Circadian clock-mediated nuclear receptors in cancer.

Circadian system coordinates the daily periodicity of physiological and biochemical functions to adapt to environmental changes. Circadian disruption has been identified to increase the risk of cancer and promote cancer progression, but the underlying mechanism remains unclear. And further mechanistic understanding of the crosstalk between clock components and cancer is urgent to achieve clinical anticancer benefits from chronochemotherapy. Recent studies discover that several nuclear receptors regulating circadian clock, also play crucial roles in mediating multiple cancer processes. In this review, we aim to summarize the latest developments of clock-related nuclear receptors in cancer biology and dissect mechanistic insights into how nuclear receptors coordinate with circadian clock to regulate tumorigenesis and cancer treatment. A better understanding of circadian clock-related nuclear receptors in cancer could help prevent tumorigenesis and improve anticancer efficacy.

E2F6/KDM5C promotes SF3A3 expression and bladder cancer progression through a specific hypomethylated DNA promoter.

BACKGROUND: Abnormal expression of splicing factor 3A subunit 3 (SF3A3), a component of the spliceosome, has been confirmed to be related to the occurrence and development of various cancers. However, the expression and function of SF3A3 in bladder cancer (BC) remains unclear. METHODS: The SF3A3 mRNA and protein level were measured in clinical samples and cell lines by quantitative real-time PCR, Western blot and immunofluorescence staining. Evaluate the clinical correlation between SF3A3 expression and clinicopathological characteristics through statistical analysis in BC patients. The function of SF3A3 in BC cells was determined in vitro using MTT and colony analysis. Co-immunoprecipitation (CoIP) assay was used to detected E2F6 and KDM5C interaction. Luciferase reporter and chromatin immunoprecipitation (ChIP) were used to examine the relationship between E2F6/KDM5C and SF3A3 expression. RESULTS: In the present study, we demonstrated that expression of SF3A3 was elevated in BC tissue compared to the normal bladder tissue. Importantly, the upregulation of SF3A3 in patients was correlated with poor prognosis. Additionally, overexpression of SF3A3 promoted while depletion of SF3A3 reduced the growth of BC cells in vivo and in vitro. Data from the TCGA database and clinical samples revealed that hypomethylation of the DNA promoter leads to high expression of SF3A3 in BC tissue. We found that upregulation of lysine-specific demethylase 5C (KDM5C) promotes SF3A3 expression via hypomethylation of the DNA promoter. The transcription factor E2F6 interacts with KDM5C, recruits KDM5C to the SF3A3 promoter, and demethylates the GpC island of H3K4me2, leading to high SF3A3 expression and BC progression. CONCLUSIONS: The results demonstrated that depletion of the KDM5C/SF3A3 prevents the growth of BC in vivo and in vitro. The E2F6/KDM5C/SF3A3 pathway may be a potential therapeutic target for BC treatment.

Structure-dependent of 3-fluorooxindole derivatives interacting with ctDNA: Binding effects and molecular docking approaches.

3-Fluorooxindole has been shown to be a biologically active structural unit, novel derivative containing 3-fluorooxindole unit has been successfully constructed using 3-fluorooxindole as a substrate in previous work. Here, the interactions between novel 3-fluorooxindole derivatives and ctDNA were explored through molecular docking, multi-spectral and NMR methods, and the dependence of the binding mechanism on the structure was revealed by combined physical chemistry and organic chemistry. Firstly, molecular docking indicated that the planarity of the molecule enhances the binding strength to ctDNA. UV absorption result showed a weak binding effect. Fluorescence spectroscopy suggested the binding mechanism of 3-fluorooxindoles and ctDNA via groove binding. Moreover, the binding mechanism of 3-fluorooxindoles to ctDNA was further confirmed by 1H NMR spectroscopy, viscometry, and CD spectroscopy as groove binding. FT-IR spectroscopy reflected a more obvious disturbance of the phosphate group in the groove region of ctDNA. Electrochemistry was also used to probe the binding strength of 3-fluorooxindoles to ctDNA, and it showed a weak binding strength. From the above study, we concluded that 3-fluorooxindoles bind mainly in the groove region of ctDNA with weak binding strength. This study provides an idea for the activity screening aspect of 3-fluorooxindole derivatives from molecular planarity consideration and relevant information on biophysical and bioorganic aspects for drug development.

