Reduced bacterial resistance antibiotics with improved microbiota tolerance in human intestinal: Molecular design and mechanism analysis.

Antibiotic selectivity and bacterial resistance are critical global public health issues. We constructed a multi-class machine learning model to study antibiotic effects on human intestinal microbiota abundance and identified key features. Binding energies of ß-lactam antibiotics with Escherichia coli PBP3 mutant protein were calculated, and a 2D-QSAR model for bacterial resistance was established. Sensitivity analysis identified key features affecting bacterial resistance. By coupling key features from the machine learning model and 2D-QSAR model, we designed ten flucloxacillin (FLU) substitutes that improved intestinal microbiota tolerance and reduced antibiotic bacterial resistance. Concurrently, the substitutes exhibited superior degradability in soil, aquatic environments, and under photolytic conditions, coupled with a reduced environmental toxicity compared to the FLU. Evaluations under combined medication revealed significant improvements in functionality and bacterial resistance for 80% of FLU substitutes, with 50% showing more than a twofold increase. Mechanistic analysis demonstrated enhanced binding to target proteins and increased biodegradability for FLU substitutes due to more concentrated surface charges. Reduced solvent hindrance and increased cell membrane permeability of FLU substitutes, mainly due to enhanced interactions with phospholipid bilayers, contributed to their functional selectivity. This study aims to address poor antibiotic selectivity and strong bacterial resistance, providing guidance for designing antibiotic substitutes.

In-silico analysis of atmospheric diffusion, crop planting degrading scheme, and health risk of dioxins from a domestic waste incineration plant.

Based on a domestic waste incineration power generation project, the dioxin emission from the waste incineration plant (WIP), phytoextraction and microbial degradation of dioxins, and dioxins human health risks reduction were investigated through in-silico methods. Based on the dioxins concentrations in soil (9.97 × 10-9-7.00 × 10-5ng/g) predicted by atmospheric dispersion model system and the Level-III fugacity model, planting schemes under different wind directions were designed considering the dioxin absorption capacity and the economic benefits for crops (i.e., barley, peanut, pea, maize and wheat). The dioxins in soils can be further degraded by five crops' rhizosphere microorganisms and fertilizers, simulated through molecular dynamic simulations. The enhanced degradation rates of dioxin by rhizosphere microorganisms of five crops reached 15.70 %-28.66 %. Finally, healthy dietary plans were developed to reduce the risk of dioxin exposure to the sensitive populations living around WIP. Results showed that the consumption of maize, fungus, mushroom and bamboo fungus could effectively reduce dioxins toxicity to humans by 58.13 %. The systematic approach developed in this study provided theoretical support for soil remediation and human health risk control of dioxins-contaminated sites.

Trifolium repens and biochar addition affecting soil nutrients and bacteria community.

Biochar has wide application prospects as a good soil conditioner, leguminous plants can fix nitrogen and improve soil available nutrients. However, it is not clear how adding biochar when planting leguminous plants affects soil bacterial community and soil available nutrients. This study investigates the effects of biochar addition on the content of ammonia nitrogen, Olsen-P, and available potassium in northeastern farmland soils under the plantation of Trifolium repens and then compared with the application of organic fertilizer. A 90-day incubation experiment was conducted to compare the changes in the structure and relative abundance of soil microflora under varied biochar additions. It was found that the addition of biochar could affect the structure of the microflora and the available nutrients in the soil. When compared with soil planted with T. repens without the addition of biochar, with the application of 3% biochar increased the content of ammonia nitrogen, Olsen-P, and available potassium in the soil by 31.71%, 21.40%, and 11.51%, respectively. High throughput sequencing revealed that the relative abundance of functional bacteria such as azotobacter, rhizobacteria, and phosphorus solubilizing bacteria in the soil increased with the addition of biochar. Furthermore, the effect was more obvious with the addition of organic fertilizers. The addition of biochar improved the microbial community structure and increased the relative abundance of functional bacteria and the content of available nutrients in the soil. This is expected to reduce the application of chemical fertilizers, thereby protecting the environment and conserving natural resources.

Regulatory strategies for inhibiting horizontal gene transfer of ARGs in paddy and dryland soil through computer-based methods.

