A Network-Based Multi-Target Computational Estimation Scheme for Anticoagulant Activities of Compounds

BACKGROUND: Traditional virtual screening method pays more attention on predicted binding affinity between drug molecule and target related to a certain disease instead of phenotypic data of drug molecule against disease system, as is often less effective on discovery of the drug which is used to treat many types of complex diseases. Virtual screening against a complex disease by general network estimation has become feasible with the development of network biology and system biology. More effective methods of computational estimation for the whole efficacy of a compound in a complex disease system are needed, given the distinct weightiness of the different target in a biological process and the standpoint that partial inhibition of several targets can be more efficient than the complete inhibition of a single target. METHODOLOGY: We developed a novel approach by integrating the affinity predictions from multi-target docking studies with biological network efficiency analysis to estimate the anticoagulant activities of compounds. From results of network efficiency calculation for human clotting cascade, factor Xa and thrombin were identified as the two most fragile enzymes, while the catalytic reaction mediated by complex IXa:VIIIa and the formation of the complex VIIIa:IXa were recognized as the two most fragile biological matter in the human clotting cascade system. Furthermore, the method which combined network efficiency with molecular docking scores was applied to estimate the anticoagulant activities of a serial of argatroban intermediates and eight natural products respectively. The better correlation (r = 0.671) between the experimental data and the decrease of the network deficiency suggests that the approach could be a promising computational systems biology tool to aid identification of anticoagulant activities of compounds in drug discovery. CONCLUSIONS: This article proposes a network-based multi-target computational estimation method for anticoagulant activities of compounds by combining network efficiency analysis with scoring function from molecular docking

Liver fibrosis and MAFLD: the exploration of multi-drug combination therapy strategies

In recent years, the prevalence of metabolic-associated fatty liver disease (MAFLD) has reached pandemic proportions as a leading cause of liver fibrosis worldwide. However, the stage of liver fibrosis is associated with an increased risk of severe liver-related and cardiovascular events and is the strongest predictor of mortality in MAFLD patients. More and more people believe that MAFLD is a multifactorial disease with multiple pathways are involved in promoting the progression of liver fibrosis. Numerous drug targets and drugs have been explored for various anti-fibrosis pathways. The treatment of single medicines is brutal to obtain satisfactory results, so the strategies of multi-drug combination therapies have attracted increasing attention. In this review, we discuss the mechanism of MAFLD-related liver fibrosis and its regression, summarize the current intervention and treatment methods for this disease, and focus on the analysis of drug combination strategies for MAFLD and its subsequent liver fibrosis in recent years to explore safer and more effective multi-drug combination therapy strategies

Structure and Properties of Polymer-Impregnated Wood Prepared by in-situ Polymerization of Reactive Monomers

This study demonstrates the preparation, structure, and properties of polymer-impregnated wood (PIW) based on novel Muchelia macclurei wood through the in-situ polymerization of vinyl and functional monomers. Mixed monomers of glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EGDMA) (2:1 molar ratio) were effectively vacuum/pressure impregnated into the cellular structure of the fast-growing wood, and then they underwent a catalytic-thermal polymerization process to form a polymer-impregnated wood composite. Scanning electron microscope (SEM) observations showed that the polymer formed from the monomers occupying the cell lumens and formed tight bonds with the wood substrate. Fourier transform infrared (FTIR) microscopy analysis indicated that the in-situ generated polymer probably chemical bonded to the wood cell wall. The resultant PIW exhibited remarkably improved mechanical properties and durability relative to untreated wood. This was attributed to the possible grafting of the polymer onto the wood cell wall and the resultant reinforcement of the wood by the polymer

In the Shadow of the Casinos: The Relationship between Religion and Health in Macau

Considerable research has shown that religion operates as a protective factor for one’s health. However, there is still a lack of understanding of the mechanisms by which religion is linked to individual health and wellbeing, especially in predominantly secular societies. This study tried to address this gap by developing a theoretical model to examine how religiosity is related to life satisfaction and health perception in a non-Western culture. Macau, a Portuguese colony until 1999, remains a diversified culture because of its intermixed historical background from the East and the West. Through structural equation modeling, the analysis of data collected from a representative sample of Macau residents, using a multistage stratified sampling procedure, indicated a positive link between religiosity and health. Moreover, altruism and prejudice mediated a portion of the relationship between religiosity and health. Additionally, our results demonstrated that Macau residents who were more religious had a higher level of altruism and a lower level of prejudice. The link between religion and prejudice in Macau differs from that of many other cultures, indicating that the effect of religion on prejudice varies by cultural context. In sum, our study showed that even in the shadow of glittering casinos, religion is positively related to health

Pyrazine-Fused Porous Graphitic Framework-Based Mixed Matrix Membranes for Enhanced Gas Separations.