Successful Urgent TAVI for Critical Aortic Valve Stenosis after ECMO Implantation.

Transcatheter aortic valve implantation (TAVI) has evolved to be the treatment of choice for patients with severe aortic stenosis and high perioperative risk. Cardiogenic shock is one of the most severe complications during the TAVI procedure, especially as the prognosis of cardiogenic shock secondary to aortic stenosis is very poor. This situation can be challenging, while extracorporeal membranous oxygenation (ECMO) can be a treatment option. Here, we reported on an 88-year-old female patient who had been diagnosed as non-ST-elevation myocardial infarction (NSTEMI) and critical aortic valve stenosis (AS) with a logistic Euroscore of 25%. Percutaneous coronary angioplasty (PCI) was performed smoothly and developed tachy-brady arrhythmia of atrial fibrillation then cardiac arrest at the beginning of the TAVI procedure. A v-a ECMO was installed at her left femoral side. Afterward, the TAVI procedure was completed accordingly; her consciousness recovered and Levosimendan therapy enhanced her left-ventricular ejection fraction (LVEF) from 22% to 40%. Five days after TAVI, ECMO was replaced by intra-aortic balloon pumping (IABP) and it was removed 3 days later. A minor complication of this therapy, e.g., muscular weakness in her left leg, was noted. The patient underwent rehabilitation for about 2 months, and was discharged from hospital with a wheel chair and clear consciousness. At the 24 month follow-up she was in good recovery and was able to walk upstairs to the second floor again. Our experience suggests that one indication of prophylactic use of ECMO is for patients with an unstable hemodynamic condition.

Epithelial cell adhesion molecule promotes breast cancer resistance protein-mediated multidrug resistance in breast cancer by inducing partial epithelial-mesenchymal transition.

Overexpression of breast cancer resistance protein (BCRP) plays a crucial role in the acquired multidrug resistance (MDR) in breast cancer. The elucidation of molecular events that confer BCRP-mediated MDR is of major therapeutic importance in breast cancer. Epithelial cell adhesion molecule (EpCAM) has been implicated in tumor progression and drug resistance in various types of cancers, including breast cancer. However, the role of EpCAM in BCRP-mediated MDR in breast cancer remains unknown. In the present study, we revealed that EpCAM expression was upregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and EpCAM knockdown using siRNA reduced BCRP expression and increased the sensitivity of MCF-7/MX cells to mitoxantrone (MX). The epithelial-mesenchymal transition (EMT) promoted BCRP-mediated MDR in breast cancer cells, and EpCAM knockdown partially suppressed EMT progression in MCF-7/MX cells. In addition, Wnt/ß-catenin signaling was activated in MCF-7/MX cells, and the inhibition of this signaling attenuated EpCAM and BCRP expression and partially reversed EMT. Together, this study illustrates that EpCAM upregulation by Wnt/ß-catenin signaling induces partial EMT to promote BCRP-mediated MDR resistance in breast cancer cells. EpCAM may be a potential therapeutic target for overcoming BCRP-mediated resistance in human breast cancer.

Detection of interleukin-8 on microgapped dual electrodes for measuring asthma complication.

Detection of asthma by a suitable biomarker is mandatory for the early identification, which helps in providing a right medication for the complete cure. Interleukins (ILs) have played a major role in asthma; in particular IL-8 is highly correlated with severe asthma. This research was focused on to detect IL-8 level by its partner antibody on a microgapped dual electrodes sensor. The sensing surface was modified into graphene oxide (GO), and an antibody was fixed by using the amine-aldehyde linker. GO enhanced the antibody immobilization and the consequence electric current flow upon interacting with IL-8. The detection limit of IL-8 was reached to 10 pg/mL in a linear range from 1 to 10,000 pg/mL with the regression of y = 0.7246x - 0.906 (R² = 0.9758); further, the sensitivity falls at 1 pg/mL. The surface does not show the antifouling effect with control antibody, and proteins, indicating the specific IL-8 detection. The detection of IL-8 helps in diagnosing and solving the related problems of asthmatic patients.

