Quantitative description of dose-response of a drug for complex systems is essential for treatment of diseases and drug discovery. Given the growth of large-scale biological data obtained by multi-level assays, computational modeling has become an important approach to understand the mechanism of drug action. However, due to complicated interactions between drugs and cellular targets, the prediction of drug efficacy is a challenge, especially for complex systems. And the biological systems can be regarded as networks, where nodes represent molecular entities (DNA, RNA, protein and small compound) and processes, edges represent the relationships between nodes. Thus we combine biological pathway-based network modeling and molecular docking to evaluate drug efficacy.

Despite good initial response to chemotherapy, 30% of Ewing's sarcoma (EWS) patients with localised tumours develop recurrent disease, associated with poor prognosis. The aim of this study was to address this challenge by conducting preclinical evaluation of a death receptor targeted agent in vitro and in vivo, and by identifying predictive biomarkers.

Olaparib (O), a polyADPribose polymerase (PARP) inhibitor, and cediranib (C), a VEGF receptor (VEGFR)1-3 inhibitor together had greater activity than O alone in women with recurrent platinum-sensitive ovarian cancer (OvCa). The objective of this study is to identify potential lead biomarker candidates for response to O + C in the setting of a multi-institutional phase II study of O with and without C in recurrent platinum-sensitive OvCa.

As part of our continual efforts to exploit 'Tujia Ethnomedicine' for their pharmacophoric functionalities, we herein investigated Kadsura heteroclita collected from a deep Wulin mountain area in northern Hunan province. The current study resulted in the isolation of three new sesquiterpenes: 6α,9α,15-trihydroxycadinan-4-en-3-one (1), (+)-3,11,12-trihydroxycalamenene (2), (-)-3,10,11,12-tetrahydroxy-calamenene (3), along with four known sesquiterpenes (4-7), and a cytochalasin H (8). Their chemical structures were elucidated by 1D-, and 2D-NMR spectroscopy, and HRESI-MS, CD spectrometry. The antioxidant, and cytotoxic activities of the compounds were evaluated. Compound 8 exhibited a strong antioxidant effect with an IC50 value of 3.67 µM on isolated human polymorphonuclear cells or neutrophils.

Glioblastoma (GBM) is the most common primary brain tumor with median survival of approximately one year. This dismal poor prognosis is due to resistance to currently available chemotherapeutics; therefore, new cytotoxic agents are urgently needed. In the present study, we reported the cytotoxicity of toosendanin (TSN) in the GBM U87 and C6 cell lines in vitro and in vivo. By using the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, flow cytometry analysis, and Western blot, we found that TSN inhibited U87 and C6 cell proliferation and induced apoptosis at a concentration as low as 10 nM. Administration of TSN also reduced tumor burden in a xenograft model of athymic nude mice. Pharmacological and molecular studies suggested that estrogen receptor β (ERβ) and p53 were prominent targets for TSN. GBM cell apoptosis induced by TSN was a stepwise biological event involving the upregulation of ERβ and contextual activation of functional p53. Collectively, our study indicates, for the first time, that TSN is a candidate of novel anti-cancer drugs for GBM. Furthermore, ERβ and p53 could act as predictive biomarkers for the sensitivity of cancer to TSN.

Due to the lack of strong evidence to identify the relationship between antihypertensive drugs use and the risk of prostate cancer, it was needed to do a systematic review to go into the subject.

Sinomenine (SIN), a pure alkaloid isolated from Sinomenium acutum, has been widely used in arthritis for its anti‑inflammatory effect, but little is known about the effect of SIN on human ulcerative colitis (UC). In the present study, the effect and mechanism of SIN was examined in a dextran sulfate sodium (DSS)‑induced murine colitis model, which mimics human UC. Oral administration of SIN significantly suppressed the elevated disease activity index and ameliorated colonic histological damage in a DSS‑induced colitis model. Tumor necrosis factor‑α, interleukin‑6 and inducible nitric oxide synthase levels were also reduced as detected by reverse transcription‑quantitative polymerase chain reaction. In addition, SIN reversed the decreased colon length and colonic superoxide dismutase activity. Furthermore, western blot analysis revealed that nuclear factor‑erythroid 2‑related factor 2 (Nrf2) and its downstream genes, heme oxygenase‑1 and NADP(H) quinone oxidoreductase 1 (NQO‑1), were markedly activated by SIN. The current results indicated that SIN alleviated DSS‑induced colitis in mice, which may be due to its antioxidant properties and was at least in part dependent on the Nrf2/NQO‑1 signaling pathway. Therefore, SIN may have potential applications as a protective drug for patients with UC.