Antibiotic resistance genes (ARGs) have been regarded as emerging pollutants due to their potential risk of resistance. Horizontal gene transfer (HGT) is the main pathway for ARGs to lead to environmental threats. Therefore, the inhabitation of ARGs' HGT can effectively inhibit ARGs' potential drug resistance risk within a single strain. In this paper, the characteristics of ARGs' HGT in paddy and dryland soils were identified and regulated by a combination of ARGs' HGT feature identification, transfer mechanism analysis and transfer process regulation. The homology modeling algorithm was used to simulate the construction of the Tn5 plasmid transposase of Escherichia coli (E. coli) for identifying ARGs' HGT characteristics. The GCG (212.617 Å) was thus determined as the target codon. Through integrated computer-based methods, results showed that the most important environmental disturbance factors for the HGT of ARGs in the paddy and dryland soils were rough farmyard manure/sewage irrigation and mining pollution, respectively. Under the disturbance of key environmental factors, the inhibitory effect of HGT of ARGs in paddy and dryland soil was reduced by 35.01 % and 34.74 %, respectively. Results demonstrated that the proposed theoretical mechanism and control strategies could effectively inhibit the HGT of E. coli ARGs in the soil environment.

Multi-Dimensional Elimination of ß-Lactams in the Rural Wetland: Molecule Design and Screening for More Antibacterial and Degradable Substitutes.

Restricted economic conditions and limited sewage treatment facilities in rural areas lead to the discharge of small-scale breeding wastewater containing higher values of residual beta-lactam antibiotics (ß-lactams), which seriously threatens the aquatic environment. In this paper, molecular docking and a comprehensive method were performed to quantify and fit the source modification for the combined biodegradation of ß-lactams. Using penicillin (PNC) as the target molecule, combined with contour maps for substitute modification, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was constructed for the high-performance combined biodegradation of ß-lactams. The selected candidate with better environmental friendliness, functionality, and high performance was screened. By using the homology modeling algorithms, the mutant penicillin-binding proteins (PBPs) of Escherichia coli were constructed to have antibacterial resistance against ß-lactams. The molecular docking was applied to obtain the target substitute by analyzing the degree of antibacterial resistance of ß-lactam substitute. The combined biodegradation of ß-lactams and substitute in the constructed wetland (CW) by different wetland plant root secretions was studied using molecular dynamics simulations. The result showed a 49.28% higher biodegradation of the substitutes than PNC when the combined wetland plant species of Eichhornia crassipes, Phragmites australis, and Canna indica L. were employed.

Bio-Enhanced Degradation Strategies for Fluoroquinolones in the Sewage Sludge Composting Stage: Molecular Modification and Resistance Gene Regulation.

The molecular/protein-protein docking and the index normalization method assisted by the entropy weight method were used to quantitatively evaluate the biodegradability of fluoroquinolones (FQs) under different biodegradation systems. Four biodegradability three-dimensional quantitative structure-activity relationship (3D-QSAR) models of FQs were constructed to design FQ derivatives with improved biodegradability. Through the evaluation of the environmental friendliness and functional properties, the FQ derivatives with high biodegradability, improved functionality, and environmental friendliness were screened. Moreover, four bio-enhanced degradation scenarios of FQs were set up according to the different temperatures and carbon-nitrogen ratio (C/N) in the sewage sludge composting stage, and the molecular dynamic (MD) simulation assisted by protein-protein docking was used to screen the external environmental factors that promote the degradation of FQs by thermophilic bacteria or group under different scenarios. Finally, MD simulation assisted by sampling method was used to validate and screen the application scheme of field measures to enhance the expression of antibacterial resistance of FQ derivatives in an agricultural soil environment after activated sludge land use. This study aims to provide theoretical support for the development of highly biodegradable FQ derivatives and the mitigation of potential risks that FQs may pose to the environment and humans through the food chain.

Validation and inhibition study for toxic expression of quinolone antibiotic resistance genes in agricultural soils of eastern China.