ß2-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia.

OBJECTIVE: ß2-Adrenoceptor agonists are widely used to treat asthma because of their bronchial-dilation effects. We previously reported that isoprenaline, via the apical and basolateral ß2-adrenoceptor, induced Cl- secretion by activating cyclic AMP (cAMP)-dependent pathways in human bronchial epithelia. Despite these results, whether and how the ß2-adrenoceptor-mediated cAMP-dependent pathway contributes to pro-inflammatory cytokine release in human bronchial epithelia remains poorly understood. METHODS: We investigated ß2-adrenoceptor-mediated signaling pathways involved in the production of two pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, in 16HBE14o- human bronchial epithelia. The effects of isoprenaline or formoterol were assessed in the presence of protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), Src, and extracellular signal-regulated protein kinase (ERK)1/2 inhibitors. The involvement of ß-arrestin2 was examined using siRNA knockdown. RESULTS: Isoprenaline and formoterol (both ß2 agonists) induced IL-6, but not IL-8, release, which could be inhibited by ICI 118,551 (ß2 antagonist). The PKA-specific inhibitor, H89, partially inhibited IL-6 release. Another intracellular cAMP receptor, EPAC, was not involved in IL-6 release. Isoprenaline-mediated IL-6 secretion was attenuated by dasatinib, a Src inhibitor, and PD98059, an ERK1/2 inhibitor. Isoprenaline treatment also led to ERK1/2 phosphorylation. In addition, knockdown of ß-arrestin2 by siRNA specifically suppressed cytokine release when a high concentration of isoprenaline (1 mM) was used. CONCLUSION: Our results suggest that activation of the ß2-adrenoceptor in 16HBE14o- cells stimulated the PKA/Src/ERK1/2 and/or ß-arrestin2 signaling pathways, leading to IL-6 release. Therefore, our data reveal that ß2-adrenoceptor signaling plays a role in the immune regulation of human airway epithelia.

Carriage of Clostridioides difficile in healthy infants in the community of Handan, China: A 1-year follow-up study.

OBJECTIVE: Clostridioides difficile may colonize healthy infants and young children asymptomatically and for the long-term. C. difficile genotypes and the rate and determinants of colonization differ substantially and vary among countries and regions. A 1-year follow-up study was performed to determine the incidence, kinetics and influencing factors of C. difficile intestinal colonization. METHODS: Twenty-nine healthy infants (14 girls and 15 boys) living at home with their parents in Handan City were followed by survey from birth to 1 year of age, specifically from October 2014 through December 2015. C. difficile isolates were typed by PCR ribotyping and analyzed for the presence of toxin genes. RESULTS: During the follow-up study period in the first year of life, 20 of the 29 total enrolled infants acquired C. difficile. A total of 437 fecal samples were obtained, and 111 (25.4%) samples contained C. difficile, including 79 (71.2%) toxigenic strains. The toxigenic isolates comprised six PCR ribotypes, and two PCR ribotypes were identified as nontoxigenic strains. CONCLUSION: Our study showed that C. difficile colonization increase with age during the 12-month period, and the dominant toxigenic types of C. difficile isolates in infants were those involved in long-term colonization. Feeding patterns may affect the dynamic progress of C. difficile colonization.

Nickel-Catalyzed Asymmetric Reductive Carbo-Carboxylation of Alkenes with CO2.

Reductive carboxylation of organo (pseudo)halides with CO2 is a powerful method to provide carboxylic acids quickly. Notably, the catalytic reductive carbo-carboxylation of unsaturated hydrocarbons via CO2 fixation is a highly challenging but desirable approach for structurally diverse carboxylic acids. There are only a few reports and no examples of alkenes via transition metal catalysis. We report the first asymmetric reductive carbo-carboxylation of alkenes with CO2 via nickel catalysis. A variety of aryl (pseudo)halides, such as aryl bromides, aryl triflates and inert aryl chlorides of particular note, undergo the reaction smoothly to give important oxindole-3-acetic acid derivatives bearing a C3-quaternary stereocenter. This transformation features mild reaction conditions, wide substrate scope, facile scalability, good to excellent chemo-, regio- and enantioselectivities. The method highlights the formal synthesis of (-)-Esermethole, (-)-Physostigmine and (-)-Physovenine, and the total synthesis of (-)-Debromoflustramide B, (-)-Debromoflustramine B and (+)-Coixspirolactam A; thereby, opening an avenue for the total synthesis of chiral natural products with CO2 .

