. More importantly, the impairment of host overall immune function and visible organ toxicity were not found. Our results provide the first experimental evidence for the direct and on-target modulation on alloreactive T cells by the biodegradable 200-nm killer NPs via co-presentation of alloantigen and multiple regulatory molecules, thus suggest a novel antigen-specific immune modulator for allograft rejections.

Apatinib inhibits macrophage-mediated epithelial-mesenchymal transition in lung cancer.

Chemotherapy is one of the main treatment approaches for lung cancer. However, few drugs can be used in the post-first-line treatment of lung cancer. Apatinib is a small molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and is widely used in advanced gastric cancer. This study aimed to investigate the therapeutic effect of apatinib in the second-line treatment of lung cancer and explore its underlying mechanism from the aspect of macrophage-mediated epithelial-mesenchymal transition (EMT). The results showed that apatinib attenuated macrophage-induced EMT and migration of lung cancer cells but not normal lung cells, as demonstrated by the loss of epithelial properties and gain of mesenchymal characteristics. Moreover, apatinib selectively decreased hepatocyte growth factor (HGF) secretion in polarized macrophages. Furthermore, apatinib down-regulated the expression of the HGF-Met signaling pathway in polarized macrophage-stimulated lung cancer cells. Taken together, our study has identified a novel pathway through which apatinib exerts its anti-cancer functions, and provided a molecular basis for apatinib potential applications in the post-first line treatment of lung cancer.

MicroRNA-454 inhibits non­small cell lung cancer cells growth and metastasis via targeting signal transducer and activator of transcription-3.

Lung cancer is one of the most common type of cancers and the leading cause of cancer­related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases. Emerging studies have suggested that microRNAs are dysregulated in NSCLC and serve important roles in NSCLC initiation and development. However, to the best of our knowledge, the expression, roles and molecular mechanism of microRNA­454 (miR­454) have not been investigated in NSCLC. In the present study, miR­454 was demonstrated to be significantly downregulated in NSCLC tissues and cell lines, as assessed by western blot analysis and reverse transcription­quantitative polymerase chain reaction. Reduced miR­454 expression was significantly correlated with aggressive clinicopathological features in NSCLC. In addition, upregulation of miR­454 suppressed proliferation, migration and invasion NSCLC cells, as assessed by Cell Counting Kit­8 and in vitro migration and invasion assays, respectively. Furthermore, bioinformatics analysis identified STAT3 as a direct target gene of miR­454, and STAT3 knockdown was demonstrated to simulate the effects of miR­454 overexpression in NSCLC. In conclusion, the present study provided convincing evidence that miR­454 is downregulated in NSCLC, and regulates growth and metastasis by directly targeting STAT3, which suggests that miR­454 may be an efficient therapeutic target for NSCLC.

Associations between pro-inflammatory cytokines, learning, and memory in late-life depression and healthy aging.

OBJECTIVES: Pro-inflammatory cytokines may play a role in learning and memory difficulties and may be exacerbated in late-life depression (LLD), where pro-inflammatory markers are already elevated because of aging and age-related vascular risk. METHODS: Learning and memory, and pro-inflammatory cytokines-Interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and Interleukin-6 (IL-6) were measured in 24 individuals with LLD and 34 healthy older adults (HOA). Hippocampal volumes were segmented using Freesurfer software. RESULTS: Pro-inflammatory cytokines were higher in LLD compared with HOA. Regression analyses demonstrated that educational level and right hippocampal volume significantly contributed to explaining the variance in learning. For memory performance, educational level, right hippocampal volume and a group-by-IL-6 interaction significantly contributed to the model. CONCLUSIONS: High levels of IL-6 impact cognition in LLD but not HOA. Results suggest that high levels of inflammation alone are not sufficient to account for cognitive difficulties, but may interact with other factors in at-risk populations like LLD, to contribute to memory difficulties. Copyright © 2017 John Wiley & Sons, Ltd.