With the extensive use of antibiotics, the problem of antibiotic resistance genes (ARGs) has gradually emerged. As agricultural soil is an important enrichment media of antibiotics and ARGs, it is particularly important to study the toxicity of ARGs, the effects of various nutrients and pollutants, and how to control them through source modification and process regulation. In this study, a combination of source modification and process regulation was used to weaken the toxic expression of Quinolones' (QNs') ARGs in soils from different agricultural areas. And the influence of soil nutrients and pollutants on this process will be explored. Protein-protein docking and molecular docking were used to construct a target protein complex for the toxic expression of QNs' ARGs and characterize the toxicity of QNs' ARGs. The two-dimensional and three-dimensional quantitative structure-activity relationships model construction and sensitivity analysis were used to molecular modification and related validation. Molecular dynamics simulations assisted by sampling survey method based on agricultural soils in Northeast China and the lower-middle reaches of the Yangtze River were carried out to generate four scenarios. The main results are: (a) A functionally improved and environmentally friendly quinolone derivative (ORB-19) was designed. It can effectively inhibit the expression of QNs' ARGs and weaken the antibiotic selection pressure risk. The application of ORB-19 in agricultural areas could significantly inhibit the toxic expression of QNs' ARGs (112.75%~169.59%); (b) QNs' ARGs have a stronger toxic expression in agricultural areas of Northeast China, which have higher nutrient elements; (c) The contribution of different types of agricultural pollution to suppressing the toxic expression of QNs' ARGs in agricultural soils varies; (d) The options of applied field measures given for the inhibition of QNs' ARG toxic expression varied between plots with different agricultural pollution types. This study provides theoretical support for inhibiting the toxic expression of QNs' ARGs in the soil environment, reducing the spread of ARGs in microbial populations, replacing green QNs derivatives, and sustainable development of agricultural soils.

A new perspective to improve the treatment of Lianhuaqingwen on COVID-19 and prevent the environmental health risk of medication.

Lianhuaqingwen (LH), one traditional Chinese medicine (TCM), has been used to treat the coronavirus disease 2019 (COVID-19), but its ecotoxicity with potential human health security has not been well investigated. To overcome such adverse effects and improve its medication efficacy, an intelligent multi-method integrated dietary scheme, screening, and performance evaluation approach was developed. Thirteen LH compounds were selected, and the main protease (Mpro) was used as the potential drug target. Resulted information showed that the more compounds of LH added, the higher medication efficacy obtained using multi-method integrated screening system, expert consultation method, and molecular dynamics simulation. Pharmacodynamic mechanism analysis showed that low total energy and polar surface area of LH active compound (i.e., ß-sitosterol) will contribute to the best therapeutic effect on COVID-19 using quantitative structure-activity relationships (QSAR) and sensitivity models. Additionally, when mild COVID-19 patients take LH with the optimum dietary scheme (i.e., ß-lactoglobulin, α-lactalbumin, vitamin A, vitamin B, vitamin C, carotene, and vitamin E), the medication efficacy were significantly improved (23.58%). Pharmacokinetics and toxicokinetics results showed that LH had certain human health risks and ecotoxicity. This study revealed the multi-compound interaction mechanism of LH treatment on COVID-19, and provided theoretical guidance for improving therapeutic effect, evaluating TCM safety, and preventing human health risk.

Theoretical design and process control of neonicotinoids insecticides suitable for synergistic degradation with the rubisco enzyme from rhizobia and carbon-fixing bacteria in soil.

In this study, we studied and developed the modification schemes of environmentally friendly substitutes of neonicotinoid insecticides (NNIs) along with the regulatory measures that effectively enhanced the synergistic degradation of NNIs by soil rhizobia and carbon-fixing bacteria. Firstly, the binding ability of NNIs to the two key proteins was characterized by molecular docking; secondly, the mean square deviation decision method, which is a comprehensive evaluation method, was used to investigate the binding ability of NNI molecules with the two Rubisco rate-limiting enzymes. The three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established for the synergistic degradation and single effect of rhizobia and carbon-fixing bacteria. Finally, after combining the 3D-QSAR model with a contour map analysis of the synergistic degradation effect of soil rhizobia and carbon-fixing bacteria, 102 NNI derivatives were designed. Flonicamid-36 and other four NNI derivatives passed the functional and environmentally friendly evaluation. Taguchi orthogonal experiment and factorial experiment-assisted molecular dynamics method were used to simulate the effects of 32 regulation schemes on the synergistic degradation of NNIS and its derivatives by rhizobia and carbon fixing bacteria. The synergistic degradation capacity of soil rhizobia and carbon-fixing bacteria was increased to 33.32% after right nitrogen supplementation. This indicated that supplementing the correct amount of nitrogen in the soil environment was beneficial to the microbial degradation of NNIs and their derivatives.