Integrating random walk and binary regression to identify novel miRNA-disease association.

BACKGROUND: In the last few decades, cumulative experimental researches have witnessed and verified the important roles of microRNAs (miRNAs) in the development of human complex diseases. Benefitting from the rapid growth both in the availability of miRNA-related data and the development of various analysis methodologies, up until recently, some computational models have been developed to predict human disease related miRNAs, efficiently and quickly. RESULTS: In this work, we proposed a computational model of Random Walk and Binary Regression-based MiRNA-Disease Association prediction (RWBRMDA). RWBRMDA extracted features for each miRNA from random walk with restart on the integrated miRNA similarity network for binary logistic regression to predict potential miRNA-disease associations. RWBRMDA obtained AUC of 0.8076 in the leave-one-out cross validation. Additionally, we carried out three different patterns of case studies on four human complex diseases. Specifically, Esophageal cancer and Prostate cancer were conducted as one kind of case study based on known miRNA-disease associations in HMDD v2.0 database. Out of the top 50 predicted miRNAs, 94 and 90% were respectively confirmed by recent experimental reports. To simulate new disease without known related miRNAs, the information of known Breast cancer related miRNAs was removed. As a result, 98% of the top 50 predicted miRNAs for Breast cancer were confirmed. Lymphoma, the verified ratio of which was 88%, was used to assess the prediction robustness of RWBRMDA based on the association records in HMDD v1.0 database. CONCLUSIONS: We anticipated that RWBRMDA could benefit the future experimental investigations about the relation between human disease and miRNAs by generating promising and testable top-ranked miRNAs, and significantly reducing the effort and cost of identification works.

lncRNA CCAT1 is a biomarker for the proliferation and drug resistance of esophageal cancer via the miR-143/PLK1/BUBR1 axis.

Recent evidence indicates that long noncoding RNA colon cancer-associated transcript-1 (lncRNA CCAT1) is abundantly expressed in esophageal cancer and is closely related to the occurrence, development, invasion, metastasis, and drug resistance of this disease. However, the role and molecular mechanisms of CCAT1 in the cell proliferation and chemoresistance of esophageal cancer are largely unknown. The correlation between CCAT1 expression and drug resistance to cisplatin (CDDP) in esophageal squamous cell carcinoma (ESCC) cells was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and quantitative real-time polymerase chain reaction (qRT-PCR) assays. CCAT1 knockdown and miR-143 overexpression or inhibition were used to verify the effects on proliferation and drug resistance via MTT, western blotting, flow cytometry, and immunofluorescence assays. qRT-PCR and western blotting were applied to detect the potential regulatory relationship among CCAT1, miR-143, PLK1, and BUBR1. A xenograft tumor assay was performed to validate the role of CCAT1 in vivo. The expression of CCAT1 was positively correlated with drug resistance in several ESCC cell lines. CCAT1 knockdown and miR-143 overexpression inhibited cell proliferation and CDDP drug resistance. Moreover, the downstream target of CCAT1 was found to be miR-143, which can regulate the expression of PLK1 and BUBR1. In vivo assays showed that CCAT1 knockdown suppressed tumor growth and enhanced the sensitivity of tumors to CDDP in nude mice. Taken together, we discovered a novel mechanism by which CCAT1 promotes cell proliferation and enhances drug resistance by regulating the miR-143/PLK1/BUBR1 signaling axis both in vitro and in vivo. Our findings further suggest that lncRNA CCAT1 may be a potential therapeutic target for overcoming chemoresistance in esophageal cancer.

Preventive Effects of Total Flavonoid C-Glycosides from Abrus mollis on Nonalcoholic Fatty Liver Disease through Activating the PPARα Signaling Pathway.

