Elucidation of protein-ligand interactions by multiple trajectory analysis methods.

The identification of interaction between protein and ligand including binding positions and strength plays a critical role in drug discovery. Molecular docking and molecular dynamics (MD) techniques have been widely applied to predict binding positions and binding affinity. However, there are few works that describe the systematic exploration of the MD trajectory evolution in this context, potentially leaving out important information. To address the problem, we build a framework, Moira (molecular dynamics trajectory analysis), which enables automating the whole process ranging from docking, MD simulations and various analyses as well as visualizations. We utilized Moira to analyze 400 MD simulations in terms of their geometric features (root mean square deviation and protein-ligand interaction profiler) and energetics (molecular mechanics Poisson-Boltzmann surface area) for these trajectories. Finally, we demonstrate the performance of different analysis techniques in distinguishing native poses among four poses.

A knowledge-guided pre-training framework for improving molecular representation learning.

Learning effective molecular feature representation to facilitate molecular property prediction is of great significance for drug discovery. Recently, there has been a surge of interest in pre-training graph neural networks (GNNs) via self-supervised learning techniques to overcome the challenge of data scarcity in molecular property prediction. However, current self-supervised learning-based methods suffer from two main obstacles: the lack of a well-defined self-supervised learning strategy and the limited capacity of GNNs. Here, we propose Knowledge-guided Pre-training of Graph Transformer (KPGT), a self-supervised learning framework to alleviate the aforementioned issues and provide generalizable and robust molecular representations. The KPGT framework integrates a graph transformer specifically designed for molecular graphs and a knowledge-guided pre-training strategy, to fully capture both structural and semantic knowledge of molecules. Through extensive computational tests on 63 datasets, KPGT exhibits superior performance in predicting molecular properties across various domains. Moreover, the practical applicability of KPGT in drug discovery has been validated by identifying potential inhibitors of two antitumor targets: hematopoietic progenitor kinase 1 (HPK1) and fibroblast growth factor receptor 1 (FGFR1). Overall, KPGT can provide a powerful and useful tool for advancing the artificial intelligence (AI)-aided drug discovery process.

Micromotor-Enabled Active Hydrogen and Tobramycin Delivery for Synergistic Sepsis Therapy.

Sepsis is a highly heterogeneous syndrome normally characterized by bacterial infection and dysregulated systemic inflammatory response that leads to multiple organ failure and death. Single anti-inflammation or anti-infection treatment exhibits limited survival benefit for severe cases. Here a biodegradable tobramycin-loaded magnesium micromotor (Mg-Tob motor) is successfully developed as a potential hydrogen generator and active antibiotic deliverer for synergistic therapy of sepsis. The peritoneal fluid of septic mouse provides an applicable space for Mg-water reaction. Hydrogen generated sustainably and controllably from the motor interface propels the motion to achieve active drug delivery along with attenuating hyperinflammation. The developed Mg-Tob motor demonstrates efficient protection from anti-inflammatory and antibacterial activity both in vitro and in vivo. Importantly, it prevents multiple organ failure and significantly improves the survival rate up to 87.5% in a high-grade sepsis model with no survival, whereas only about half of mice survive with the individual therapies. This micromotor displays the superior therapeutic effect of synergistic hydrogen-chemical therapy against sepsis, thus holding great promise to be an innovative and translational drug delivery system to treat sepsis or other inflammation-related diseases in the near future.

Bladder microenvironment actuated proteomotors with ammonia amplification for enhanced cancer treatment.

Enzyme-driven micro/nanomotors consuming in situ chemical fuels have attracted lots of attention for biomedical applications. However, motor systems composed by organism-derived organics that maximize the therapeutic efficacy of enzymatic products remain challenging. Herein, swimming proteomotors based on biocompatible urease and human serum albumin are constructed for enhanced antitumor therapy via active motion and ammonia amplification. By decomposing urea into carbon dioxide and ammonia, the designed proteomotors are endowed with self-propulsive capability, which leads to improved internalization and enhanced penetration in vitro. As a glutamine synthetase inhibitor, the loaded l-methionine sulfoximine further prevents the conversion of toxic ammonia into non-toxic glutamine in both tumor and stromal cells, resulting in local ammonia amplification. After intravesical instillation, the proteomotors achieve longer bladder retention and thus significantly inhibit the growth of orthotopic bladder tumor in vivo without adverse effects. We envision that the as-developed swimming proteomotors with amplification of the product toxicity may be a potential platform for active cancer treatment.