Photocatalytic Penicillin Degradation Performance and the Mechanism of the Fragmented TiO2 Modified by CdS Quantum Dots.

In this study, a novel method was adopted to construct a CdS-TiO2 heterostructure to degrade penicillin under sunlight. A potato extract was used during the synthesis process of CdS QDs as a stabilizer and a modifier. The CdS-TiO2 composite with a heterostructure delivers high photocatalytic degradation efficiency. In detail, 0.6 mg/mL of CdS-TiO2 can successfully decompose penicillin after 2 h, and 5‰ CdS-TiO2 shows the optimal degradation efficiency with the degradation rate reaching 88%. Furthermore, the underlying mechanisms of the penicillin decomposition reaction were investigated by the EPR test and trapping experiment. It was found that the high photocatalytic degradation efficiency was attributed to the heterojunction of CdS-TiO2, which successfully suppresses the recombination of the conduction band of CdS and the valence band of TiO2. Moreover, it was confirmed that the reaction is the O2-consuming process, and introducing O2 can greatly accelerate the generation of a superoxide radical during the photocatalytic degradation process, which eventually improves the degradation of penicillin and shortens the degradation time. Finally, this work provides the possible penicillin degradation pathways, which will inspire the researchers to explore and design novel photocatalysts in the field of wastewater treatment in the future.

Control strategies for the vertical gene transfer of quinolone ARGs in Escherichia coli through molecular modification and molecular dynamics.

This study investigates the regulation of the vertical gene transfer of quinolones' antibiotic resistance genes (ARGs) through a combination of source modification and process control. In source prevention, 29 Escherichia coli (E. coli) DNA gyrase subunit A mutant proteins were constructed, the B-G mutant protein displayed the greatest reduction in binding effect (-25.98%). Based on this, a 3D-QSAR model was constructed, and LEV-2 and LEV-9 QNs derivatives were designed based on Levofloxacin (LEV), and their binding effect with B-G mutant protein was found be increased by 13.24% and 19.40%. The drug resistance mechanism of E. coli was explored based on molecular docking technology and protein hydrophobic interaction theory. Most of the amino acid resistance mutations changed from hydrophilic to lipophilic, which inhibited the binding of QNs to mutant protein A subunit, and further reduced the bactericidal effect of QNs. In process control, Huoxiang-Zhengqi, stroke-physiological saline solution (SPSS), and Lycium barbarum (L. barbarum) was found to be 164.82% higher than that of the blank control group. The purpose of this study is to provide a theoretical support for the joint regulation of QNs' ARGs in organisms and the research and development on green alternatives to QNs compounds.

Identification and regulation of ecotoxicity of polychlorinated naphthalenes to aquatic food Chain (green algae-Daphnia magna-fish).

Polychlorinated naphthalenes (PCNs) are widely distributed in the aquatic environment and can be transmitted through the food chain, which can amplify their toxic effects on human. To inhibit their transmission in the trophic level, this study aimed to predict the joint toxicity mechanism of polychlorinated naphthalenes (PCNs) to the key organisms and control scheme of its toxicity in the aquatic food chain (green algae-Daphnia magna-fish). The toxic effect grade and mode of action (MoA) of PCNs on the food chain were first predicted to guide the establishment of toxic mechanism model. QSAR models were constructed to quantify the mechanism of aquatic toxicity due to PCNs. The results showed the PCN compounds studied were highly toxic at all the trophic levels of the aquatic food chain. The binding ability of PCNs to the aquatic organisms was the main factor causing the toxicity of PCNs in the food chain, followed by electronic parameters EHOMO and ELUMO. Moreover, the binding ability between PCNs and food chain receptors was related to the molecular hydrophobicity, the hydrophobicity can be changed by adjusting the ability of PCNs to be adsorbed by sediment and their chlorine substituents, while the effect of PCNs electronic parameters (EHOMO and ELUMO) can be adjusted by their solvation effect. In addition, the macro-control scheme of PCN-based aquatic toxicity mechanism was established, and the molecular dynamics (MD) simulation confirmed its effectiveness and accessibility. The MD simulation showed the inhibition effect of nutrition-grade toxicity in the food chain was significant when the external stimulation conditions of solvation, anaerobic dechlorination and molecular adsorption were improved, with the decrease range of 66.26-263.16%, 198.93-323.98% and 189.24-549.48%, respectively. This work reveals new insights into the mechanism of PCNs joint toxicity to aquatic ecosystem food chain and develop appropriate strategies for its ecological risk management.