The hepatitis C virus (HCV) core protein is a multifunctional protein that can interfere with the induction of an immune response. It has been reported that the HCV core protein inhibits HBV replication in vitro. In this study, we test the effect of the HCV core gene on the priming of the immune response to hepatitis B surface antigen (HBsAg) and on the replication of HBV in vivo. Our results showed that the full-length HCV core gene inhibits the induction of an immune response to the heterogeneous antigen, HBsAg, at the site of inoculation when HCV core (pC191) and HBsAg (pHBsAg) expression plasmids are co-administered as DNA vaccines into BALB/c mice. The observed interference effect of the HCV core occurs in the priming stage and is limited to the DNA form of the HBsAg antigen, but not to the protein form. The HCV core reduces the protective effect of the HBsAg when the HBsAg and the HCV core are co-administered as vaccines in an HBV hydrodynamic mouse model because the HCV core induces immune tolerance to the heterogeneous HBsAg DNA antigen. These results suggest that HCV core may play an important role in viral persistence by the attenuation of host immune responses to different antigens. We further tested whether the HCV core interfered with the priming of the immune response in hepatocytes via the hydrodynamic co-injection of an HBV replication-competent plasmid and an HCV core plasmid. The HCV core inhibited HBV replication and antigen expression in both BALB/c (H-2d) and C57BL/6 (H-2b) mice, the mouse models of acute and chronic hepatitis B virus infections. Thus, the HCV core inhibits the induction of a specific immune response to an HBsAg DNA vaccine. However, HCV C also interferes with HBV gene expression and replication in vivo, as observed in patients with coinfection.

Diabetic cardiomyopathy is a common disease in postmenopausal women, in whom the estrogen deficiency aggravates the pathology. In this study, we have found that estrogen deficiency due to ovariectomy aggravates the inflammation in the hearts of diabetic mice, as depicted by excessive proinflammatory type 1 macrophages (M1) over anti-inflammatory type 2 macrophages (M2). Accordingly, an additional increase of reactive oxygen species, cell apoptosis, cardiac hypertrophy, and fibrosis was observed in the hearts of ovariectomized diabetic mice, in comparison with the diabetes-only group. Significantly, miR155, a potent promoter of M1 polarization, was found to be additionally enhanced in the macrophages and hearts by ovariectomy. Tail vein injection of miR155-AuNP, in which thiol-modified antago-miR155 was covalently conjugated with gold nanoparticle (AuNP), preferentially delivered the nucleic acids into the macrophages via phagocytosis. Together with the increased M2 ratio and reduced inflammation, in vivo delivery of antago-miR155 reduced cell apoptosis and restored the cardiac function. The restoration efficacy of miR155-AuNP was much better than general macrophage depletion by clodrosome. In summary, we revealed that M1/M2 imbalance contributes to the aggravated cardiomyopathy in ovariectomized diabetic mice, and therapeutically reducing miR155 in macrophages by AuNP serves as a promising strategy in improving cardiac function.

An efficient route without metal catalyst has been developed for synthesis of 4-biphenylamino-5-halo-2(5H)-furanones. The antitumor activities against various tumor cells of all the compounds have been evaluated by MTT assay. Among them, the compound 3j exhibits significant inhibitory activity against MCF-7 human breast cancer cells with an IC50 value of 11.8 μM and low toxicity toward HaCaT human normal cells. The mechanism studies confirm that 3j can induce cell cycle arrest at G2/M phase in MCF-7 cells. Compared with compound 3e, 3j has stronger binding affinity to c-myc G-quadruplex (G4) DNA via π-π stacking and H-bonding interactions. Western blot analysis also further confirms that compound 3j can down-regulate the expression of c-myc in MCF-7 cells.

Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Our recent study demonstrates that N-type Ca2+ currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Only AVG nerve terminals innervate the ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG neurons with ventricular arrhythmogenesis in CHF rats. Methods and Results: CHF was induced in male Sprague-Dawley rats by surgical ligation of the left coronary artery. The data from 24-h continuous radiotelemetry ECG recording in conscious rats showed that ventricular tachycardia/fibrillation (VT/VF) occurred in 3 and 14-week CHF rats but not 8-week CHF rats. Additionally, as an index for vagal control of ventricular function, changes of left ventricular systolic pressure (LVSP) and the maximum rate of left ventricular pressure rise (LV dP/dtmax) in response to vagal efferent nerve stimulation were blunted in 14-week CHF rats but not 3 or 8-week CHF rats. Results from whole-cell patch clamp recording demonstrated that N-type Ca2+ currents in AVG neurons began to decrease in 8-week CHF rats, and that there was also a significant decrease in 14-week CHF rats. Correlation analysis revealed that N-type Ca2+ currents in AVG neurons negatively correlated with the cumulative duration of VT/VF in 14-week CHF rats, whereas there was no correlation between N-type Ca2+ currents in AVG neurons and the cumulative duration of VT/VF in 3-week CHF. Conclusion: Malignant ventricular arrhythmias mainly occur in the early and late stages of CHF. Electrical remodeling of AVG neurons highly correlates with the occurrence of ventricular arrhythmias in the late stage of CHF.

Porcine circovirus type 1 (PCV1) was discovered in 1974 as a contaminant of a porcine kidney (PK-15) cell line and was generally accepted to be nonpathogenic. But recently it was shown to cause lesions in experimentally infected pig fetuses. Serological evidence and genetic studies suggested that PCV1 was widespread in domestic pigs. Thus, the molecular epidemiology and genetic variation of PCV1 are still necessary to understand.

Lonicera japonica Thunb, rich in chlorogenic acid (CHA), is used for viral upper respiratory tract infection treatment caused by influenza virus, parainfluenza virus, and respiratory syncytial virus, ect in China. It was reported that CHA reduced serum hepatitis B virus level and death rate of influenza virus-infected mice. However, the underlying mechanisms of CHA against the influenza A virus have not been fully elucidated. Here, the antiviral effects and potential mechanisms of CHA against influenza A virus were investigated. CHA revealed inhibitory against A/PuertoRico/8/1934(H1N1) (EC50 = 44.87 μM), A/Beijing/32/92(H3N2) (EC50 = 62.33 μM), and oseltamivir-resistant strains. Time-course analysis showed CHA inhibited influenza virus during the late stage of infectious cycle. Indirect immunofluorescence assay indicated CHA down-regulated the NP protein expression. The inhibition of neuraminidase activity confirmed CHA blocked release of newly formed virus particles from infected cells. Intravenous injection of 100 mg/kg/d CHA possessed effective antiviral activity in mice, conferring 60% and 50% protection from death against H1N1 and H3N2, reducing virus titres and alleviating inflammation in the lungs effectively. These results demonstrate that CHA acts as a neuraminidase blocker to inhibit influenza A virus both in cellular and animal models. Thus, CHA has potential utility in the treatment of the influenza virus infection.

Porcine deltacoronavirus (PDCoV) has been detected sporadically in China since its first description in 2012. In our study, 62 faecal and intestinal samples from pigs with diarrhoea were collected in Guangxi Province, China, during 2017 and 2018. Twelve samples (19.4%, 12/62) were positive for PDCoV. Five complete genomes of PDCoV were then determined, and sequence alignment revealed that the five strains had discontinuous deletions at 400-401 aa in non-structural protein 2 (NSP2) and 758-760 aa in non-structural protein 3 (NSP3) compared with the respective proteins in the HKU15-44 strain. Notably, the CHN-GX81-2018 strain contained two insertions in the S gene and 3'-UTR. Multiple sequence alignment and phylogenetic analysis showed that four strains shared 98.2%-98.4% nucleotide identity with CHN-AH-2004 and were classified into a new cluster of China lineage strains, whereas the CHN-GX81-2018 strain shared 98.7% nucleotide identity with Vietnam/Binh21/2015 and belonged to the Vietnam/Laos/Thailand lineage. Recombination analyses revealed that four strains were the result of recombination between CHN-HB-2014 and Vietnam/Binh21/2015 strains. This study demonstrated the co-existence of multiple lineages of PDCoV in China, and our findings will aid the reorganization and evolution of the virus.

