The cancer atavistic theory suggests that carcinogenesis is a reverse evolution process. It is thus of great interest to explore the evolutionary origins of cancer driver genes and the relevant mechanisms underlying the carcinogenesis. Moreover, the evolutionary features of cancer driver genes could be helpful in selecting cancer biomarkers from high-throughput data. In this study, through analyzing the cancer endogenous molecular networks, we revealed that the subnetwork originating from eukaryota could control the unlimited proliferation of cancer cells, and the subnetwork originating from eumetazoa could recapitulate the other hallmarks of cancer. In addition, investigations based on multiple datasets revealed that cancer driver genes were enriched in genes originating from eukaryota, opisthokonta, and eumetazoa. These results have important implications for enhancing the robustness of cancer prognosis models through selecting the gene signatures by the gene age information. Full article

As one of the promising renewable energy resources, solar-wind energy has increasingly become a regional engine in leading the economy and raising competitiveness. Selecting a solar-wind power station location can contribute to efficient utilization of resource and instruct long-term development of socio-economy. Since the selection procedure consists of several location alternatives and many influential criteria factors, the selection can be recognized as a multiple criteria decision-making (MCDM) problem. To better express multiple uncertainty information during the selection procedure, fuzzy set theory is introduced to manage that issue. Interval neutrosophic sets (INSs), which are characterized by truth-membership, indeterminacy-membership and falsity-membership functions in the interval numbers (INs) form, are feasible in modeling more uncertainty of reality. In this paper, a newly extended weighted aggregated sum product assessment (WASPAS) technique, which involves novel three procedures, is utilized to handle MCDM issues under INSs environment. Some modifications are conducted in the extended method comparing with the classical WASPAS method. The most obvious improvement of the extended method relies on that it can generate more realistic criteria weight information by an objective and subjective integrated criteria weight determination method. A case study concerning solar-wind power station location selection is implemented to demonstrate the applicability and rationality of the proposed method in practice. Its validity and feasibility are further verified by a sensitivity analysis and a comparative analysis. These analyses effectively reveal that the extended WASPAS technique can well match the reality and appropriately handle the solar-wind power station location selection problem. Full article

Oxidative damage can lead to a wide range of diseases. Nrf2 is an important transcription factor that regulates many of the cytoprotective enzymes involved in the oxidative stress response. Therefore, targeting the regulation of Nrf2 activation is one logical and effective strategy to prevent or lower the risk of oxidative stress-related diseases. Until now, most research has focused on electrophilic indirect Nrf2 activators, but the risk of ‘off-target’ effects may be associated with these activators. To find novel small non-electrophilic modulators of Nrf2, we started from chemical agents derived from a connectivity map (cMap) and identified 22 non-electrophilic potential Nrf2-activating drugs through a drug repositioning tactic. By determining the expression changes of antioxidant genes in MCF7 cells that were treated with the potential Nrf2 activators using quantitative real-time polymerase chain reaction RT-PCR (real-time polymerase chain reaction) (qRT-PCR), astemizole was found to have a greater scale of upregulating antioxidant genes NQO1, HO-1, and GCLM than the positive control d,l-sulforaphane, although the testing concentration was lower than that of the control. Astemizole is a good potential redox regulator and deserves more pharmacodynamic experimentation to test and verify its feasibility for use as an Nrf2 activator. Full article

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). Due to the extensive use of anti-tuberculosis drugs and the development of mutations, the emergence and spread of multidrug-resistant tuberculosis is recognized as one of the most dangerous threats to global tuberculosis control. Some single mutations have been identified to be significantly linked with drug resistance. However, the prior research did not take gene-gene interactions into account, and the emergence of transmissible drug resistance is connected with multiple genetic mutations. In this study we use the bioinformatics software GBOOST (The Hong Kong University, Clear Water Bay, Kowloon, Hong Kong, China) to calculate the interactions of Single Nucleotide Polymorphism (SNP) pairs and identify gene pairs associated with drug resistance. A large part of the non-synonymous mutations in the drug target genes that were included in the screened gene pairs were confirmed by previous reports, which lent sound solid credits to the effectiveness of our method. Notably, most of the identified gene pairs containing drug targets also comprise Pro-Pro-Glu (PPE) family proteins, suggesting that PPE family proteins play important roles in the drug resistance of Mtb. Therefore, this study provides deeper insights into the mechanisms underlying anti-tuberculosis drug resistance, and the present method is useful for exploring the drug resistance mechanisms for other microorganisms. Full article