Membrane-based separations can mitigate the capital- and energy-intensive challenges associated with traditional thermally driven processes. To further push the boundary of gas separations, mixed matrix membranes (MMMs) have been extensively exploited; however, identifying an optimal nanofiller to boost the separation performance of MMMs beyond Robeson permeability-selectivity upper bounds remains an ongoing challenge. Here, a new class of MMMs based on pyrazine-fused crystalline porous graphitic frameworks (PGFs) is reported. At a loading of 6 wt % PGFs, the MMMs surpass the current H2/CH4 Robeson upper bound, ideally suited for applications such as H2 regeneration. In addition, the fabricated MMMs exhibit appealing CO2 separation performance, closely approaching the current Robeson upper bounds for CO2 separation. Compared with the pristine polymeric membranes, the PGF-based MMMs display a record-high enhancement of gas permeability over 120% while maintaining intrinsic gas selectivities. Highlighting the crucial role of the crystallinity of nanofillers, this study demonstrates a facile and effective approach in formulating high-performance MMMs, complementing state-of-the-art membrane formation processes. The design principles open the door to energy-efficient separations of gas mixtures with enhanced productivity compatible with the current membrane manufacturing

Inhibitory Mechanisms of DHA/CQ on pH and Iron Homeostasis of Erythrocytic Stage Growth of <i>Plasmodium falciparum</i>

Malaria is an infectious disease caused by Plasmodium group. The mechanisms of antimalarial drugs DHA/CQ are still unclear today. The inhibitory effects (IC50) of single treatments with DHA/CQ or V-ATPase inhibitor Baf-A1 or combination treatments by DHA/CQ combined with Baf-A1 on the growth of Plasmodium falciparum strain 3D7 was investigated. Intracellular cytoplasmic pH and labile iron pool (LIP) were labeled by pH probe BCECF, AM and iron probe calcein, AM, the fluorescence of the probes was measured by FCM. The effects of low doses of DHA (0.2 nM, 0.4 nM, 0.8 nM) on gene expression of V-ATPases (vapE, vapA, vapG) located in the membrane of DV were tested by RT-qPCR. DHA combined with Baf-A1 showed a synergism effect (CI = 0.524) on the parasite growth in the concentration of IC50. Intracellular pH and irons were effected significantly by different doses of DHA/Baf-A1. Intracellular pH was decreased by CQ combined with Baf-A1 in the concentration of IC50. Intracellular LIP was increased by DHA combined with Baf-A1 in the concentration of 20 IC50. The expression of gene vapA was down-regulated by all low doses of DHA (0.2/0.4/0.8 nM) significantly (p &lt; 0.001) and the expression of vapG/vapE were up-regulated by 0.8 nM DHA significantly (p &lt; 0.001). Interacting with ferrous irons, affecting the DV membrane proton pumping and acidic pH or cytoplasmic irons homeostasis may be the antimalarial mechanism of DHA while CQ showed an effect on cytoplasmic pH of parasite in vitro. Lastly, this article provides us preliminary results and a new idea for antimalarial drugs combination and new potential antimalarial combination therapies

Analyzing the factors associated with efficacy among teriparatide treatment in postmenopausal women with osteoporosis