Self-Propelled Proteomotors with Active Cell-Free mtDNA Clearance for Enhanced Therapy of Sepsis-Associated Acute Lung Injury.

Acute lung injury (ALI) is a frequent and serious complication of sepsis with limited therapeutic options. Gaining insights into the inflammatory dysregulation that causes sepsis-associated ALI can help develop new therapeutic strategies. Herein, the crucial role of cell-free mitochondrial DNA (cf-mtDNA) in the regulation of alveolar macrophage activation during sepsis-associated ALI is identified. Most importantly, a biocompatible hybrid protein nanomotor (NM) composed of recombinant deoxyribonuclease I (DNase-I) and human serum albumin (HSA) via glutaraldehyde-mediated crosslinking is prepared to obtain an inhalable nanotherapeutic platform targeting pulmonary cf-mtDNA clearance. The synthesized DNase-I/HSA NMs are endowed with self-propulsive capability and demonstrate superior performances in stability, DNA hydrolysis, and biosafety. Pulmonary delivery of DNase-I/HSA NMs effectively eliminates cf-mtDNAs in the lungs, and also improves sepsis survival by attenuating pulmonary inflammation and lung injury. Therefore, pulmonary cf-mtDNA clearance strategy using DNase-I/HSA NMs is considered to be an attractive approach for sepsis-associated ALI.

Improving comparative analyses of Hi-C data via contrastive self-supervised learning.

Hi-C is a widely applied chromosome conformation capture (3C)-based technique, which has produced a large number of genomic contact maps with high sequencing depths for a wide range of cell types, enabling comprehensive analyses of the relationships between biological functionalities (e.g. gene regulation and expression) and the three-dimensional genome structure. Comparative analyses play significant roles in Hi-C data studies, which are designed to make comparisons between Hi-C contact maps, thus evaluating the consistency of replicate Hi-C experiments (i.e. reproducibility measurement) and detecting statistically differential interacting regions with biological significance (i.e. differential chromatin interaction detection). However, due to the complex and hierarchical nature of Hi-C contact maps, it remains challenging to conduct systematic and reliable comparative analyses of Hi-C data. Here, we proposed sslHiC, a contrastive self-supervised representation learning framework, for precisely modeling the multi-level features of chromosome conformation and automatically producing informative feature embeddings for genomic loci and their interactions to facilitate comparative analyses of Hi-C contact maps. Comprehensive computational experiments on both simulated and real datasets demonstrated that our method consistently outperformed the state-of-the-art baseline methods in providing reliable measurements of reproducibility and detecting differential interactions with biological meanings.

Magnetically Actuated Biodegradable Nanorobots for Active Immunotherapy.

An efficient and cost-effective therapeutic vaccine is highly desirable for the prevention and treatment of cancer, which helps to strengthen the immune system and activate the T cell immune response. However, initiating such an adaptive immune response efficiently remains challenging, especially the deficient antigen presentation by dendritic cells (DCs) in the immunosuppressive tumor microenvironment. Herein, an efficient and dynamic antigen delivery system based on the magnetically actuated OVA-CaCO3 -SPIO robots (OCS-robots) is rationally designed for active immunotherapy. Taking advantage of the unique dynamic features, the developed OCS-robots achieve controllable motion capability under the rotating magnetic field. Specifically, with the active motion, the acid-responsiveness of OCS-robots is beneficial for the tumor acidity attenuating and lysosome escape as well as the subsequent antigen cross-presentation of DCs. Furthermore, the dynamic OCS-robots boost the crosstalk between the DCs and antigens, which displays prominent tumor immunotherapy effect on melanoma through cytotoxic T lymphocytes (CTLs). Such a strategy of dynamic vaccine delivery system enables the active activation of immune system based on the magnetically actuated OCS-robots, which presents a plausible paradigm for incredibly efficient cancer immunotherapy by designing multifunctional and novel robot platforms in the future.