Pressure ulcer is a complex and significant health problem in long-term bedridden patients, and there is currently no effective treatment or efficient prevention method. Furthermore, the molecular mechanisms and pathogenesis contributing to the deep injury of pressure ulcers are unclear. The aim of the study was to explore the role of endoplasmic reticulum (ER) stress and Akt/GSK3β signaling in pressure ulcers. A model of pressure-induced deep tissue injury in adult Sprague-Dawley rats was established. Rats were treated with 2-h compression and subsequent 0.5-h release for various cycles. After recovery, the tissue in the compressed regions was collected for further analysis. The compressed muscle tissues showed clear cellular degenerative features. First, the expression levels of ER stress proteins GRP78, CHOP, and caspase-12 were generally increased compared to those in the control. Phosphorylated Akt and phosphorylated GSK3β were upregulated in the beginning of muscle compression, and immediately significantly decreased at the initiation of ischemia-reperfusion injury in compressed muscles tissue. These data show that ER stress may be involved in the underlying mechanisms of cell degeneration after pressure ulcers and that the Akt/GSK3β signal pathway may play an important role in deep tissue injury induced by pressure and ischemia/reperfusion. Full article

Polyprenols of Ginkgo biloba L. leaves (GBP) are a new type of lipid with 14–24 isoprenyl units, which in humans have strong bioactivity like the dolichols. A large amount of work showed that GBP had good antibacterial activity and powerful protective effects against acute hepatic injury induced by carbon tetrachloride and alcohol, as well as antitumor activity, but the safety of GBP was not considered. The current study was designed to evaluate the toxicity of these polyprenols. Acute toxicity in mice was observed for 14 days after GBP oral dosing with 5, 7.5, 10, 15 and 21.5 g/kg body weight (b. wt.) Further, an Ames toxicity assessment was carried out by plate incorporation assay on spontaneous revertant colonies of TA97, TA98, TA100 and TA102, with GBP doses designed as 8, 40, 200, 1000 and 5000 μg/dish, and subchronic toxicity was evaluated in rats for 91 days at GBP doses of 500, 1000 and 2000 mg/kg b. wt./day. The weight, food intake, hematological and biochemical indexes, the ratio of viscera/body weight, and histopathological examinations of tissue slices of organs were all investigated. The results showed that no animal behavior and appearance changes and mortality were seen during the observation period with 21.5 g/kg GBP dose in the acute toxicity test. Also, no mutagenicity effects were produced by GBP (mutation rate < 2) on the four standard Salmonella strains (p > 0.05) in the Ames toxicity test. Furthermore, the no observed adverse effect level (NOAEL) of GBP was 2000 mg/kg for 91 days feeding of rats in the subchronic toxicity tests. Results also showed the hematological and biochemical indexes as well as histopathological examination changed within a small range, and all clinical observation indexes were normal. No other distinct impacts on cumulative growth of body weight, food intake and food utilization rate were discovered with GBP. No significant difference was discovered for the rats’ organ weight and the ratio of viscera to body weight (p > 0.05). Reversible pathological changes in the histopathological examinations of tissue slices of organs were not observed. GBP could therefore be considered as a safe material with minor side effects. Full article

