The Tian-Men-Dong decoction suppresses the tumour-infiltrating G-MDSCs via IL-1ß-mediated signalling in lung cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine (TCM) Tian-Men-Dong decoction (TD) has been able to effectively treat lung cancer in China for thousands of years. TD improves the quality of life in lung cancer patients by promoting nourishment of yin and reducing dryness, clearing the lung and removing toxins. Pharmacological studies show that TD contains active antitumour ingredients, but its underlying mechanism remains unknown. AIM OF THE STUDY: This study aims at exploring potential mechanisms of TD in the treatment of lung cancer by regulating granulocytic-myeloid-derived suppressor cells (G-MDSCs). MATERIALS AND METHODS: An orthotopic lung cancer mouse model was generated by intrapulmonary injection with LLC-luciferase cells in immunocompetent C57BL/6 mice or immunodeficient nude mice. TD/saline was orally administered once to the model mice daily for 4 weeks. Live imaging was conducted to monitor tumour growth. Immune profiles were detected by flow cytometry. H&E and ELISA were applied to test the cytotoxicity of the TD treatment. RT-qPCR and western blotting were performed to detect apoptosis-related proteins in G-MDSCs. A neutralizing antibody (anti-Ly6G) was utilized to exhaust the G-MDSCs via intraperitoneal injection. G-MDSCs were adoptively transferred from wild-type tumour-bearing mice. Immunofluorescence, TUNEL and Annexin V/PI staining were conducted to analyse apoptosis-related markers. A coculture assay of purified MDSCs and T cells labelled with CFSE was performed to test the immunosuppressive activity of MDSCs. The presence of TD/IL-1ß/TD + IL-1ß in purified G-MDSCs cocultured with the LLC system was used for ex vivo experiments to detect IL-1ß-mediated apoptosis of G-MDSCs. RESULTS: TD prolonged the survival of immune competent C57BL/6 mice in an orthotopic lung cancer model, but did not have the same effect in immunodeficient nude mice, indicating that its antitumour properties of TD are exerted by regulating immunity. TD induced G-MDSC apoptosis via the IL-1ß-mediated NF-κB signalling cascade leading to effectively weaken the immunosuppressive activity of G-MDSCs and promote CD8+ T-cell infiltration, which was supported by both the depletion and adoptive transfer of G-MDSCs assays. In addition, TD also showed minimal cytotoxicity both in vivo and in vitro. CONCLUSION: This study reveals for the first time that TD, a classic TCM prescription, is able to regulate G-MDSC activity and trigger its apoptosis via the IL-1ß-mediated NF-κB signalling pathway, reshaping the tumour microenvironment and demonstrating antitumour effects. These findings provide a scientific foundation the clinical treatment of lung cancer with TD.

[Textual research on classical famous prescription Dajianzhong Decoction].

The classical famous prescription Dajianzhong Decoction is recorded in Synopsis of the Golden Chamber written by Zhang Zhongjing in the Eastern Han Dynasty. It has a long history and definite clinical effects, while this prescription has not been manufactured into Chinese patent medicine preparation. We collected many ancient books of traditional Chinese medicine(TCM) by using the method of bibliometrics and got 211 valid data terms which involved 67 ancient books. The history, main treated syndromes, formulation principle, origins and processiong of medicinal materials, and decoction method of Dajianzhong Decoction were analyzed. Despite the different views of various generations of medical experts toward the composition of this prescription, the compatibility ratio of Ginseng Radix et Rhizoma to Zingiberis Rhizoma Recens is constant. Furthermore, we explored the origins of synonyms of Dajianzhong Decoction. On the basis of this study, we hope to gain an insight into the research and development of the compound preparations of Dajianzhong Decoction and provide reference for the heritage and innovation of other classical prescriptions.

[Effect of CO2 fractional laser on the early control of scar post-secondary repair in patients with a cleft lip].

OBJECTIVE: To observe and compare the clinical efficacy of CO2 fractional laser in the early control of scar post-secondary repair in patients with a cleft lip. METHODS: In the treatment group, 43 patients with secondary repair of cleft lip were treated via CO2 fractional laser. The control group covered 70 patients post-cheiloplasty. The effect in the two groups after six months was compared. The duration from the beginning of the laser treatment to surgery and patient gender were analyzed to determine if they affected the efficacy of the laser treatment for scars. RESULTS: 1) The curative effect in the treatment group was better than that in the control group (P<0.000 1), the total effectiveness rate was 90.7% in the treatment group. 2) No significant statistical difference in efficacy was observed between men and women (P=0.487). Moreover, no significant statistical difference in efficacy (P=0.055) was observed among patients one year after surgery, within the duration of <3 months, and within the duration of ≥3 months. CONCLUSIONS: CO2 fractional laser had a definite effect on the treatment of scar post-secondary repair in patients with a cleft lip. No significant correlation was observed between treatment effect and patient gender, and no difference was noted among patients one year after surgery. In the beginning of the laser treatment, no difference was observed between the durations of <3 months and ≥3 months after the reconstruction, Therefore, early intervention of scars a year after secondary repair of a cleft lip can achieve good results.