Immunostimulant In Situ Fibrin Gel for Post-operative Glioblastoma Treatment by Macrophage Reprogramming and Photo-Chemo-Immunotherapy.

Tumor recurrence remains the leading cause of treatment failure following surgical resection of glioblastoma (GBM). M2-like tumor-associated macrophages (TAMs) infiltrating the tumor tissue promote tumor progression and seriously impair the efficacy of chemotherapy and immunotherapy. In addition, designing drugs capable of crossing the blood-brain barrier and eliciting the applicable organic response is an ambitious challenge. Here, we propose an injectable nanoparticle-hydrogel system that uses doxorubicin (DOX)-loaded mesoporous polydopamine (MPDA) nanoparticles encapsulated in M1 macrophage-derived nanovesicles (M1NVs) as effectors and fibrin hydrogels as in situ delivery vehicles. In vivo fluorescence imaging shows that the hydrogel system triggers photo-chemo-immunotherapy to destroy remaining tumor cells when delivered to the tumor cavity of a model of subtotal GBM resection. Concomitantly, the result of flow cytometry indicated that M1NVs comprehensively improved the immune microenvironment by reprogramming M2-like TAMs to M1-like TAMs. This hydrogel system combined with a near-infrared laser effectively promoted the continuous infiltration of T cells, restored T cell effector function, inhibited the infiltration of myeloid-derived suppressor cells and regulatory T cells, and thereby exhibited a strong antitumor immune response and significantly inhibited tumor growth. Hence, MPDA-DOX-NVs@Gel (MD-NVs@Gel) presents a unique clinical strategy for the treatment of GBM recurrence.

Experimental study on the effects of simvastatin in reversing the femoral metaphyseal defects induced by sodium valproate in normal and ovariectomized rats.

Introduction: Long-term treatment with antiepileptic drugs may cause secondary osteoporosis. The present study investigated the influence of simvastatin (SIM) in reversing the effects of valproate on bone defect healing in normal and ovariectomized (OVX) rats. Methods: Bone defects in femora were established in seven experimental groups of rats: control (vehicle), sodium valproate (SVP; 300 mg/kg/d), SVP plus SIM (25 mg/kg/d), sham control (sham), OVX, OVX SVP and OVX SVP plus SIM. All rats were euthanized at 8 weeks after bone defect creation. Results: Micro-CT, biomechanical and histological evaluations demonstrated lower bone strength and delayed bone healing in the SVP therapy group compared with the SVP plus SIM therapy group. Biochemical and immunohistochemical results showed that osteocalcin (OCN), collagen I (Col I) and procollagen type I N-terminal propeptide (P1NP) levels decreased, tartrate-resistant acid phosphatase type 5 precursor (TRACP-5b) expression increased, and Dickkopf-1 (DKK-1) and receptor activator of nuclear factor-κ B ligand (RANKL) expression were upregulated in the SVP therapy rats compared with the SVP plus SIM therapy group. Bone loss was exacerbated by OVX, but the effect of SIM in ameliorating bone loss was also more marked in the OVX rats. Conclusions: This study indicated lower bone strength and delayed healing of bone defects in rats given SVP therapy, especially the OVX SVP treatment group. In contrast, treatment with SIM was effective in enhancing bone strength and promoting bone defect repair and showed significant influence on promoting osteogenesis and inhibiting osteoclastogenesis.

Melatonin alleviates hydrogen peroxide induced oxidative damage in MC3T3-E1 cells and promotes osteogenesis by activating SIRT1.

