Molecular interactions between metformin and D-limonene inhibit proliferation and promote apoptosis in breast and liver cancer cells.

BACKGROUND: Cancer is a fatal disease that severely affects humans. Designing new anticancer strategies and understanding the mechanism of action of anticancer agents is imperative. HYPOTHESIS/PURPOSE: In this study, we evaluated the utility of metformin and D-limonene, alone or in combination, as potential anticancer therapeutics using the human liver and breast cancer cell lines HepG2 and MCF-7. STUDY DESIGN: An integrated systems pharmacology approach is presented for illustrating the molecular interactions between metformin and D-limonene. METHODS: We applied a systems-based analysis to introduce a drug-target-pathway network that clarifies different mechanisms of treatment. The combination treatment of metformin and D-limonene induced apoptosis in both cell lines compared with single drug treatments, as indicated by flow cytometric and gene expression analysis. RESULTS: The mRNA expression of Bax and P53 genes were significantly upregulated while Bcl-2, iNOS, and Cox-2 were significantly downregulated in all treatment groups compared with normal cells. The percentages of late apoptotic HepG2 and MCF-7 cells were higher in all treatment groups, particularly in the combination treatment group. Calculations for the combination index (CI) revealed a synergistic effect between both drugs for HepG2 cells (CI = 0.14) and MCF-7 cells (CI = 0.22). CONCLUSION: Our data show that metformin, D-limonene, and their combinations exerted significant antitumor effects on the cancer cell lines by inducing apoptosis and modulating the expression of apoptotic genes.

Improving integrated management of weed control by determination of weed seed bank in sandy and clay soil.

Knowledge of soil weed seed bank is important for population dynamics studied, establishment of appropriate weed management programs, a little effort in understanding weed seed bank can give valuable information about what weeds to expect in growing season, weed density, and when most weed germination will take place. In this study, a two - year's, two sites were carried out with the aim of assessing weed seed bank status of the soil throughout 2018 and 2019. A site was worked out in Sakha Agriculture Research farm act as a clay soil, Kafr El-Sheikh Governorate, Agriculture Research Center (ARC). Another site was worked out in El-Ismailia Agr; Res; farm act as sandy soil, El-Ismailia Governorate, ARC. At each site, soil samples were selected from nine different places as like three Zigzag shapes divided into three, six and nine sites, "W" to act the whole soil area (30 faddan in Sakha farm, and 15 faddan in El-Ismailia farm). The soil samples were taken from topsoil 0-10 cm depth with an auger (core) 10 cm diameter the soils without tillage and before sowing the summer crop. The result of present the study in two different stations and soils, revealed that the number of soil samples to estimate weed seed banks should be either six or nine sites; each sample weighted 0.50 Kg soil with zigzag shape act a direct seed extraction technique to able recognize the abundance of weed species into the soil and their seed density. The aim is to improve integrated weed control.

In vivo and in vitro management of Meloidogyne incognita (Tylenchida: Heteroderidae) using rhizosphere bacteria, Pseudomonas spp. and Serratia spp. compared with oxamyl.

Biological control using rhizosphere bacteria, Pseudomonas spp. and Serratia spp. is a prospective alternative technique to overcome plant parasitic nematodes infection. So, the current study was conducted in vitro on five egg-masses, 100 free eggs and 100 infective juveniles (IJs) of Meloidogyne incognita as well as greenhouse treatments on Luffa aegyptiaca L. to evaluate the nematicidal potential of six strains belong to Pseudomonas spp. and Serratia spp. as compared to oxamyl. Results showed that the inhibitory effect and juvenile mortality varied according to bacteria species, strains and exposure time. All the tested bacteria significantly (P ≤ 0.05) inhibited egg hatching and increased juvenile mortality in vitro. After 3 days of treatment, Pseudomonas spp. were more effective against eggs (48.31to 55.15%) and IJs (20.98 to 25.30%) than Serratia spp. (44.55 to 49.75% with eggs) and (19.06 to 21.61% with IJs), respectively. In the pot experiment, Luffa aegyptiaca L. treated with Serratia spp. and Pseudomonas spp. displayed significantly higher (P ≤ 0.05) levels of growth (as indicated by root length, fresh roots weight and fresh shoots weight) compared to control plants and significantly (P ≤ 0.05) suppressed galling (number of galls) and reproduction (as indicated by number of egg-masses on roots and number of eggs and juveniles in pot soil). Meanwhile, among the treated plants, Serratia spp. and Pseudomonas spp. gave the best results in shoot weight of pots infected by eggs of M. incognita than those infected with IJs as compared with positive control. While, oxamyl treatment gave the best results in pots infected by eggs and IJs. The lowest galling (gall index), number of eggs and juveniles in soil was observed in the treatment with mixture of Serratia spp. and Pseudomonas spp. as well as, enhanced growth of sponge gourd more than application each of them alone. Pots treated with oxamyl overwhelmed those treated with mixture of Serratia spp. and Pseudomonas spp.