Abrus pulchellus subsp. mollis (Hance) Verdc. (Leguminosae) is a well-known edible plant usually added to soups and beverages. In this study, vicenin-2 (1: ), isoschaftoside (2: ), schaftoside (3: ), and their enrichment fraction, total flavonoid C-glycosides, derived from the extracts of A. mollis, were firstly found to prevent nonalcoholic fatty liver disease both in vitro and in vivo. In the in vitro study, total flavonoid C-glycosides decreased the lipid accumulation in oleic acid-treated HepG2 cells. The mechanisms of total flavonoid C-glycosides are involved in the regulation of peroxisome proliferator-activated receptor α and its downstream, and the reduction of proinflammatory cytokines. In high-fat diet-induced fatty liver rats, total flavonoid C-glycosides decreased the levels of glutamic-oxalacetic transaminease and glutamic-pyruvic transaminase, and decreased the lipid accumulation both in the liver and blood without affecting food intake. In addition, total flavonoid C-glycosides also increased the activities of the antioxidant enzyme system in vivo. In conclusion, total flavonoid C-glycosides are active components of A. mollis on nonalcoholic fatty liver disease, and can be used in functional food and supplements for nonalcoholic fatty liver disease prevention and treatment.

Epidemiological investigation of Clostridioides difficile colonization in Chinese community infants.

Clostridioides difficile is a colonizer of the human gut; asymptomatic colonization has been reported to be more common in infants and is highly variable across regions even with no symptoms of diarrhea or death. Antibiotic treatment strategies might increase the antibiotic resistance of C. difficile. We performed a one-point study involving 1098 healthy infants (0-36 months) to address the deficiency of reports on C. difficile colonization in Chinese community infants. The C. difficile colonization rate was 22.8% (250/1098), and more than half of the strains (55.2%) were toxigenic isolates. Among the 138 toxigenic isolates, 111 were of the A+B+CDT- genotype, 26 strains were A-B+CDT-, and one strain was A+B+CDT+. Fifteen different PCR ribotypes were found among the 250 isolates, and PCR-ribotype HB03 appeared to be dominant type, accounting for 19.6% (49/250). High levels of resistance to antimicrobial agents were observed. Our study showed that age and hospitalization before stool collection were positively correlated with the C. difficile colonization rate, whereas the delivery term was negatively related to the colonization rate. Particular attention should be paid to the increasing resistance of C. difficile to rifamycin.

The Utilization of Stress Tests Prior to Percutaneous Coronary Intervention for Stable Coronary Artery Disease in Taiwan.

BACKGROUND: Ischemia shown in non-invasive tests is considered to be a fundamental requirement for treating patients with stable coronary artery disease (CAD) with a percutaneous coronary intervention (PCI). In a nationwide cohort, we investigated the utilization of stress tests, including myocardial perfusion imaging (MPI), treadmill exercise test (TET) and stress echocardiography (SE) prior to elective PCI. METHODS: This retrospective study used the Longitudinal Health Insurance Database 2000 (LHID2000) of the National Health Insurance program in Taiwan. The LHID2000 is comprised of one million randomly sampled beneficiaries. We enrolled patients receiving elective PCI for stable CAD from 2000 to 2013. Stress tests performed within 90 days prior to PCI and patient characteristics correlated with the utilization of stress tests were investigated. RESULTS: During the investigation period, 3,163 patients received elective PCI for stable CAD and 1,847 (58.4%) patients had at least one stress test within 90 days prior to PCI. Among them, 1,461 (79.1%) had MPI, 1,228 had TET (66.4%) and only 1 had SE (0.05%). Age < 80 years, regional hospital and hyperlipidemia were independently associated with an increased likelihood of receiving stress tests. On the other hand, Charlson-comorbidity index score ≥ 1, prior catheterization and heart failure were independently associated with a decreased likelihood of receiving stress tests. CONCLUSIONS: In the setting of stable CAD, almost 60% of our patients received stress tests within 90 days prior to elective PCI, and MPI was the most commonly used test.