Oxidative stress is an important contributor to the development of osteoporosis. Melatonin, an indoleamine secreted by the pineal gland, has antioxidant properties. This study aims to explore whether melatonin can promote bone formation and elucidate the mechanisms underlying this process. In this study, we used an in vitro hydrogen peroxide (H2O2)-induced oxidative stress model in MC3T3-E1 cells and an in vivo ovariectomized osteoporotic bone defect model in rats to explore the protective effects of melatonin against osteoporotic bone defects along with the mechanism underlying these effects. We found that melatonin significantly increased alkaline phosphatase activity, mineralization capacity, and the expression of BMP2, RUNX2, and OPN in MC3T3-E1 cells treated with H2O2. Furthermore, melatonin was found to activate SIRT1, SIRT3 and inhibit p66Shc, reduce the intracellular reactive oxygen species levels, stabilize mitochondria, reduce malondialdehyde levels, increase superoxide dismutase activity, and reduce apoptosis in MC3T3-E1 cells treated with H2O2. Intriguingly, these effects could be reversed by the SIRT1 inhibitor EX527. In vivo experiments confirmed that melatonin improves the microstructure and bone mineral density of the distal femoral bone trabecula and promotes bone formation. Meanwhile, melatonin activated SIRT1, inhibited p66Shc and increased SIRT3 expression. Taken together, our findings showed that melatonin can restrain oxidative damage in MC3T3-E1 cells and promote osteogenesis by activating SIRT1 which regulate the activity of SIRT3 and inhibit the expression of p66Shc, suggesting that melatonin could be a potential therapeutic agent for osteoporosis-related bone metabolic diseases.

[Role of p22phox and NOX5 in autophagy and apoptosis of osteoblasts induced by hypoxia].

OBJECTIVE: To investigate the role of p22phox and NOX5 in autophagy and apoptosis of osteoblasts induced by hypoxia. METHODS: The skull tissue of newborn rats was cut into small pieces, and the osteoblasts were separated and purified by the tissue block adherent method and the differential adherent method. The first generation cells were harvested and identified by HE staining, Alizarin red staining, alkaline phosphatase (ALP) staining, and flow cytometry. A three-gas incubator was used to prepare a hypoxia model of osteoblasts. At 0, 3, 6, 12, and 24 hours of hypoxia, the expressions of p22phox, NOX5, and LC3Ⅱ/Ⅰ were detected by Western blot, and the level of reactive oxygen species (ROS) and cell apoptosis rate were detected by flow cytometry. And the time point of the highest level of ROS was selected as the hypoxia time point for subsequent experiments. The first generation osteoblasts were divided into normal group, si-p22phox hypoxia group, and si-NOX5 hypoxia group and subjected to corresponding transfection and hypoxia treatment. The inhibition efficiency of si-p22phox and si-NOX5 were detected by RT-PCR. Then the osteoblasts were divided into normal group, si-NC hypoxia group, si-p22phox hypoxia group, and si-NOX5 hypoxia group. After transfection and hypoxia treatment, Western blot was used to detect the expressions of p22phox, NOX5, autophagy-related proteins (LC3Ⅱ/Ⅰ, Beclin), and apoptosis-related proteins (Bcl-2, Bax), and flow cytometry was used to detect the cell apoptosis rate and level of ROS. The first generation osteoblasts were divided into a hypoxia group for 12 hours (hypoxia group) and a group that simultaneously inhibited si-p22phox and si-NOX5 and hypoxia for 12 hours (inhibition+hypoxia group). The expressions of Beclin and Bax were observed by immunofluorescence staining after the corresponding treatment. RESULTS: After identification, the isolated cells were osteoblasts. After hypoxia treatment, the relative expressions of p22phox, NOX5, and LC3Ⅱ/Ⅰ proteins and the apoptosis rate of osteoblasts gradually increased ( P<0.05), and the level of ROS also significantly increased ( P<0.05) and reached the peak value at 12 hours. The 12-hour hypoxia model was selected for subsequent experiments. Silencing the p22phox gene did not affect the expression of NOX5, and silencing the NOX5 gene did not affect the expression of p22phox. Compared with hypoxia treatment, the relative expressions of LC3Ⅱ/Ⅰ, Beclin, and Bax proteins after inhibiting the expression of p22phox or NOX5 gene significantly decreased ( P<0.05), the relative expression of Bcl-2 protein significantly increased ( P<0.05), the cell apoptosis rate and level of ROS also significantly decreased ( P<0.05). After silencing the expressions of p22phox and NOX5 genes at the same time, the immunofluorescence staining showed that the fluorescence of Beclin and Bax were weak. CONCLUSION: Inhibiting the expressions of p22phox and NOX5 genes can reduce the level of ROS in osteoblasts under hypoxia-induced conditions, and at the same time reduce autophagy and apoptosis, especially attenuate the excessive apoptosis of cells in the early to late stages, and strengthen the hypoxic osteoblasts proliferation.