Effects of seasonal variation on the biology and morphology of the dusky cotton bug, Oxcarenus laetus (Kirby).

The dusky cotton bug (Oxycarenus laetus, KIRBY) a pest of several crops. The effects of winter and summer on the biology and morphology was investigated. The sampled eggs of dusky cotton bug (DCB) were kept under controlled environment for biological and morphological investigations. In winter, the mating duration of DCB was observed longer significantly (74.2 days), egg development period (3.93 days), an egg laying period (3.6 days) and hatching period (6.66 days) noted longer in winter season. Interestingly, average number of hatched egg (16.8 days) observed significantly higher in summer and the percentage of the hatching of eggs (81.95%) were also observed higher in summer as compare to winter. Whereas, the longevity of all nymph stages in winter longer days as compare to summer nymph stages. Moreover, differences were also observed between male and female development days between winter and summer. In the winter, female DCB development was suggestively higher as compare to summer (24 days). Whereas, the developmental days were noted considerably more in winter for males as compare to summer (14.93 days). On other hand, for morphological parameters, no differences were observed between winter and summer population of DCB.

NOGEA: A Network-oriented Gene Entropy Approach for Dissecting Disease Comorbidity and Drug Repositioning.

Rapid development of high-throughput technologies has permitted the identification of an increasing number of disease-associated genes (DAGs), which are important for understanding disease initiation and developing precision therapeutics. However, DAGs often contain large amounts of redundant or false positive information, leading to difficulties in quantifying and prioritizing potential relationships between these DAGs and human diseases. In this study, a network-oriented gene entropy approach (NOGEA) is proposed for accurately inferring master genes that contribute to specific diseases by quantitatively calculating their perturbation abilities on directed disease-specific gene networks. In addition, we confirmed that the master genes identified by NOGEA have a high reliability for predicting disease-specific initiation events and progression risk. Master genes may also be used to extract the underlying information of different diseases, thus revealing mechanisms of disease comorbidity. More importantly, approved therapeutic targets are topologically localized in a small neighborhood of master genes in the interactome network, which provides a new way for predicting drug-disease associations. Through this method, 11 old drugs were newly identified and predicted to be effective for treating pancreatic cancer and then validated by in vitro experiments. Collectively, the NOGEA was useful for identifying master genes that control disease initiation and co-occurrence, thus providing a valuable strategy for drug efficacy screening and repositioning. NOGEA codes are publicly available at https://github.com/guozihuaa/NOGEA.

Multi-Omics Integration Reveals a Competitive Endogenous RNAs Network for the Identification of Progression Biomarkers and the Stratification of Patients Diagnosed With Nephroblastoma.

Specific types of nephroblastoma (Wilms' tumor, WT) are known to associate with poor overall survival. Emerging experimental evidence has demonstrated that competitive endogenous RNA (ceRNA) networks have important roles in regulating cancer occurrence, but the roles of ceRNAs in regulating the WT progression and the patient outcomes remain unclear. Using the multi-omics data of 132 WT patients collected from TARGET database, an integration analysis pipeline was performed to construct a highly reliable ceRNA network. As results, a total of 147 nodes (116 mRNAs, 15 miRNAs, and 16 lncRNAs) were identified and used to explore the underlying mechanism for WT progression. WGCNA analysis further identified several prognostic molecules, including hsa-mir-93, LINC00087 and RP5-1086K13, that significantly associated with the overall survival rate. And, enrichment analysis verified the participation of these molecules in tumor-related pathways, such as those controlling autophagy and cadherin-mediated adhesion. Importantly, the WT patients were classified into three categories according to the ceRNA network, which significantly correlated with the overall survival. In conclusion, the ceRNA network could be a promising tool to further validate the prognostic biomarkers and categories of patients diagnosed with WT.

System-Pharmacology Dissection of Traditional Chinese herbs SINI Decoction for Treatment of Cardiovascular Diseases.