Abstract Background Teriparatide (TPTD) is a widely used anabolic agent for the treatment of osteoporosis. Several factors have been identified to be related to bone mineral density (BMD) increase in anti-osteoporosis treatment with other agents; however, there has been no systematic analysis to summarize the associated determinants of BMD reaction to daily teriparatide treatment. Methods In this retrospective study, we performed a comprehensive investigation involving not only clinical data but also several relevant lifestyle factors to be examined for their potential contribution to BMD response. This post-hoc analysis included 258 post-menopaused patients with osteoporosis who received TPTD at 20 µg/day for 12 months. Univariate and multivariate analyses were conducted to distinguish the response variables of lumbar spine (LS) BMD transformation, the principal outcome measure of efficacy, from the baseline at 12 months. Results Twelve months of TPTD treatment resulted in an absolute 0.39 ± 0.37 increase in T-score of LS BMD. Gastrointestinal disease, prior bisphosphonate or glucocorticoid treatment, no vitamin K2 supplementation, low levels of serum 25(OH)D and PINP, weak increment of PINP and β-CTX at 3 months, unhealthy lifestyle (excessive smoking, tea, coffee, and drinking), vegetarian diet pattern, low ALT level, and high BMD at baseline were determined by univariate analyses to be related to the weak reaction of TPTD treatment (P < 0.10). In the multiple regression model, postmenopausal women with vitamin K2 supplementation, higher baseline serum 25(OH)D level, and higher PINP concentration at 3 months indicated a good reaction of LS BMD at 12 months (P < 0.05). Patients with gastrointestinal disease, prior bisphosphonate and glucocorticoid treatment, vegetarian diet pattern, and higher baseline BMD were significantly more likely to have a lower absolute LS BMD response compared to patients without these characteristics (P < 0.05). Further analysis confirmed the negative effect of unhealthy lifestyle on TPTD treatment. Conclusion Our results emphasize the significance of a comprehensive assessment of clinical or lifestyle-related characteristics of postmenopausal women with osteoporosis in the management of TPTD therapy in routine care

Hydrogen-bonded hybrid membranes based on hydroxylated metal-organic frameworks and PIM-1 for ultrafast hydrogen separation

Membrane separation technology provides an alternative to traditional thermally driven separations, owing to its advantages including low cost, energy-savings and environmental friendliness. However, the current membrane technology for gas separations using polymeric materials suffers the challenge of gas permeability-selectivity trade-offs. To overcome this hurdle, high-separation performance hybrid membranes are developed herein using microporous UiO-66-(OH)2 and PIM-1. Due to the stable interfacial hydrogen bonding, the MOF loading crosses the percolation threshold in hybrid membranes, and dual-path transport mechanisms govern the gas diffusion. Accordingly, the hybrid membranes with 40 wt% MOF loading exhibit a H2 permeability up to 9167.6 Barrer, transcending the 2008 H2/CH4 and H2/N2 Robeson upper bounds. Compared to neat PIM-1 membranes with a H2 permeability of 2378.3 Barrer, the H2 permeability of hybrid membranes increases over 285%, demonstrating ultra-high gas permeability. The design approach of hybrid membranes provides a viable pathway for the manufacture of hydrogen-bonded hybrid membranes with potential applications for hydrogen separation and CO2 capture

Comprehensive Analysis of Differentially Expressed Long Noncoding RNA-mRNA in the Adenoma-Carcinoma Sequence of DNA Mismatch Repair Proficient Colon Cancer

DNA proficient mismatch repair colon cancer (pMMR CC) is the most common subtype of sporadic CC. We aimed to investigate the role of long noncoding RNAs (lncRNAs) in pMMR CC carcinogenesis. In the present study, we conducted transcriptomic analysis of lncRNAs-mRNAs in five low-grade intraepithelial neoplasia (LGIN), five high-grade intraepithelial neoplasia (HGIN), four pMMR CC, and five normal control (NC) tissues. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway, and coexpression network analyses were performed to elucidate the functions of lncRNAs and mRNAs as well as their interactions. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate five dysregulated lncRNAs in a large set of colon tissues. Receiver-operating characteristic (ROC) curves were employed to evaluate the performance of the candidate lncRNAs. A set of 5783 differentially expressed lncRNAs and 4483 differentially expressed mRNAs were detected among the LGIN, HGIN, pMMR CC, and NC samples. These differentially expressed lncRNAs and mRNAs were assigned to 275 significant GO terms and 179 significant KEGG enriched pathways. qRT-PCR confirmed that the expression of five selected lncRNAs (ENST00000521815, ENST00000603052, ENST00000609220, NR_026543, and ENST00000545920) were consistent with the microarray data. ROC analysis showed that four lncRNAs (ENST00000521815, ENST00000603052, ENST00000609220, and NR_026543) had larger area under the ROC curve (AUC) values compared to serum carcinoembryonic antigens, thereby distinguishing NC from pMMR CC. In conclusion, several lncRNAs play various roles in the adenoma-carcinoma sequence and may serve as potential biomarkers for the early diagnosis of pMMR CC