Circulating tumor cells (CTCs) have been regarded as an independent prognostic marker for metastatic castration-resistant prostate cancer (mCRPC). Its prognostic value, however, in nonmetastatic prostate cancer (NMPC) is still unclear.

Kidney stones have become a worldwide public health problem. The purpose of this research is to study the relationship between plasma cadmium level and the prevalence of kidney stones in an adult population.

Diterpene Ginkgolides Meglumine Injection (DGMI) is made of extracts from Ginkgo biloba L, including Ginkgolides A, B, and K and some other contents, and has been widely used as the treatment of cerebral ischemic stroke in clinic. It can be learned from the "Compendium of Materia Medica" that Ginkgo possesses the effect of "dispersing toxin". The ancient Chinese phrase "dispersing toxin" is now explained as elimination of inflammation and oxidative state in human body. And it led to the original ideas for today's anti-oxidation studies of Ginkgo in apoptosis induced by optic nerve crush injury.

N6-methyladenosine (m6A), the most common form of RNA modification, controls CD4+ T cell homeostasis by targeting the IL-7/STAT5/SOCS signaling pathways. The role of m6A modification in unconventional T cell development remains unknown. Using mice with T cell-specific deletion of RNA methyltransferase METTL14 (T-Mettl14-/-), we demonstrate that m6A modification is indispensable for iNKT cell homeostasis. Loss of METTL14-dependent m6A modification leads to the upregulation of apoptosis in double-positive thymocytes, which in turn decreases Vα14-Jα18 gene rearrangements, resulting in drastic reduction of iNKT numbers in the thymus and periphery. Residual T-Mettl14-/- iNKT cells exhibit increased apoptosis, impaired maturation, and decreased responsiveness to IL-2/IL-15 and TCR stimulation. Furthermore, METTL14 knockdown in mature iNKT cells diminishes their cytokine production, correlating with increased Cish expression and decreased TCR signaling. Collectively, our study highlights a critical role for METTL14-dependent-m6A modification in iNKT cell development and function.

Mesothelin (MSLN) is overexpressed by many cancers, including pancreatic ductal adenocarcinoma (PDAC) and has consequently become a target for anti-cancer therapeutics. Mature, membrane bound MSLN is cleaved by proteases, releasing a shed form that transits to the circulation. Many patients with mesothelioma and ovarian cancer have abnormally high serum MSLN concentration. However, serum MSLN concentration in PDAC patients rarely exceeds levels of healthy controls. Here, serum MSLN concentration in advanced PDAC patients was examined pre- and post-treatment. Serum MSLN did not correlate with tumor MSLN expression, nor with changes in tumor burden as assessed by PDAC serum tumor marker CA19-9. Subsequently, tumor-bearing mouse models were used to investigate the fate of shed MSLN in PDAC versus a control cervical cancer model. Efficiency of MSLN secretion into the serum was cell-line dependent. Tumors from some PDAC lines had poor MSLN secretion efficiency although these lines had similar or higher MSLN shedding rate, total and surface MSLN expression. Measurements of compartment-specific MSLN concentration taken at equilibrium suggested that tumors with poor MSLN secretion efficiency trapped shed MSLN in the tumor microenvironment (TME), a finding confirmed by dynamic experiments using a doxycycline-inducible MSLN expression system. Tumors with the poorest MSLN secretion efficiency had higher collagen density and increased abundance of MSLN binding partner MUC16. The tumor with the worst secretion efficiency could rebind shed MSLN to the cancer cell surface. Altogether, these data suggest that PDAC can trap shed MSLN within the TME. This finding has potential significance for design of MSLN-targeted therapeutics.

The long-term effect of extracorporeal shock wave lithotripsy (SWL) is still controversial. A previous meta-analysis showed no association between new-onset hypertension and entire upper urinary urolithiasis after SWL. Recently, there have been some reports on this topic. Therefore, we aimed to examine the association between new-onset hypertension and nephrolithiasis after SWL therapy.