Abstract: Cardiovascular diseases (CVDs) are leading causes of death in the world, owing to noticeable incidence and mortality. Traditional Chinese Medicine (TCM) SINI Decoction (SND) is used to prevent and treat CVDs, which has attracted extensive attention for its moderate and little side effects. However, the involved molecular mechanisms are exceedingly complicated and remain unclear. Systems pharmacology, as a novel approach that integrates systems biology and pharmacology plays a significant role in investigating the molecular mechanism of TCM. In systems pharmacology approach, we use to systematically uncover the mechanisms of action in Chinese medicinal formula SND as an effective treatment for CVDs, which mainly includes:1) molecular database building; 2) ADME evaluation; 3) target-fishing 4) network construction and analysis. The results show that 78 underlying valid ingredients and their corresponding 71 direct targets of SND were obtained. And SND take part in cardiomyocyte protection, blood pressure regulation, and lipid regulation module in treatment of CVDs by cooperative way. Systems pharmacology as an emerging field that investigates the molecular mechanisms of TCM through pharmacokinetic evaluation target prediction, and pathway analysis, which will facilitate the development of traditional Chinese herbs in modern medicine.

Systems pharmacology approach to investigate the molecular mechanisms of herb Rhodiola rosea L. radix.

Rhodiola rosea L. radix (RRL) is one of the most popular medical herb which has been widely used for the treatment of different diseases effectively, including cardiovascular diseases and nerve system diseases. However, due to the multiple compounds in RRL, the underlying molecular mechanisms of RRL are remained unclear. To decipher the action mechanisms of RRL from a systematic perspective, a systems pharmacology approach integrated absorption, distribution, metabolism, and excretion (ADME) system, drug targeting, and network analysis was introduced. First, by the ADME screening system and the target fishing process, 56 potential active compounds and 62 targets were obtained, respectively. In addition, compound-target network demonstrated that most compounds interacted with multiple targets, indicating that RRL may enhance its therapeutic effects probably through hitting on multiple targets in a holistic level. Moreover, target-pathway network and gene ontology analysis showed that multiple targets of RRL were involved in several biological pathways, i.e. Neuroactive ligand-receptor interaction, calcium signaling pathway, adrenergic signaling in cardiomyocytes, and VEGF signaling pathway, which dissecting the therapeutic effects of RRL on various diseases, such as cardiovascular diseases, depression, adaptation diseases, etc. In summary, this work successfully explains the potential active compounds and the multi-scale curative action mechanisms of RRL for treating various diseases; meanwhile, it implies that RRL could be applied as a novel therapeutic agent in arthritic diseases. Most importantly, this work provides an in silico strategy to understand the action mechanisms of herbal medicines from molecular/system levels, which will promote the new drug development of traditional Chinese medicine.

Enhancement of Spirulina biomass production and cadmium biosorption using combined static magnetic field.

The effect of static magnetic field (SMF) on Spirulina platensis growth and its influence on cadmium ions (Cd2+) removal efficiency were studied. Application of 6 h day-1 SMF resulted in the highest significant biomass productivity of 0.198 g L-1 day-1. However, 10 and 15 mg L-1 of Cd2+ resulted in significant reduction in biomass productivity by 8.8 and 12.5%, respectively, below the control. Combined SMF showed 30.1% significant increase in biomass productivity over the control. On the other hand, increase of initial Cd2+ concentration resulted in significant reduction of Cd2+ removal efficiency, representing 79.7% and 61.5% at 10 and 15 mg L-1, respectively, after 16 days. Interestingly, application of SMF for 6 h day-1 enhanced Cd2+ removal efficiency counted by 91.4% and 82.3% after 20 days for cultures with initial Cd2+ concentration of 10 and 15 mg L-1, representing increase by 6.3 and 25.3%, respectively, over the SMF-untreated cultures.

Correction to: dengue virus causes changes of MicroRNA-genes regulatory network revealing potential targets for antiviral drugs.

After publication of the article [1], it has been brought to our attention that an author's name was spelt incorrectly in the original published article. Yonghua Wang was previously spelt "Yonghua Wan". This has now been corrected in the revised version of the article.

Clarifying of the potential mechanism of Sinisan formula for treatment of chronic hepatitis by systems pharmacology method.