N-Methylcytisine Ameliorates Dextran-Sulfate-Sodium-Induced Colitis in Mice by Inhibiting the Inflammatory Response.

This study aimed to investigate the anti-inflammatory effects of N-methylcytisine (NMC) in a dextran sulfate sodium (DSS)-induced colitis model and explore its possible mechanisms. Experimental colitis was induced by administering the mice with 5% DSS for 7 days. Different doses of NMC (1, 4 and 16 mg/kg) and 5-aminosalicylic acid (100 mg/kg) were given orally once every day for 7 days. The protective effect of NMC was evaluated using the disease activity index, colon length and results of histopathological examination. The possible mechanisms of NMC were explored by evaluating the expression levels of tumour necrosis factor-α, interleukin-1ß and interleukin-6 (IL-6) using ELISA and analysing the protein expression levels of nuclear factor (NF)-κB p65, p-NF-κB p65, p-IκB, IκB, IκB kinase (IKK) and p-IKK using western blots. Results demonstrated that the oral administration of NMC attenuated the DSS-induced clinical symptoms and pathological damage. In addition, NMC treatment significantly reduced myeloperoxidase activity and level of pro-inflammatory cytokines. Further studies revealed that NMC blocked the activation of NF-κB by inhibiting IκB and IKK phosphorylation. These findings suggested that NMC exerts anti-inflammatory effects on DSS-induced colitis, and its mechanism may be related to the suppression of NF-κB activation. Thus, NMC may have potential therapeutic value in the treatment of colitis.

Formulation, Characterization, and Pharmacokinetic Studies of 6-Gingerol-Loaded Nanostructured Lipid Carriers.

In this study, an optimized nanostructured lipid carriers (NLCs) were developed and investigated for improving the solubility and oral availability of 6-Gingerol (6G), an active and abundant component of ginger with limited applications due to its poor water solubility plus oral biological availability. The NLCs consisted of a solid lipid (glyceryl monostearate), another liquid lipid (decanoyl/octanoyl-glycerides) and mixed surfactants (Tween 80 and Poloxamer 188), and was prepared by high pressure homogenization method. The optimal 6G-NLC formulation was evaluated through physical properties such as appearance, mean particle size, zeta potential, encapsulation efficiency, and in vitro drug release, alongside techniques viz., transmission electron microscopy (TEM), differential scanning calorimetry (DSC), as well as powder X-ray diffraction (XRD). Pharmacokinetics were also evaluated in rats. The 6G-NLCs prepared with optimal formulation exhibited a homogenous spherical shape with mean particle size and zeta potential of 63.59 ± 5.54 nm and - 12.18 ± 1.06 mV. Encapsulation efficiency and drug loading were 76.71 ± 1.11 and 1.17 ± 0.35%, respectively. In vitro release profile of 6G from NLCs was sustained and fitted with Weibull equation. After oral administration of the 6G-NLCs, drug concentrations in serum, MRT, and AUC0-t were significantly higher as compared with the free 6G suspension. All these results indicated that the developed NLC formulation could be effective and promising drug carriers to improve the water solubility of 6G while sustaining the drug release as well as prolonging in vivo acting time of the drug coupled with oral bioavailability enhancement.

MKRMDA: multiple kernel learning-based Kronecker regularized least squares for MiRNA-disease association prediction.