In order to improve the bioavailability levels of polyprenols (derived from ginkgo leaves (GBP)) in the human body, a GBP nanoemulsion was prepared, and its antiviral activity was evaluated against influenza A H3N2 and hepatitis B virus in vitro. Methods: A GBP nanoemulsion was prepared by inversed-phase emulsification (IPE). Next, we investigated the antiviral activity of the GBP nanoemulsion on influenza A H3N2 and hepatitis B virus in vitro by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenlytetrezolium bromide) method. ELISA and the fluorescent quantitative PCR method were used to measure the content of HBsAg, HBeAg and DNA virus in human samples. Results: The GBP nanoemulsion exhibited uniformity at an average particle size 97 nm with a hydrophilic-lipophilic balance (HLB) of 9.5. GBP is non-toxic to normal cells, hepatitis B virus DNA, hepatitis B virus antigen and HepG2215. Furthermore, GBP could reach a 70% virucidal activity and a 74.9% protection rate (*** p < 0.001) on MDCK cells infected with H₃N₂ virus at a high concentration of 100 μg/mL. GBP had a good inhibition rate on HBsAg (52.11%, ** p < 0.01) at 50 μg/mL and Day 9 of incubation, and a 67.32% inhibition effect on HBeAg at a high concentration of 100 μg/mL and Day 9. GBP had good inhibition on HBV DNA with CT 18.6 and lower copies (** p < 0.01) at a middle concentration of 12.5 to 25 μg/mL. Conclusions: The GBP nanoemulsion was very stable and non-toxic and had very strong antiviral activity against influenza A H₃N₂ and hepatitis B virus in vitro. The inhibitory effects and reactive mechanisms were similar to the drug, 3TC; by lengthening the incubation time and increasing the drug concentration, GBP has promising potential as an antiviral drug. Full article

In order to find bamboo leaves with high contents of bioactive polysaccharides, 32 samples were chosen to analyze their polysaccharide content by GC and sulfuric acid-anthrone colorimetric assays. Purified polysaccharides (BLPS) were separated from the four varieties P. nigra (Lodd.) Munro (PN), P. vivax McClure (PV), Chimonobambusa quadrangularis (Fenzi) Makino (CQ), and P. bambussoides cv. Tanakae (PB) by ultrasound extraction, solution precipitation, ion exchange resin, DEAE-52 and Sephadex G-100 chromatography. BLPS structural characterization was accomplished by HPLC-GPC, Fourier transform infra-red spectroscopy (FTIR) and NaIO₄-HIO₄ oxidation reactions. The results showed that the total polysaccharides of the bamboo leaves in samples 1–32 ranged between 1.4% and 5.4%, Samples No. 29–No. 32 (PN, PV, CQ, and PB) contained 2–3 fold more polysaccharides than No. 1~No. 28 among the 32 different species, particularly the content of galactose was in a range of 21.5%–34.1% for these four typical bamboo species leaves, which was also more than 2–3 fold higher than in No. 1–No. 28. Sugar analysis indicated that PN-PBLPS-1, PV-PBLPS-1, CQ-PBLPS-1 and PB-PBLPS-1 from the four varieties were homogeneous polysaccharides with molecular weights of 2.04 × 10⁴, 1.15 × 10⁴, 8.75 × 10⁴ and 1.48 × 10⁴ Da, respectively. PB-PBLPS-1 was a mixture of α-galactopyranose and β-d-glucopyranose linkages with α-(1→6) or β-(1→6)glycosidic bonds, while PN-PBLPS-1, PV-PBLPS-1, and CQ-PBLPS-1 had α galactopyranose linkages with α-(1→6) glycosidic bonds. Full article

Natural medicines have attracted wide attention in recent years. It is of great significance to clarify the pharmacological mechanisms of natural medicines. In prior studies, we established a method for elucidating pharmacological mechanisms of natural products contained in connectivity map (cMap), in terms of module profiles of gene expression in chemical treatments. In this study, we explore whether this methodology is applicable to dissecting the pharmacological mechanisms of natural medicines beyond the agents contained in cMap. First, the gene expression profiles of curcumin (a typical isolated natural medicine) and Si-Wu-Tang (a classic traditional Chinese medicine formula) treatments were merged with those of cMap-derived 1309 agents, respectively. Then, a biclustering analysis was performed using FABIA method to identify gene modules. The biological functions of gene modules provide preliminary insights into pharmacological mechanisms of both natural medicines. The module profile can be characterized by a binary vector, which allowed us to compare the expression profiles of natural medicines with those of cMap-derived agents. Accordingly, we predicted a series of pharmacological effects for curcumin and Si-Wu-Tang by the indications of cMap-covered drugs. Most predictions were supported by experimental observations, suggesting the potential use of this method in natural medicine dissection. Full article

