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1.
Chemosphere ; 242: 125269, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31896199

RESUMO

The occurrence and distribution of 14 antibiotics in the surface water and sediment of Nansi Lake's inflowing rivers were studied. The concentrations of the antibiotics in the sediment and water were not detected (ND)-193,440 ng kg-1 and ND-694 ng L-1, respectively, and ofloxacin was identified as the main antibiotic. The target antibiotics were identified at decreased levels in the study area compared with the inflowing rivers of other lakes. The decreased antibiotic concentrations resulted from the dilution effect, strong biodegradation, and rapid photolysis during the wet season. The spatial variations were due to the differences in regional contributions; the concentrations of antibiotics from Jining and Peixian were the highest. Antibiotic pollution in different seasons originated from different sources; pollution levels were determined by water levels and rainfall as well as complicated runoff generation and confluence mechanisms. Based on the risk quotients, ofloxacin, sulfamethoxazole and sulfadiazine were identified as the main antibiotics that contributed to high ecological risks. Algae and aquatic plants were the main model organisms exposed to these risks. This study has great significance for environmental prevention and the control of antibiotic contamination in Nansi Lake, which is an important water transport channel and the main impounded lake for the eastern route of the south-to-north water diversion project.


Assuntos
Antibacterianos/análise , Monitoramento Ambiental/métodos , Lagos/química , Rios/química , Poluentes Químicos da Água/análise , China , Modelos Lineares , Análise de Componente Principal , Estações do Ano
2.
Bioresour Technol ; 301: 122722, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31983576

RESUMO

Constructed wetlands (CWs) have been widely utilized for various types of wastewater treatment due to their merits, including high cost-effectiveness and easy operation. However, a few intrinsic drawbacks have always restricted their application and long-term stability, especially their weak performance at temperatures under 10 °C (low temperatures) due to the deterioration of microbial assimilation and plant uptake processes. The existing modifications to improve CWs performance from the direct optimization of internal components to the indirect adjunction of external resources promoted the wastewater treatment efficiency to a certain degree, but the sustainability and sufficiency of pollutants removal remains a challenge. With the goal of optimizing CW components, the integrity of the CW ecosystem and the removal of emerging pollutants, future directions for research should include radiation plant breeding, improvements to CW ecosystems, and the combination or integration of certain treatment processes with CWs to enhance wastewater treatment effects at low temperatures.

3.
Int J Biol Macromol ; 149: 70-80, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31987943

RESUMO

In bacteria, protein lysine acetylation circuits can control core processes such as carbon metabolism. In E. coli, cyclic adenosine monophosphate (cAMP) controls the transcription level and activity of protein lysine acetyltransferase (PAT). The M. tuberculosis PatA (Mt-PatA) resides in two different conformations; the activated state and autoinhibited state. However, the mechanism of cAMP allosteric regulation of Mt-PatA remains mysterious. Here, we performed extensive all-atom molecular dynamics (MD) simulations (three independent run for each system) and built a residue-residue dynamic correlation network to show how cAMP mediates allosteric activation. cAMP binds at the regulatory site in the regulatory domain, which is 32 Å away from the catalytic site. An extensive conformational restructuring relieves autoinhibition caused by a molecular Lid (residues 161-203) that shelters the substrate-binding surface. In the activated state, the regulatory domain rotates (~40°) around Ser144, which links both domains. Rotation removes the C-terminus from the cAMP site and relieves the autoinhibited state. Also, the molecular Lid refolds and creates an activator binding site. A conserved residue, His173, was mutated into Lys in the Lid, and during an MD trajectory of the activated state, positioned itself near an acetyl donor molecule in the catalytic domain, suggesting a direct mechanism for acetylation. This study describes the allosteric framework for Mt-PatA and prerequisite intermediate states that permit long-distance signal transmission.