Interleukin-35 suppresses antitumor activity of circulating CD8+ T cells in osteosarcoma patients.

Purpose/Aim of the study: Interleukin (IL)-35 is a newly identified IL-12 cytokine family member and reveals immunosuppressive activity to CD8+ T cells in inflammation, infectious diseases, and cancers. However, little is known regarding IL-35 function in osteosarcoma. Thus, the aim of the current study was to investigate the regulatory function of IL-35 to CD8+ T cells in osteosarcoma. Materials and methods: Thirty-five osteosarcoma patients and 20 healthy individuals were enrolled. Serum CD4+CD25+CD127dim/- regulatory T cells (Tregs) and CD8+ T cells were purified. IL-35 concentration in serum and cultured supernatants was measured by enzyme-linked immunosorbent assay. Osteosarcoma cell line MG-63 cells and CD8+ T cells were stimulated with recombinant IL-35 in vitro, and modulatory function of IL-35 on these cells was assessed by investigation of cellular proliferation, cell cycle, apoptosis, and cytokine production. Results: Serum IL-35 and Treg-secreting IL-35 were significantly elevated in osteosarcoma patients. IL-35 stimulation did not affect proliferation, apoptosis, or cell cycle of MG-63 cells. Purified peripheral CD8+ T cells from osteosarcoma patients revealed dysfunctional property, which presented as decreased mRNA expressions for perforin, granzyme B, and granulysin, as well as reduced cytolytic (direct lysis of target MG-63 cells) and noncytolytic (interferon-γ and tumor necrosis factor-α production) function in coculture systems. Moreover, IL-35 stimulation further diminished cytolytic and noncytolytic activity of CD8+ T cells from osteosarcoma patients. Conclusions: The current data indicated that IL-35 contributed to CD8+ T-cell dysfunction and limited antitumor immune response in osteosarcoma.

Untargeted metabolomics using liquid chromatography coupled with mass spectrometry for rapid discovery of metabolite biomarkers to reveal therapeutic effects of Psoralea corylifolia seeds against osteoporosis.

Liquid chromatography coupled with mass spectrometry has been used as metabolomics profiling tool to discover and identify the metabolites in metabolic diseases. Osteoporosis (OP) syndrome is a chronic metabolic disease characterized by bone mass reduction and changes in bone microstructure. Psoralea corylifolia Linn. seeds (PCS) have a therapeutic effect on osteoporosis, but their action mechanism and therapeutic target are still unclear. This study aims to explore the metabolic changes of the urine profile in glucocorticoid-induced OP model rats and the therapeutic effect of PCS. High-throughput metabolomics based on the liquid chromatography coupled with mass spectrometry quadrupole time-of-flight mass spectrometry and multivariate data analysis were used to analyze the urine metabolites. The results showed that has an obvious separation between model and control groups. OPLS-DA was used to further analyze and discover substances that contributed to the separation. 42 potential biomarkers and 12 related metabolic pathways were identified in combination with network databases. After the intervention of PCS, 24 biomarkers were significantly regulated, mainly with glycone, serine and threonine metabolism, glutathione metabolism and purine metabolism and other metabolic pathways are related and discovered. This study has proved that PCS has therapeutic effect against OP by regulating that metabolic pathways disturbed in the OP. It provided a basis for the research and future development of new drugs for OP treatment.

Effects of chemotherapeutic agent bendamustine for non-hodgkin lymphoma on spermatogenesis in mice.

Non-Hodgkin lymphoma (NHL) is one of the most common cancers affecting men of reproductive age. The high response rate of bendamustine as first-line treatment for NHL, coupled with young age of patients, makes elucidation of the impact of treatment on male reproduction important. Our aim was to determine the effects of bendamustine on male reproduction by animal model. Male mice were treated with bendamustine (40 mg/kg) through tail vein injection while cisplatin was given as a standard (3 mg/kg) through intraperitoneal injection. After 3 weeks, bendamustine induced weight loss and sperm morphology abnormalities were compared to the control. Additionally, sperm with folded tails were the most frequent abnormality in bendamustine-treated mice. But the mechanism of sperm abnormality induced by bendamustine remains to be elucidated. These results indicate bendamustine may affect spermatozoa of patients who have been treated for NHL.