Due to the diverse medicinal effects, polyphenols are among the most intensively studied natural products. However, it is a great challenge to elucidate the polypharmacological mechanisms of polyphenols. To address this challenge, we establish a method for identifying multiple targets of chemical agents through analyzing the module profiles of gene expression upon chemical treatments. By using FABIA algorithm, we have performed a biclustering analysis of gene expression profiles derived from Connectivity Map (cMap), and clustered the profiles into 49 gene modules. This allowed us to define a 49 dimensional binary vector to characterize the gene module profiles, by which we can compare the expression profiles for each pair of chemical agents with Tanimoto coefficient. For the agent pairs with similar gene expression profiles, we can predict the target of one agent from the other. Drug target enrichment analysis indicated that this method is efficient to predict the multiple targets of chemical agents. By using this method, we identify 148 targets for 20 polyphenols derived from cMap. A large part of the targets are validated by experimental observations. The results show that the medicinal effects of polyphenols are far beyond their well-known antioxidant activities. This method is also applicable to dissect the polypharmacology of other natural products. Full article

Primitive proteins are proposed to have utilized organic cofactors more frequently than transition metals in redox reactions. Thus, an experimental validation on whether a protein constituted solely by early amino acids and an organic cofactor can perform electron transfer activity is an urgent challenge. In this paper, by substituting “late amino acids (C, F, M, T, W, and Y)” with “early amino acids (A, L, and V)” in a flavodoxin, we constructed a flavodoxin mutant and evaluated its characteristic properties. The major results showed that: (1) The flavodoxin mutant has structural characteristics similar to wild-type protein; (2) Although the semiquinone and hydroquinone flavodoxin mutants possess lower stability than the corresponding form of wild-type flavodoxin, the redox potential of double electron reduction E_m,7 (fld) reached −360 mV, indicating that the flavodoxin mutant constituted solely by early amino acids can exert effective electron transfer activity. Full article

Epidemiological analyses in a large Chinese population have revealed that consumption of vegetables and legumes is inversely associated with the risk of type 2 diabetes (T2D). However, the health benefits of these plants have not been fully explained, which stimulated our interest to identify antidiabetic components from vegetables and legumes through searching medicinal databases, especially those containing traditional Chinese medicines. The results not only provide meaningful clues to understanding the antidiabetic potentials of these plants but also display the possibility of pinpointing food component functions by searching medicinal databases. Full article

Accumulating evidence indicates that consumption of tea, especially green tea, is good for preventing cancer. To elucidate the cancer preventive mechanisms of green tea, much effort has been devoted to investigating the anticancer effects of (-)-epigallocatechin-3-gallate (EGCG), the major component of green tea. It has been revealed that EGCG restrained carcinogenesis in a variety of tissues through inhibition of mitogen-activated protein kinases (MAPK), growth factor-related cell signaling, activation of activator protein 1 (AP-1) and nuclear factor-B (NF-κB), topoisomerase I, matrix metalloproteinases and other potential targets. Therefore, EGCG is a multipotent anticancer agent, which not only provides solid evidence to support the anticancer potential of green tea, but also offers new clues for discovering multiple-targeted anticancer drugs. Full article

By examination of the 8659 drugs recorded in the Comprehensive Medicinal Chemistry (CMC) database, 78 catecholics (including five pyrogallolics) were identified, of which 17 are currently prescribed by FDA. Through analyzing the substitutent patterns, ClogPs and O-H bond dissociation enthalpies(BDEs) of the catecholic drugs, some molecular features that may benefit circumventing the toxicity of catecholics were revealed: i) strong electron-donating substituents are excluded; ii) ClogP 3; iii) an energy penalty exists for quinone formation. Besides, the present analyses also suggest that the clinical usage and dosage of currently prescribed catecholic drugs are of importance in designing or screening catecholic antioxidants. Full article