Interfering with hyaluronic acid metabolism suppresses glioma cell proliferation by regulating autophagy.

The tumor microenvironment plays an important role in tumor progression. Hyaluronic acid (HA), an important component of the extracellular matrix in the tumor microenvironment, abnormally accumulates in a variety of tumors. However, the role of abnormal HA accumulation in glioma remains unclear. The present study indicated that HA, hyaluronic acid synthase 3 (HAS3), and a receptor of HA named CD44 were expressed at high levels in human glioma tissues and negatively correlated with the prognosis of patients with glioma. Silencing HAS3 expression or blocking CD44 inhibited glioma cell proliferation in vitro and in vivo. The underlying mechanism was attributed to the inhibition of autophagy flux and maintaining glioma cell cycle arrest in G1 phase. More importantly, 4-methylumbelliferone (4-MU), a small competitive inhibitor of Uridine diphosphate (UDP) with the ability to penetrate the blood-brain barrier (BBB), also inhibited glioma cell proliferation in vitro and in vivo. Thus, approaches that interfere with HA metabolism by altering the expression of HAS3 and CD44 and the administration of 4-MU potentially represent effective strategies for glioma treatment.

Synthesis and Evaluation of Novel α-Aminoamides Containing Benzoheterocyclic Moiety for the Treatment of Pain.

Novel α-aminoamide derivatives containing different benzoheterocyclics moiety were synthesized and evaluated as voltage-gated sodium ion channels blocks the treatment of pain. Compounds 6a, 6e, and 6f containing the benzofuran group displayed more potent in vivo analgesic activity than ralfinamide in both the formalin test and the writhing assay. Interestingly, they also exhibited potent in vitro anti-Nav1.7 and anti-Nav1.8 activity in the patch-clamp electrophysiology assay. Therefore, compounds 6a, 6e, and 6f, which have inhibitory potency for two pain-related Nav targets, could serve as new leads for the development of analgesic medicines.

The increasing expression of GPX7 related to the malignant clinical features leading to poor prognosis of glioma patients.

BACKGROUND: Glioma is the most common malignant brain tumor in adults. The standard treatment scheme of glioma is surgical resection combined alternative radio- and chemotherapy. However, the outcome of glioma patients was unsatisfied. Here, we aimed to explore the molecular and biological function characteristics of GPX7 in glioma. METHODS: The multidimensional data of glioma samples were downloaded from Chinese Glioma Genome Atlas (CGGA). RT-qPCR method was used to identify the expression status of GPX7. Kaplan-Meier curves and Cox regression analysis were used to explore the prognostic value of GPX7. Gene Set Enrichment Analysis (GSEA) was applied to investigate the GPX7-related functions in glioma. RESULTS: The results indicated that the expression of GPX7 in glioma was higher compared to that in normal brain tissue. Univariate and multivariate Cox regression analyses confirmed that the expression value of GPX7 was an independent prognostic factor in glioma. The GSEA analysis showed that GPX7 was significantly enriched in the cell cycle pathway, ECM pathway, focal adhesion pathway, and toll-like receptor pathway. CONCLUSIONS: The GPX7 was recommended as an independent risk factor for patients diagnosed with glioma for the first time and GPX7 could be potentially used as the therapy target in future. Furthermore, we attempted to explore a potential biomarker for improving the diagnosis and prognosis of patients with glioma.

Effect of alendronate on the femoral metaphyseal defect under carbamazepine in ovariectomized rats.