Combined toxicity characteristics and regulation of residual quinolone antibiotics in water environment.

In this study, the mixture toxicity index method was used to evaluate the combined toxicity of residual Quinolones (QNs) on algae in twelve groups of water environment reported in the literature. The selected three sets of data (II, Ⅺ, and Ⅻ) combined with full factorial design method were used to analyze the significance of the combined toxicity. Subsequently, molecular docking was used to reveal the significant mechanism of the primary effect of the combined toxicity. Finally, based on the sensitivity analysis method, the acid-base conditions affecting the combined toxicity were screened, and molecular dynamics simulation was used to control the combined toxicity in the water environment. The results of the mixture toxicity index method showed that the combined toxicity in all the twelve groups of water environments was synergistic. The full factorial design method revealed that ciprofloxacin, norfloxacin, enrofloxacin, lomefloxacin, and their binary combinations from the combined toxicity system of QNs, were the significant factors that caused the synergistic toxicity of QNS on algae. Molecular docking confirmed that the total number of amino acids, the number of significant amino acids, and hydrogen bonds of QNs toxic targets were significantly related to the synergistic effect of the combined toxicity. In addition, the molecular dynamics simulation showed that the binding energy of residual QNs and toxic targets changes with the acid-base conditions of the water environment. Thus, the combined toxicity can be slowed down or reduced by adequately adjusting the acid-base condition of the water.

Environmentally Friendly Quinolones Design for a Two-Way Choice between Biotoxicity and Genotoxicity through Double-Activity 3D-QSAR Model Coupled with the Variation Weighting Method.

Quinolone (QN) antibiotics are widely used, which lead to their accumulation in soil and toxic effects on ryegrass in pasture. In this study, we employed ryegrass as the research object and selected the total scores of 29 QN molecules docked with two resistant enzyme structures, superoxide dismutase (SOD, PDB ID: 1B06) and proline (Pro, PPEP-2, PDB ID: 6FPC), as dependent variables. The structural parameters of QNs were used as independent variables to construct a QN double-activity 3D-QSAR model for determining the biotoxicity on ryegrass by employing the variation weighting method. This model was constructed to determine modification sites and groups for designing QNs molecules. According to the 3D contour map of the model, by considering enrofloxacin (ENR) and sparfloxacin (SPA) as examples, 23 QN derivatives with low biotoxicity were designed, respectively. The functional properties and environmental friendliness of the QN derivatives were predicted through a two-way selection between biotoxicity and genotoxicity before and after modification; four environmentally friendly derivatives with low biotoxicity and high genotoxicity were screened out. Mixed toxicity index and molecular dynamics methods were used to verify the combined toxicity mechanism of QNs on ryegrass before and after modification. By simulating the combined pollution of ENR and its derivatives in different soils (farmland, garden, and woodland), the types of combined toxicity were determined as partial additive and synergistic. Binding energies were calculated using molecular dynamics. The designed QN derivatives with low biotoxicity, high genotoxicity, and environmental friendliness can highly reduce the combined toxicity on ryegrass and can be used as theoretic reserves to replace QN antibiotics.

Optimization of Ecological Water Supplement Scheme for Improved Suitable Habitat Area for Rare Migratory Birds in Nature Reserves Using Interval-Parameter Fuzzy Two-Stage Stochastic Programming Model.