4.
Sci Total Environ ; 710: 136403, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-31927294

RESUMO

Considering its ubiquitous occurrence and potential adverse effects of organophosphorus flame retardant (OPFR), it is urgent to explore the efficient treatment for OPFRs wastewater. Thus, integrated vertical-flow constructed wetlands (IVCWs) were set up to comparatively evaluate their nitrogen removal capacity under tidal flow operations and to investigate environmental behavior and rhizosphere microbial responses after short-term exposure to three OPFRs. The results show that IVCWs have an excellent TN removal rate (628.13 ± 110.63 mg m-2 d-1) and moderate mitigation efficiencies (48.37 ± 9.52 to 82.28 ± 7.48%) for target OPFRs when treating low-C/N ratio wastewater. Moreover, the sorption of selected OPFRs to soil (28.85-308.41 ng g-1, dry weight (dw)), igneous rock (659.85-970.80 ng g-1 dw) and zeolite (1045.60-1351.70 ng g-1 dw) and accumulation in tissues of C. alternifolius (0-289.68 ng g-1 dw) and P. australis (0.56-108.22 ng g-1 dw) showed a hydrophobicity-specific feature. Namely, the highly hydrophobic compound tricresyl phosphate (TCrP) partitioned preferentially to sediment, and the chlorinated analytes were more easily taken up and then translocated into the plant body. Simultaneously, further mass balance analysis revealed the fate of OPFRs in IVCW components. A total of 53.25% of the highly hydrophobic TCrP inflow mass settled in sediment, while tris (2-chloroethyl) phosphate (TCEP) and tris (1-chloro-2-propyl) phosphate (TCPP) were more liable to discharge (35.33-50.89%) and other pathways (38.77-39.87%). Furthermore, the abundance of aerobic denitrifying bacteria (AD) in rhizosphere soil (2.25-5.12%), jointly with the prevalence of nitrobacteria (NOBs, 1.84-13.60%) and denitrifying bacteria (DNBs, 5.84-7.89%) in sublayer matrices, was responsible for superior TN removal. Additionally, the rhizosphere microbial richness, diversity and nitrogen-related microorganisms were clearly influenced by the presence of OPFRs. Notably, the genera Pseudomonas and Sphingobium might be the functional microorganisms for mixture OPFRs biodegradation.

5.
J Biomol Struct Dyn ; 38(1): 89-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30661457

RESUMO

Acute lymphocytic leukemia (ALL) is one of the most dangerous types of leukemia, and about 40% of them is Philadelphia chromosome-positive acute lymphocytic leukemia (Ph + ALL). Ph + ALL is caused by the fusion of the breakpoint cluster region (BCR) and the Ableson (ABL) genes, named the BCR-ABL fused gene that codes for an autonomously active tyrosine kinase. Tyrosine kinase inhibitors (TKIs) are among the first-line therapeutic agents for the treatment of Ph + ALL. Drug resistance are the major obstacle, limiting their clinical utility. The latest third-generation TKIs, ponatinib, can tackle most abnormal BCR-ABL kinases, including the T315I mutant that is resistant to first- and second-generations TKIs such as imatinib. However, drug resistance still emerges with the novel T315L mutation and the underlying mechanisms remain elusive. Here, using molecular dynamics (MD) simulations, we explored into the detailed interactions between ponatinib and BCR-ABL in the wild-type (WT), T315I, and T315L systems. The simulations revealed the significant conformational changes of ponatinib in its binding site due to the T315L mutation and the underlying structural mechanisms. Binding free energy analysis unveiled that the affinity of ponatinib to BCR-ABL decreased upon T315L mutation, which resulted in its unfavorable binding and drug resistance. Key residues responsible for the unfavored unbinding were also identified. This study elucidates the detailed mechanisms for the resistance of ponatinib in Ph + ALL triggered by the T315L mutation and will provide insights for future drug development and optimization.

6.
Sci Total Environ ; 708: 135156, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31780166

RESUMO

Fluoroquinolones (FQs) has caused increasing concerns regarding its potential environmental risks. However, their effects on bacterial community and microbial interactions in wetland system remains unclear. To verify these issues, a lab-scale constructed wetland exposed to low concentration FQs mixture was carried out for two months. The results showed that the removal efficiencies of COD and TP were negatively affected. FQs significantly increased the bacterial diversity and altered the overall bacterial community structure. Proteobacteria significantly decreased while Firmicutes exhibited opposite tendency (P < 0.05). Dechloromonas and Delftia, involved in phosphorus removal, decreased significantly (P < 0.05). Molecular ecological network analysis suggested that FQs promoted the network complexity and microbial interactions. A super module emerged at FQs and among-module connections were weakened obviously. Additionally, Nodes of Betaproteobacteria lost most interactions while Clostridia acquired more interactions at the presence of FQs. This study provided insights into how the bacterial community and their molecular ecological network respond to FQs in constructed wetland system.

7.
Langmuir ; 36(3): 789-795, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31815486

RESUMO

We report a facile yet general in situ seed-mediated method for the synthesis of polymer-grafted gold nanoparticles with narrow size distributions (<10%), accurately tunable sizes, and excellent colloidal stability. This method can be extended to a broad range of types and molecular weights of polymer ligands. Nanoparticles with different shapes can also be prepared by using preformed shaped nanoparticles directly as the seeds.