BACKGROUND: The use of antiepileptic drugs and estrogen deficiency put forward higher requirements for bone defect regeneration. The present study investigated the effects of alendronate (ALN) on femoral bone defect in ovariectomized (OVX) rats under the influence of carbamazepine (CBZ). METHODS: One hundred female SD rats at 3 months of age were either sham-operated or OVX and divided into four groups: sham control (CON); OVX control (OVX); ovariectomized rats treated with CBZ via gavage (75 mg/kg/day; CBZ); ovariectomized rats treated with CBZ plus ALN (2 mg/kg/day; CBZ-ALN). A critical-sized femoral metaphyseal bone defect was established in all female SD rats. Animals from the CBZ and CBZ-ALN groups received drugs by gavage the day after bone defect surgery was performed. After the rats were sacrificed, the defected area located in the distal femur was harvested for evaluation by microcomputed tomography (micro-CT), hematoxylin and eosin (HE) staining, and Masson's trichrome staining. The samples were also analyzed by biomechanics and immunohistochemical evaluation (IHC). Besides, biochemical analysis evaluates all serum samples. RESULTS: The present study showed that ovariectomy changed the microstructural parameters of bone. The use of CBZ further decreased femur bone mass while treatment with ALN prevented bone loss. Compared to OVX and CBZ groups, CBZ-ALN group promoted bone neoformation and enhanced the ultimate load of the femur bone. However, the group of CBZ-ALN did not return to normal levels compared with the CON group. Besides, we noticed that CBZ-ALN group reduced tartrate-resistant acid phosphatase-5b (Tracp-5b) expression and had no significant effect on the expression of osteocalcin (OCN) and type I collagen (Col-I) in IHC compared with CBZ group. Biochemical analysis results presented that systemic delivery of CBZ showed pernicious effects on bone formation and resorption in ovariectomized rats, with the worse effects on C-terminal crosslinked telopeptide of type I collagen (CTX-1). Besides, a significant decrease in CTX-1 levels was observed in CBZ-ALN group as compared to the group of CBZ. CONCLUSION: These results demonstrated that ALN can effectively reverse the effects of CBZ on the microarchitectural properties of bone, and thus can have a positive effect on local bone neoformation in rats with osteoporosis. CLINICAL RELEVANCE: The dose of 2 mg/kg ALN improves the negative effect of prescription of CBZ at 75 mg/kg and promotes bone neoformation of femoral bony deficits.

Left ventricular ejection fraction as an independent predictor of poor outcome in acute intracerebral hemorrhage.

INTRODUCTION: Few studies of the effect of cardiac abnormalities on acute intracerebral hemorrhage (ICH) outcomes have been published. We sought to determine whether the left ventricular ejection fraction (LVEF) is associated with the functional outcome and mortality of acute ICH patients. METHODS: We conducted a retrospective study on 364 acute ICH patients from January to December 2016. The primary outcome was defined by the modified Rankin Scale and mortality at 3 months. The associations between LVEF and outcome were investigated using univariable and multivariable logistic regression models. RESULTS: Depressed LVEF was significantly associated with a poor functional outcome with an odds ratio [OR] of 0.966, 95% confidence interval (CI) 0.942-0.991, p = .008, and high mortality (OR 0.968 [95% CI 0.943-0.994], p = .015) at 3 months for acute ICH patients by univariate analysis. Multivariable logistic regression analysis indicated that LVEF was an independent predictor of a poor functional outcome (OR 0.961 [95% CI 0.935-0.988], p = .005) and mortality (OR 0.949 [95% CI 0.918-0.981], p = .002). The percentage of acute ICH patients with poor functional outcome (p = .005) and mortality (p = .002) was obviously higher in the group of patients with a LVEF of <50%. CONCLUSIONS: LVEF is an independent predictor of functional outcome and mortality at 3 months for acute ICH patients. These findings could provide the evidence needed for prognosis prediction in acute ICH patients.

Construction of lncRNA-associated ceRNA networks to identify prognostic lncRNA biomarkers for glioblastoma.

Long noncoding RNAs (lncRNAs) serve as competitive endogenous RNAs (ceRNAs) that play significant regulatory roles in the pathogenesis of tumors. However, the role of lncRNAs, especially the lncRNA-related ceRNA regulatory network, in glioblastoma (GBM) has not been fully elucidated. The goal of the current study was to construct lncRNA-microRNA-mRNA-related ceRNA networks for further investigation of their mechanism of action in GBM. We downloaded data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases and identified differential lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) associated with GBM. A ceRNA network was constructed and analyzed to examine the relationship between lncRNAs and patients' overall survival. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGGs) were used to analyze the related mRNAs to indirectly explain the mechanism of action of lncRNAs. The potential effective drugs for the treatment of GBM were identified using the connectivity map (CMap). After integrated analysis, we obtained a total of 210 differentially expressed lncRNAs, 90 differentially expressed miRNAs, and 2508 differentially expressed mRNAs (DEmRNAs) from the TCGA and GEO databases. Using these differential genes, we constructed a lncRNA-associated ceRNA network. Six lncRNAs in the ceRNA network were associated with the overall survival of patients with GBM. Through KEGG analysis, it was found that the DEmRNAs involved in the network are related to cancer-associated pathways, for instance, mitogen-activated protein kinase and Ras signaling pathways. CMap analysis revealed four small-molecule compounds that could be used as drugs for the treatment of GBM. In this study, a multi-database joint analysis was used to construct a lncRNA-related ceRNA network to help identify the regulatory functions of lncRNAs in the pathogenesis of GBM.