The optimization of ecological water supplement scheme in Momoge National Nature Reserve (MNNR), using an interval-parameter two-stage stochastic programming model (IPTSP), still experiences problems with fuzzy uncertainties and the wide scope of the obtained optimization schemes. These two limitations pose a high risk of system failure causing high decision risk for decision-makers and render it difficult to further undertake optimization schemes respectively. Therefore, an interval-parameter fuzzy two-stage stochastic programming (IPFTSP) model derived from an IPTSP model was constructed to address the random variable, the interval uncertainties and the fuzzy uncertainties in the water management system in the present study, to reduce decision risk and narrow down the scope of the optimization schemes. The constructed IPFTSP model was subsequently applied to the optimization of the ecological water supplement scheme of MNNR under different scenarios, to maximize the recovered habitat area and the carrying capacity for rare migratory water birds. As per the results of the IPFTSP model, the recovered habitat areas for rare migratory birds under low, medium and high flood flow scenarios were (14.06, 17.88) × 103, (14.92, 18.96) × 103 and (15.83, 19.43) × 103 ha, respectively, and the target value was (14.60, 18.47) × 103 ha with a fuzzy membership of (0.01, 0.83). Fuzzy membership reflects the possibility level that the model solutions satisfy the target value and the corresponding decision risk. We further observed that the habitat area recovered by the optimization schemes of the IPFTSP model was significantly increased compared to the recommended scheme, and the increases observed were (5.22%, 33.78%), (11.62%, 41.88%) and (18.44%, 45.39%). In addition, the interval widths of the recovered habitat areas in the IPFTSP model were reduced by 17.15%, 17.98% and 23.86%, in comparison to those from the IPTSP model. It was revealed that the IPFTSP model, besides generating the optimal decision schemes under different scenarios for decision-makers to select and providing decision space to adjust the decision schemes, also shortened the decision range, thereby reducing the decision risk and the difficulty of undertaking decision schemes. In addition, the fuzzy membership obtained from the IPFTSP model, reflecting the relationship among the possibility level, the target value, and the decision risk, assists the decision-makers in planning the ecological water supplement scheme with a preference for target value and decision risk.

KIF4A Promotes Clear Cell Renal Cell Carcinoma (ccRCC) Proliferation in vitro and in vivo.

PURPOSE: To evaluate the expression in human clear cell renal cell carcinoma (ccRCC) tissues and explore the effects of kinesin family member 4A (KIF4A) on ccRCC progression. METHODS: GEPIA was used to evaluate the mRNA levels of KIF4A in human ccRCC tissues from TCGA database, and Immunohistochemistry (IHC) assays were performed to assess its expression in human ccRCC tissues collected in our hospital. The clinical-pathological analysis was performed to explore the correlation with KIF4A expression. The effects of KIF4A on ccRCC cell proliferation were detected through colony formation and MTT assays. Finally, the effects of KIF4A on tumor growth were measured using a mice model. RESULTS: Bioinformation results showed the expression of KIF4A mRNA was upregulated in ccRCC tissues and high expression of KIF4A was related with poor prognosis in ccRCC patients. We also found a high expression of KIF4A in human ccRCC tissues collected in our hospital. We also found its expression level was correlated with clinical characteristics, including T stage (P=0.035*) and lymphatic metastasis (P=0.028*). We further confirmed that knockdown of KIF4A suppressed cell proliferation in HTB-47 and CRL-1932 cells. Furthermore, KIF4A contributes to tumor growth of ccRCC cells in mice. CONCLUSION: We found the abnormal high expression of KIF4A in human ccRCC tissues and demonstrated that KIF4A could serve as a tumor induction gene.

Fuzzy Comprehensive Evaluation Assistant 3D-QSAR of Environmentally Friendly FQs to Reduce ADRs.

Most studies on adverse drug reactions (ADRs) of fluoroquinolones (FQs) have focused on the mechanisms of single ADRs, and no quantitative structure-activity relationship (QSAR) method studies have been carried out that combine several ADRs of FQs. In this study, an improved three-dimensional (3D) QSAR method was established using fuzzy comprehensive evaluation. This method could simultaneously consider three common ADRs of FQs using molecular parameters. The improved method could comprehensively predict three ADRs of FQs and provide direction for the development of new drugs with lower ADRs than the originals. According to the improved method, 48 derivatives with lower ADRs (decreased by 4.86% to 50.92%) were designed from pazufloxacin. Three derivatives with a higher genotoxicity, higher photodegradation, and lower bioconcentration than pazufloxacin were selected using the constructed QSAR methods of the FQs. Finally, three traditional 3D-QSAR methods of single ADR were constructed to validate the improved method. The improved method was reasonable, with a relative error range of 0.96% to 4.30%. This study provides valuable reference data and will be useful for the development of strategies to produce new drugs with few ADRs. In the absence of complementary biological studies of these adverse drug reactions, the results reported here may be quite divergent from those found in humans or experimental animals in vivo. One major reason for this is that many adverse drug reactions are dependent upon enzyme-catalyzed metabolic activation (toxication) or on non-enzymatic conversion to toxic products and are not due to the parent drug moiety.

Lessons from an active surveillance pilot to assess the pneumonia of unknown etiology surveillance system in China, 2016: the need to increase clinician participation in the detection and reporting of emerging respiratory infectious diseases.