Chronic hepatitis is a general designation class of diseases, which results in different degrees of liver necrosis and inflammatory reaction, followed by liver fibrosis, may eventually develop into cirrhosis. However, the molecular pathogenesis of chronic hepatitis is too complex to elucidate. Herbal medicines, featured with multiple targets and compounds, have long displayed therapeutic effect in treating chronic hepatitis, though their molecular mechanisms of contribution remain indistinct. This research utilized the network pharmacology to confirm the molecular pathogenesis of chronic hepatitis through providing a comprehensive analysis of active chemicals, drug targets and pathways' interaction of Sinisan formula for treating chronic hepatitis. The outcomes showed that 80 active ingredients of Sinisan formula interacting with 91 therapeutic proteins were authenticated. Sinisan formula potentially participates in immune modulation, anti-inflammatory and antiviral activities, even has regulating effects on lipid metabolism. These mechanisms directly or indirectly are involved in curing chronic hepatitis by an interaction way. The network pharmacology based analysis demonstrated that Sinisan has multi-scale curative activity in regulating chronic hepatitis related biological processes, which provides a new potential way for modern medicine in the treatment of chronic diseases.

Dengue virus causes changes of MicroRNA-genes regulatory network revealing potential targets for antiviral drugs.

BACKGROUND: Dengue virus (DENV) is an increasing global health threat and associated with induction of both a long-lived protective immune response and immune-suppression. So far, the potency of treatment of DENV via antiviral drugs is still under investigation. Recently, increasing evidences suggest the potential role of microRNAs (miRNAs) in regulating DENV. The present study focused on the function of miRNAs in innate insusceptible reactions and organization of various types of immune cells and inflammatory responses for DENV. Three drugs were tested including antiviral herbal medicine ReDuNing (RDN), Loratadine (LRD) and Acetaminophen. RESULTS: By the microarray expression of miRNAs in 165 Patients. Results showed that 89 active miRNAs interacted with 499 potential target genes, during antiviral treatment throughout the critical stage of DENV. Interestingly, reduction of the illness threats using RDN combined with LRD treatment showed better results than Acetaminophen alone. The inhibitions of DENV was confirmed by decrease concentrations of cytokines and interleukin parameters; like TNF-α, IFN-γ, TGF-ß1, IL-4, IL-6, IL-12, and IL-17; after treatment and some coagulants factors increased. CONCLUSIONS: This study showed a preliminary support to suggest that the herbal medicine RDN combined with LRD can reduce both susceptibility and the severity of DENV.

Systems Pharmacology Dissection of the Integrated Treatment for Cardiovascular and Gastrointestinal Disorders by Traditional Chinese Medicine.

Though cardiovascular diseases (CVDs) and gastrointestinal disorders (GIDs) are different diseases associated with different organs, they are highly correlated clinically. Importantly, in Traditional Chinese Medicine (TCM), similar treatment strategies have been applied in both diseases. However, the etiological mechanisms underlying them remain unclear. Here, an integrated systems pharmacology approach is presented for illustrating the molecular correlations between CVDs and GIDs. Firstly, we identified pairs of genes that are associated with CVDs and GIDs and found that these genes are functionally related. Then, the association between 115 heart meridian (HM) herbs and 163 stomach meridian (SM) herbs and their combination application in Chinese patent medicine was investigated, implying that both CVDs and GIDs can be treated by the same strategy. Exemplified by a classical formula Sanhe Decoration (SHD) treating chronic gastritis, we applied systems-based analysis to introduce a drug-target-pathway-organ network that clarifies mechanisms of different diseases being treated by the same strategy. The results indicate that SHD regulated several pathological processes involved in both CVDs and GIDs. We experimentally confirmed the predictions implied by the effect of SHD for myocardial ischemia. The systems pharmacology suggests a novel integrated strategy for rational drug development for complex associated diseases.

Pred-binding: large-scale protein-ligand binding affinity prediction.

Drug target interactions (DTIs) are crucial in pharmacology and drug discovery. Presently, experimental determination of compound-protein interactions remains challenging because of funding investment and difficulties of purifying proteins. In this study, we proposed two in silico models based on support vector machine (SVM) and random forest (RF), using 1589 molecular descriptors and 1080 protein descriptors in 9948 ligand-protein pairs to predict DTIs that were quantified by Ki values. The cross-validation coefficient of determination of 0.6079 for SVM and 0.6267 for RF were obtained, respectively. In addition, the two-dimensional (2D) autocorrelation, topological charge indices and three-dimensional (3D)-MoRSE descriptors of compounds, the autocorrelation descriptors and the amphiphilic pseudo-amino acid composition of protein are found most important for Ki predictions. These models provide a new opportunity for the prediction of ligand-receptor interactions that will facilitate the target discovery and toxicity evaluation in drug development.