Identification of hub genes and small-molecule compounds in medulloblastoma by integrated bioinformatic analyses.

BACKGROUND: Medulloblastoma (MB) is the most common intracranial malignant tumor in children. The genes and pathways involved in the pathogenesis of MB are relatively unknown. We aimed to identify potential biomarkers and small-molecule drugs for MB. METHODS: Gene expression profile data sets were obtained from the Gene Expression Omnibus (GEO) database and the differentially expressed genes (DEGs) were identified using the Limma package in R. Functional annotation, and cell signaling pathway analysis of DEGs was carried out using DAVID and Kobas. A protein-protein interaction network was generated using STRING. Potential small-molecule drugs were identified using CMap. RESULT: We identified 104 DEGs (29 upregulated; 75 downregulated). Gene ontology analysis showed enrichment in the mitotic cell cycle, cell cycle, spindle, and DNA binding. Cell signaling pathway analysis identified cell cycle, HIF-1 signaling pathway, and phospholipase D signaling pathway as key pathways. SYN1, CNTN2, FAIM2, MT3, and SH3GL2 were the prominent hub genes and their expression level were verified by RT-qPCR. Vorinostat, resveratrol, trichostatin A, pyrvinium, and prochlorperazine were identified as potential drugs for MB. The five hub genes may be targets for diagnosis and treatment of MB, and the small-molecule compounds are promising drugs for effective treatment of MB. CONCLUSION: In this study we obtained five hub genes of MB, SYN1, CNTN2, FAIM2, MT3, and SH3GL2 were confirmed as hub genes. Meanwhile, Vorinostat, resveratrol, trichostatin A, pyrvinium, and prochlorperazine were identified as potential drugs for MB.

Circulating MicroRNAs as Potential Noninvasive Biomarkers of Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a common and severe neurological disorder that has been associated with high rates of mortality and morbidity. It is urgent to find new biomarkers for the early diagnosis and prevention of ICH. In recent years, micro-RNAs (miRNAs) have been proved to play an important role in vascular damage and inflammation in cerebrovascular diseases, including ICH. In the peripheral blood, circulating miRNAs will be present at a remarkably steady level. In the present study, we explored the circulating plasma microRNA (miR)-181b, miR-223, miR-155, and miR-145 as new potential biomarkers for the diagnosis of ICH. METHODS: The plasma samples from 106 patients with ICH and 50 patients without ICH (control group) were collected and subjected to quantitative real-time polymerase chain reaction analyses for the expression levels of circulating miR-181b, miR-223, miR-155, and miR-145. RESULTS: The expression levels of plasma circulating miR-145 (P < 0.001), miR-223, and miR-155 were increased in patients with ICH compared with those in the control group (P < 0.05). However, the expression of plasma circulating miR-181b was decreased in patients with ICH compared with that in the control group (P < 0.001). Receiver operating characteristic curve analyses were performed to determine the diagnostic sensitivity and specificity of miR-145 and miR-181b to detect ICH. The area under the curve for miR-145 was 0.766 (95% confidence interval, 0.689-0.838) and for miR-181b was 0.78 (95% confidence interval, 0.70-0.86), suggesting that circulating miR-145 and miR-181b can be used to differentiate patients with ICH from those without ICH. CONCLUSION: Our results have shown that measurement of circulating miR-181b, miR-223, miR-155, and miR-145 in plasma samples could serve as a potential noninvasive tool for ICH detection.