Human Microbe-Disease Association Prediction Based on Adaptive Boosting.

There are countless microbes in the human body, and they play various roles in the physiological process. There is growing evidence that microbes are closely associated with human diseases. Researching disease-related microbes helps us understand the mechanisms of diseases and provides new strategies for diseases diagnosis and treatment. Many computational models have been proposed to predict disease-related microbes, in this paper, we developed a model of Adaptive Boosting for Human Microbe-Disease Association prediction (ABHMDA) to reveal the associations between diseases and microbes by calculating the relation probability of disease-microbe pair using a strong classifier. Our model could be applied to new diseases without any known related microbes. In order to assess the prediction power of the model, global and local leave-one-out cross validation (LOOCV) were implemented. As shown in the results, the global and local LOOCV values reached 0.8869 and 0.7910, respectively. What's more, 10, 10, and 8 out of the top 10 microbes predicted to be most likely to be associated with Asthma, Colorectal carcinoma and Type 1 diabetes were all verified by relevant literatures or database HMDAD, respectively. The above results verify the superior predictive performance of ABHMDA.

Differential Diagnosis of Pulmonary Artery Sarcoma and Central Chronic Pulmonary Thromboembolism Using CT and MR Images.

BACKGROUND: Clinical and imaging manifestations are similar in pulmonary artery sarcomas (PAS) and thromboembolic diseases, especially central chronic pulmonary thromboembolism (CPTE). The feasibility of utilising clinical imaging tools such as computed tomography (CT) and magnetic resonance imaging (MRI) for differential diagnosis of PAS and CPTE has not been fully explored, especially MRI. METHODS: Patients with PAS (n=18) and central CPTE (n=20) treated at our hospital between January 2013 and September 2016 were identified retrospectively. Computed tomography and MRI findings of pulmonary artery (PA) filling defects including the location, the involvement of pulmonary artery, morphology, signal intensities and enhancement in MRI, calcification, sizes of right atrium and ventricle, inner diameters of the pulmonary artery trunk and branches, and mediastinal collateral circulation in both groups were examined, and differences were analysed by Fisher exact test and independent sample t-test. RESULTS: Compared to those of central CPTE, PAS lesions were in full shape or expansive growth (p<0.001), and the proximal end of the tumours was often bulging or lobulated (p<0.001). These lesions were aneurysm- or grape-like distally (p<0.01) with inhomogeneous enhancement (p<0.001). The MRI contrast enhancement pattern of PAS lesions were cloudy with inhomogeneous delayed enhancement and the time-density curves for some of the lesions increased gradually. CONCLUSION: Computed tomographic and MR imaging manifestations may resemble PAS and central CPTE; however, some manifestations still have great value for the differential diagnosis of these two conditions, specifically the morphology and MRI enhancement patterns.

ASDCD: antifungal synergistic drug combination database.

Finding effective drugs to treat fungal infections has important clinical significance based on high mortality rates, especially in an immunodeficient population. Traditional antifungal drugs with single targets have been reported to cause serious side effects and drug resistance. Nowadays, however, drug combinations, particularly with respect to synergistic interaction, have attracted the attention of researchers. In fact, synergistic drug combinations could simultaneously affect multiple subpopulations, targets, and diseases. Therefore, a strategy that employs synergistic antifungal drug combinations could eliminate the limitations noted above and offer the opportunity to explore this emerging bioactive chemical space. However, it is first necessary to build a powerful database in order to facilitate the analysis of drug combinations. To address this gap in our knowledge, we have built the first Antifungal Synergistic Drug Combination Database (ASDCD), including previously published synergistic antifungal drug combinations, chemical structures, targets, target-related signaling pathways, indications, and other pertinent data. Its current version includes 210 antifungal synergistic drug combinations and 1225 drug-target interactions, involving 105 individual drugs from more than 12,000 references. ASDCD is freely available at http://ASDCD.amss.ac.cn.

A computational framework to infer human disease-associated long noncoding RNAs.

As a major class of noncoding RNAs, long noncoding RNAs (lncRNAs) have been implicated in various critical biological processes. Accumulating researches have linked dysregulations and mutations of lncRNAs to a variety of human disorders and diseases. However, to date, only a few human lncRNAs have been associated with diseases. Therefore, it is very important to develop a computational method to globally predict potential associated diseases for human lncRNAs. In this paper, we developed a computational framework to accomplish this by combining human lncRNA expression profiles, gene expression profiles, and human disease-associated gene data. Applying this framework to available human long intergenic noncoding RNAs (lincRNAs) expression data, we showed that the framework has reliable accuracy. As a result, for non-tissue-specific lincRNAs, the AUC of our algorithm is 0.7645, and the prediction accuracy is about 89%. This study will be helpful for identifying novel lncRNAs for human diseases, which will help in understanding the roles of lncRNAs in human diseases and facilitate treatment. The corresponding codes for our method and the predicted results are all available at http://asdcd.amss.ac.cn/MingXiLiu/lncRNA-disease.html.