BACKGROUND: Recently, as the research of microRNA (miRNA) continues, there are plenty of experimental evidences indicating that miRNA could be associated with various human complex diseases development and progression. Hence, it is necessary and urgent to pay more attentions to the relevant study of predicting diseases associated miRNAs, which may be helpful for effective prevention, diagnosis and treatment of human diseases. Especially, constructing computational methods to predict potential miRNA-disease associations is worthy of more studies because of the feasibility and effectivity. METHODS: In this work, we developed a novel computational model of multiple kernels learning-based Kronecker regularized least squares for MiRNA-disease association prediction (MKRMDA), which could reveal potential miRNA-disease associations by automatically optimizing the combination of multiple kernels for disease and miRNA. RESULTS: MKRMDA obtained AUCs of 0.9040 and 0.8446 in global and local leave-one-out cross validation, respectively. Meanwhile, MKRMDA achieved average AUCs of 0.8894 ± 0.0015 in fivefold cross validation. Furthermore, we conducted three different kinds of case studies on some important human cancers for further performance evaluation. In the case studies of colonic cancer, esophageal cancer and lymphoma based on known miRNA-disease associations in HMDDv2.0 database, 76, 94 and 88% of the corresponding top 50 predicted miRNAs were confirmed by experimental reports, respectively. In another two kinds of case studies for new diseases without any known associated miRNAs and diseases only with known associations in HMDDv1.0 database, the verified ratios of two different cancers were 88 and 94%, respectively. CONCLUSIONS: All the results mentioned above adequately showed the reliable prediction ability of MKRMDA. We anticipated that MKRMDA could serve to facilitate further developments in the field and the follow-up investigations by biomedical researchers.

HAMDA: Hybrid Approach for MiRNA-Disease Association prediction.

For decades, enormous experimental researches have collectively indicated that microRNA (miRNA) could play indispensable roles in many critical biological processes and thus also the pathogenesis of human complex diseases. Whereas the resource and time cost required in traditional biology experiments are expensive, more and more attentions have been paid to the development of effective and feasible computational methods for predicting potential associations between disease and miRNA. In this study, we developed a computational model of Hybrid Approach for MiRNA-Disease Association prediction (HAMDA), which involved the hybrid graph-based recommendation algorithm, to reveal novel miRNA-disease associations by integrating experimentally verified miRNA-disease associations, disease semantic similarity, miRNA functional similarity, and Gaussian interaction profile kernel similarity into a recommendation algorithm. HAMDA took not only network structure and information propagation but also node attribution into consideration, resulting in a satisfactory prediction performance. Specifically, HAMDA obtained AUCs of 0.9035 and 0.8395 in the frameworks of global and local leave-one-out cross validation, respectively. Meanwhile, HAMDA also achieved good performance with AUC of 0.8965 ±â€¯0.0012 in 5-fold cross validation. Additionally, we conducted case studies about three important human cancers for performance evaluation of HAMDA. As a result, 90% (Lymphoma), 86% (Prostate Cancer) and 92% (Kidney Cancer) of top 50 predicted miRNAs were confirmed by recent experiment literature, which showed the reliable prediction ability of HAMDA.

Exploration of intrinsic and extrinsic apoptotic pathways in zearalenone-treated rat sertoli cells.

Zearalenone (ZEA) is a nonsteroidal estrogenic mycotoxin produced mainly by Fusarium. ZEA causes reproductive disorders and is both cytotoxic and genotoxic in animals; however, little is known regarding the molecular mechanism(s) leading to ZEA toxicity. Sertoli cells are somatic cells that support the development of spermatogenic cells. The objective of this study was to explore the effects of ZEA on the proliferation, apoptosis, and necrosis of rat Sertoli cells to uncover signaling pathways underlying ZEA cytotoxicity. ZEA reduced the proliferation of rat Sertoli cells in a dose-dependent manner, as indicated by a CCK8 assay, while flow cytometry revealed that ZEA caused both apoptosis and necrosis. Immunoblotting revealed that ZEA treatment increased the ratio of Bax/Bcl-2, as well as the expression of FasL and caspases-3, -8, and -9, in a dose-dependent manner. Collectively, these data suggest that ZEA induced apoptosis and necrosis in rat Sertoli cells via extrinsic and intrinsic apoptotic pathways. This study provides new insights into the molecular mechanisms by which ZEA exhibits cytotoxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1731-1739, 2016.

[Recent advances in natural product induced DNA damage response in cancer cells].

The DNA structures could be altered or even damaged by exogeous or endogenous factors during cell proliferation. Failure of effective and timely repair will lead to cell cycle arrest or apoptosis. By taking the advantage of the quick proliferation of cancer cells, DNA damage induction, cell cycle arrest and apoptosis promotion have become important strategies for ant-cancer chemotherapy. Previous reports showed that an array of natural compounds inhibit cancer cell proliferation by inducing DNA damage, which have therapeutic potentials for anti-cancer drug research and development.