BACKGROUND: We sought to assess reporting in China's Pneumonia of Unknown Etiology (PUE) passive surveillance system for emerging respiratory infections and to identify ways to improve the PUE surveillance system's detection of respiratory infections of public health significance. METHODS: From February 29-May 29, 2016, we actively identified and enrolled patients in two hospitals with acute respiratory infections (ARI) that met all PUE case criteria. We reviewed medical records for documented exposure history associated with respiratory infectious diseases, collected throat samples that were tested for seasonal and avian influenza, and interviewed clinicians regarding reasons for reporting or not reporting PUE cases. We described and analyzed the proportion of PUE cases reported and clinician awareness of and practices related to the PUE system. RESULTS: Of 2619 ARI admissions in two hospitals, 335(13%) met the PUE case definition; none were reported. Of 311 specimens tested, 18(6%) were seasonal influenza virus-positive; none were avian influenza-positive. < 10% PUE case medical records documented whether or not there were exposures to animals or others with respiratory illness. Most commonly cited reasons for not reporting cases were no awareness of the PUE system (76%) and not understanding the case definition (53%). CONCLUSIONS: Most clinicians have limited awareness of and are not reporting to the PUE system. Exposures related to respiratory infections are rarely documented in medical records. Increasing clinicians' awareness of the PUE system and including relevant exposure items in standard medical records may increase reporting.

Combined QSAR/QSPR and molecular docking study on fluoroquinolones to reduce biological enrichment.

With the aim of reducing the adverse effects of fluoroquinolones in the environment, a complete design and screening system for the low biological enrichment and high photodegradabilities of 29 fluoroquinolones was established through a three-dimensional quantitative structure-activity relationship (3D-QSAR) model and molecular docking. The interaction mechanisms of the fluoroquinolones with Gram-negative bacteria (DNA gyrase in Escherichia coli) and Gram-positive bacteria (Topoisomerase IV in Staphylococcus aureus) were also evaluated. Consequently, the 3D-QSAR model showed that the 3- and 18-positions of the fluoroquinolones strongly affected their biological enrichment, and that the introduction of electropositive or hydrophobic groups at these positions reduced the logarithm of the octanol-water partition coefficient. Using nadifloxacin as a template, 23 derivatives with lower biological enrichment than nadifloxacin (decreased by 30.12%-94.18%) were designed. Meanwhile, the photodegradabilities of 15 derivatives were increased compared with nadifloxacin. Finally, the further screening by molecular docking of nadifloxacin and the above 15 derivatives with DNA gyrase and Topoisomerase IV showed that 13 of the derivatives had lower biological enrichment (decreased by 0.30%-16.76%) than nadifloxacin in the bacteria.

Inhibition of NF-κB activation improves insulin resistance of L6 cells.

To explore the role of NF-κB activation in the development of insulin resistance and investigate whether or not that the inhibition of NF-κB activation by PDTC will improve the insulin resistance of L6 cells exposed to H2O2. L6 cells were treated with H2O2, PDTC or both H2O2 and PDTC for 4 hours. The uptake of glucose with stimulation of insulin, the expression of P38-MAPK, p- P38-MAPK, NF-κBp65, p- NF-κBp65, IRS-1, IRS-2, p-IRS-2, PI3K, IκBα, p- IκBα, caspase-8 and GLUT4, the production of ROS, TNF-α, IL-6 and IL-1ß as well as the apoptosis rate of L6 cells were determined and compared in L6 treated with H2O2 alone or both H2O2 and PDTC. Compared with the L6 cells treated with H2O2 alone, the L6 cells treated with both H2O2 and PDTC showed (1) significantly lower production of ROS, TNF-α, IL-6 and IL-1ß; (2) significantly decreased expression of P38-MAPK, p- P38-MAPK and NF-κBp65, p- NF-κBp65, p- IκBα and caspase-8; (3) significantly lower rate of apoptosis; (4) significantly higher expression of IRS-2, p-IRS-2 (Tyr 612), PI3K and GLUT4; (5) significantly higher uptake of glucose with stimulation of insulin; (6) significantly increased expression of Bcl2 and decreased ratio of Bax to Bcl2. Based on the findings of the present study, inhibition of NF-κB activation by PDTC would improve the insulin resistance of L6 cells exposed to H2O2.