Prediction of disease-related interactions between microRNAs and environmental factors based on a semi-supervised classifier.

Accumulated evidence has shown that microRNAs (miRNAs) can functionally interact with a number of environmental factors (EFs) and their interactions critically affect phenotypes and diseases. Therefore, in-silico inference of disease-related miRNA-EF interactions is becoming crucial not only for the understanding of the mechanisms by which miRNAs and EFs contribute to disease, but also for disease diagnosis, treatment, and prognosis. In this paper, we analyzed the human miRNA-EF interaction data and revealed that miRNAs (EFs) with similar functions tend to interact with similar EFs (miRNAs) in the context of a given disease, which suggests a potential way to expand the current relation space of miRNAs, EFs, and diseases. Based on this observation, we further proposed a semi-supervised classifier based method (miREFScan) to predict novel disease-related interactions between miRNAs and EFs. As a result, the leave-one-out cross validation has shown that miREFScan obtained an AUC of 0.9564, indicating that miREFScan has a reliable performance. Moreover, we applied miREFScan to predict acute promyelocytic leukemia-related miRNA-EF interactions. The result shows that forty-nine of the top 1% predictions have been confirmed by experimental literature. In addition, using miREFScan we predicted and publicly released novel miRNA-EF interactions for 97 human diseases. Finally, we believe that miREFScan would be a useful bioinformatic resource for the research about the relationships among miRNAs, EFs, and human diseases.

RWRMDA: predicting novel human microRNA-disease associations.

Recently, more and more research has shown that microRNAs (miRNAs) play critical roles in the development and progression of various diseases, but it is not easy to predict potential human miRNA-disease associations from the vast amount of biological data. Computational methods for predicting potential disease-miRNA associations have gained a lot of attention based on their feasibility, guidance and effectiveness. Differing from traditional local network similarity measures, we adopted global network similarity measures and developed Random Walk with Restart for MiRNA-Disease Association (RWRMDA) to infer potential miRNA-disease interactions by implementing random walk on the miRNA-miRNA functional similarity network. We tested RWRMDA on 1616 known miRNA-disease associations based on leave-one-out cross-validation, and achieved an area under the ROC curve of 86.17%, which significantly improves previous methods. The method was also applied to three cancers for accuracy evaluation. As a result, 98% (Breast cancer), 74% (Colon cancer), and 88% (Lung cancer) of top 50 predicted miRNAs are confirmed by published experiments. These results suggest that RWRMDA will represent an important bioinformatics resource in biomedical research of both miRNAs and diseases.

Drug-target interaction prediction by random walk on the heterogeneous network.

Predicting potential drug-target interactions from heterogeneous biological data is critical not only for better understanding of the various interactions and biological processes, but also for the development of novel drugs and the improvement of human medicines. In this paper, the method of Network-based Random Walk with Restart on the Heterogeneous network (NRWRH) is developed to predict potential drug-target interactions on a large scale under the hypothesis that similar drugs often target similar target proteins and the framework of Random Walk. Compared with traditional supervised or semi-supervised methods, NRWRH makes full use of the tool of the network for data integration to predict drug-target associations. It integrates three different networks (protein-protein similarity network, drug-drug similarity network, and known drug-target interaction networks) into a heterogeneous network by known drug-target interactions and implements the random walk on this heterogeneous network. When applied to four classes of important drug-target interactions including enzymes, ion channels, GPCRs and nuclear receptors, NRWRH significantly improves previous methods in terms of cross-validation and potential drug-target interaction prediction. Excellent performance enables us to suggest a number of new potential drug-target interactions for drug development.

[Expression of annexin A7 in spermatogonial stem cells].

OBJECTIVE: To study the expression of Annexin A7 in the mouse testis, especially in different types of spermatogonia. METHODS: We prepared Annexin A7 recombinant protein using prokaryotic expression, adsorbed the Annexin A7 antibody with it after identified by mass spectrometry, and detected the expression of Annexin A7 by Western-blot and immunohistochemistry. RESULTS: Annexin A7 was expressed in a development-dependent manner in the spermatogonia of the prepubertal mice and in the type-A single (As) and type-A paired (Apr) spermatogonia of adult mice. These results were confirmed by the co-localization of Annexin A7 and Stra8, a known determinant of differentiated spermatogonial stem cells (SSCs). CONCLUSION: Annexin A7 is the internal factor of As and Apr spermatogonia, which might be involved in the biological functions of SSCs.