Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics.

Knowledge of therapeutic targets and early drug candidates is useful for improved drug discovery. In particular, information about target regulators and the patented therapeutic agents facilitates research regarding druggability, systems pharmacology, new trends, molecular landscapes, and the development of drug discovery tools. To complement other databases, we constructed the Therapeutic Target Database (TTD) with expanded information about (i) target-regulating microRNAs and transcription factors, (ii) target-interacting proteins, and (iii) patented agents and their targets (structures and experimental activity values if available), which can be conveniently retrieved and is further enriched with regulatory mechanisms or biochemical classes. We also updated the TTD with the recently released International Classification of Diseases ICD-11 codes and additional sets of successful, clinical trial, and literature-reported targets that emerged since the last update. TTD is accessible at http://bidd.nus.edu.sg/group/ttd/ttd.asp. In case of possible web connectivity issues, two mirror sites of TTD are also constructed (http://db.idrblab.org/ttd/ and http://db.idrblab.net/ttd/).

Physiological and biochemical responses of Microcystis aeruginosa to phosphine (PH3) under elevated CO2.

Phosphine (PH3) is an important factor driving the outbreak of cyanobacterial blooms that produce toxic microcystin threating human health. To clarify the physiological and biochemical responses of cyanobacteria to PH3 under elevated CO2 concentration, Microcystis aeruginosa was used in the coupling treatment of 1000 ppmv CO2 and PH3 at different concentrations respectively. The chlorophyll a (Chl-a), carotenoid, net photosynthetic rate and total protein of M. aeruginosa exhibited evidently increasing tendency under the coupling treatment of 1000 ppmv CO2 and PH3 at different concentrations (7.51 × 10-3, 2.48 × 10-2, 7.51 × 10-2 mg/L). The coupling treatments resulted in the higher concentrations of Chl-a and carotenoid of M. aeruginosa, compared to those in the control and the treatment with CO2 alone, and their enhancement increased with the increase in PH3 concentrations. The total antioxidant capacity (T-AOC) in the coupling treatment with CO2 and PH3 of 2.48 × 10-2 mg/L and 7.51 × 10-3 mg/L showed increasing tendency, compared to the treatment with PH3 alone. Additionally, the coupling treatment with 1000 ppmv CO2 and PH3 also altered the pH and DO level in the culture medium. In this regard, the coupling treatment with CO2 and PH3 at an appropriate concentration can enhance the resistance of M. aeruginosa to PH3 toxicity and is beneficial to the reproduction of M. aeruginosa, presumably resulting in potential for the outbreak of cyanobacteria bloom. Given the concern about global warming and the increase in atmospheric CO2 level, our research laid a foundation for the scientific understanding of the correlation between PH3 and cyanobacteria blooms.

In situ remediation of hexavalent chromium contaminated soil by CMC-stabilized nanoscale zero-valent iron composited with biochar.

In this study, the remediation experiments were performed outdoors in natural conditions. Carboxymethyl cellulose (CMC)-stabilized nanoscale zero-valent iron (CMC-nZVI), biochar (BC) and CMC-stabilized nanoscale zero-valent iron composited with biochar (CMC-nZVI/BC) were synthesized and investigated for their effect on the in situ remediation of hexavalent chromium [Cr(VI)] contaminated soil and the concentration of available iron was tested after the remediation, compared with the untreated soil. The results of toxicity characteristic leaching procedure (TCLP) test showed that CMC-nZVI and CMC-nZVI/BC used as remediation materials could obviously improve the remediation rate of Cr contaminated soil and when the ratio of CMC-nZVI to Fe0 was 2.5 g/Kg, the leachability of Cr(VI) and Crtotal can be reduced by 100% and 95.8% simultaneously. Moreover, sequential extraction procedure (SEP) showed that most exchangeable Cr converted to carbonate-bound and Fe-Mn oxides-bound, reducing the availability and leachability of Cr in the soil.

Insight into the roles of endogenous minerals in the activation of persulfate by graphitized biochar for tetracycline removal.

Owing to its environmental-friendliness, low-cost, and outstanding characteristics, biochar has been widely used for the catalytic degradation of various organic pollutants. In this study, a pre- and post-deashing graphitized biochar (DBC800 and PBC800-A) was prepared and compared with the pristine biochar (PBC800) to activate persulfate (PS) for tetracycline (TC) degradation. The influence of the natural endogenous mineral on the catalytic ability of biochar was investigated. Characterization results show that the inherent endogenous mineral in biochar not only acted as a natural pore-forming agent to promote the formation of the porous structure, but also facilitated the formation of edge defective structures, and altered the surface functional groups, as well as increased the carbonization and graphitization degree of biochar. The PBC800-A exhibited a much higher catalytic efficiency on PS activation and TC oxidative degradation with the reaction rate of 0.06055 min-1, 7.14 times as that of DBC800 (0.00861 min-1) and 4.63 times as that of PBC800 (0.00158 min-1). The endogenous minerals were conducive to the generation of free radicals and promoted the oxidative degradation of TC, which was mainly attributed to the improved carbon configuration. The post-deashing treatment was also found to significantly improve the electron transport efficiency of biochar by removing the residual ash, thereby promoting the generation of singlet oxygen. This study demonstrated that the natural minerals in biochar was beneficial for the degradation of TC, and more alternative natural minerals can be applied to co-pyrolysis with biochar for the remediation of refractory organic pollutants.

Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile.

Checkpoint kinase 1 (CHK1) plays an important role in the DNA damage response pathway, being a potential anti-cancer drug target. In this study, we used a strategy for trifluoromethyl substitution to obtain orally bioavailable CHK1 inhibitors to overcome the limitations of lead compound 1, which can only be administered intravenously. After detailed investigation, we identified compound 6c as an oral CHK1 inhibitor, which demonstrated a considerably higher plasma exposure in mice. Compound 6c also showed good kinase selectivity. Moreover, it exhibited a significant antiproliferative effect in MV-4-11 cells singly and a synergistic effect in combination with gemcitabine in HT-29, A549, and RPMI-8226 cells. Additionally, compound 6c could inhibit tumor growth in the MV-4-11 xenograft mouse model. The combination of 6c and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Thus, compound 6c was found to be a selective and oral potential anticancer CHK1 inhibitor.

Physiological and biochemical responses of Microcystis aeruginosa to phosphine.

The frequent outbreaks of cyanobacteria bloom are often accompanied by the generation and release of reduced phosphorus species (e.g., phosphine), which raises interesting questions regarding their potential algae-related effects. To clarify the physiological and biochemical responses of cyanobacteria to phosphine, Microcystis aeruginosa was treated with different concentrations of phosphine. Net photosynthetic rate, total antioxidant capacity (T-AOC), catalase (CAT) activity, and the concentrations of chlorophyll a, carotenoid and total protein were investigated and scanning electron microscopy (SEM) was conducted to elucidate the physiological and biochemical responses of M. aeruginosa to phosphine. The results showed that phosphine was beneficial to the growth of algal cells after M. aeruginosa acclimatized to the treatment of phosphine, and treatment with 2.48 × 10-2 mg/L phosphine had a greater positive effect on the growth and reproduction of M. aeruginosa than 7.51 × 10-3 mg/L phosphine, in which most algal cells were smooth and flat on day 16. Treatment with the high concentration of phosphine (7.51 × 10-2 mg/L) for 16 d reduced T-AOC, CAT activity, net photosynthetic rate, and the concentrations of chlorophyll a, carotenoid and total protein of M. aeruginosa to the minimums, resulting in the lysis and death of M. aeruginosa cells, which indicates phosphine has a toxic effect on the growth of algal cells. However, the high concentration of phosphine (7.51 × 10-2 mg/L) had a greater positive effect on the growth of M. aeruginosa cells than the lower two (7.51 × 10-3 mg/L and 2.48 × 10-2 mg/L) from 3 d to 12 d. Our findings provide insight into how phosphine potentially affects the growth of M. aeruginosa cells and the important roles of elevated phosphine on the outbreak of cyanobacteria bloom.

Recent Technological Advances in the Mass Spectrometry-based Nanomedicine Studies: An Insight from Nanoproteomics.

Nanoscience becomes one of the most cutting-edge research directions in recent years since it is gradually matured from basic to applied science. Nanoparticles (NPs) and nanomaterials (NMs) play important roles in various aspects of biomedicine science, and their influences on the environment have caused a whole range of uncertainties which require extensive attention. Due to the quantitative and dynamic information provided for human proteome, mass spectrometry (MS)-based quantitative proteomic technique has been a powerful tool for nanomedicine study. In this article, recent trends of progress and development in the nanomedicine of proteomics were discussed from quantification techniques and publicly available resources or tools. First, a variety of popular protein quantification techniques including labeling and label-free strategies applied to nanomedicine studies are overviewed and systematically discussed. Then, numerous protein profiling tools for data processing and postbiological statistical analysis and publicly available data repositories for providing enrichment MS raw data information sources are also discussed.

Determining the Balance Between Drug Efficacy and Safety by the Network and Biological System Profile of Its Therapeutic Target.

One of the most challenging puzzles in drug discovery is the identification and characterization of candidate drug of well-balanced profile between efficacy and safety. So far, extensive efforts have been made to evaluate this balance by estimating the quantitative structure-therapeutic relationship and exploring target profile of adverse drug reaction. Particularly, the therapeutic index (TI) has emerged as a key indicator illustrating this delicate balance, and a clinically successful agent requires a sufficient TI suitable for it corresponding indication. However, the TI information are largely unknown for most drugs, and the mechanism underlying the drugs with narrow TI (NTI drugs) is still elusive. In this study, the collective effects of human protein-protein interaction (PPI) network and biological system profile on the drugs' efficacy-safety balance were systematically evaluated. First, a comprehensive literature review of the FDA approved drugs confirmed their NTI status. Second, a popular feature selection algorithm based on artificial intelligence (AI) was adopted to identify key factors differencing the target mechanism between NTI and non-NTI drugs. Finally, this work revealed that the targets of NTI drugs were highly centralized and connected in human PPI network, and the number of similarity proteins and affiliated signaling pathways of the corresponding targets was much higher than those of non-NTI drugs. These findings together with the newly discovered features or feature groups clarified the key factors indicating drug's narrow TI, and could thus provide a novel direction for determining the delicate drug efficacy-safety balance.