8.
Int J Biol Macromol ; 144: 643-655, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31816384

RESUMO

Ras is a key member in the superfamily of small GTPase. Transforming between GTP-bound active state and GDP-bound inactive state in response to exogenous signals, Ras serves as a binary switch in various signaling pathways. One of its downstream effectors is phosphatidylinositol-4,5-bisphosphate 3-kinase α (PI3Kα), which phosphorylates phosphatidylinositol 4,5-bisphosphate into phosphatidylinositol 3,4,5-trisphosphate in the PI3K/Akt/mTOR pathway and mediates an array of important cellular activities including cell growth, migration and survival. Hyperactivation of PI3Kα induced by the Ras isoform K-Ras4B has been unveiled as a key event during the oncogenesis of pancreatic ductal adenocarcinoma, but the underlying mechanism of how K-Ras4B allosterically activates PI3Kα still remains largely unsolved. Here, we employed accelerated molecular dynamic simulations and allosteric pathway analysis to explore into the activation process of PI3Kα by K-Ras4B and unraveled the underlying structural mechanisms. We found that K-Ras4B binding induced more conformational dynamics within PI3Kα and triggered its step-wise transition from a self-inhibited state towards an activated state. Moreover, K-Ras4B binding markedly disrupted the interactions along the p110/p85 interface, especially the ones between nSH2 in p85 and its nearby functional domains in p110 like C2, helical, and kinase domains. The altered inter-domain interactions exposed the kinase domain, which promoted the membrane association and substrate phosphorylation of PI3Kα, thereby facilitating its activation. In particular, the community networks and allosteric pathways analysis further revealed that in PI3Kα/K-Ras4B system, allosteric signaling regulating p110/p85 interaction was rewired from the helical domain to the kinase domain and several important residues and their related allosteric pathways mediating PI3Kα autoinhibition were bypassed. The obtained structural mechanisms provide an in-depth mechanistic insight into the allosteric activation of PI3Kα by K-Ras4B as well as shed light on its drug discovery.

9.
Drug Discov Today ; 25(1): 177-184, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634592

RESUMO

Allosteric drugs have several significant advantages over traditional orthosteric drugs, encompassing higher selectivity and lower toxicity. Although allosteric drugs have potential advantages as therapeutic agents to treat human diseases, allosteric drug-resistance mutations still occur, rendering these drugs ineffective. Here, we review the emergence of allosteric drug-resistance mutations with an emphasis on examples covering clinically important therapeutic targets, including Breakpoint cluster region-Abelson tyrosine kinase (Bcr-Abl), Akt kinase [also called Protein Kinase B (PKB)], isocitrate dehydrogenase (IDH), MAPK/ERK kinase (MEK), and SRC homology 2 domain-containing phosphatase 2 (SHP2). We also discuss challenges associated with tackling allosteric drug resistance and the possible strategies to overcome this issue.

10.
Nucleic Acids Res ; 48(D1): D394-D401, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31665428

RESUMO

Allosteric regulation is one of the most direct and efficient ways to fine-tune protein function; it is induced by the binding of a ligand at an allosteric site that is topographically distinct from an orthosteric site. The Allosteric Database (ASD, available online at http://mdl.shsmu.edu.cn/ASD) was developed ten years ago to provide comprehensive information related to allosteric regulation. In recent years, allosteric regulation has received great attention in biological research, bioengineering, and drug discovery, leading to the emergence of entire allosteric landscapes as allosteromes. To facilitate research from the perspective of the allosterome, in ASD 2019, novel features were curated as follows: (i) >10 000 potential allosteric sites of human proteins were deposited for allosteric drug discovery; (ii) 7 human allosterome maps, including protease and ion channel maps, were built to reveal allosteric evolution within families; (iii) 1312 somatic missense mutations at allosteric sites were collected from patient samples from 33 cancer types and (iv) 1493 pharmacophores extracted from allosteric sites were provided for modulator screening. Over the past ten years, the ASD has become a central resource for studying allosteric regulation and will play more important roles in both target identification and allosteric drug discovery in the future.

11.
Environ Pollut ; 257: 113365, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31818612

RESUMO

The overuse and misuse of antibiotics could promote the emergence of antibiotic resistance genes (ARGs) and pose a potential risk to human health and the ecological environment. In this study, fifteen antibiotics and their corresponding ARGs in water, sediment and sewage treatment plant (STP) effluent were analysed to investigate their occurrence and correlation in the Yangtze River (Jiangsu section) for the first time. The concentrations of erythromycin-H2O (EM-H2O) (2.08-30 ng L-1) and ofloxacin (OFL) (290-8400 ng kg-1) were the highest in the water and sediment, respectively, and EM-H2O and clarithromycin (CLA) posed the highest risks to aquatic organisms. The concentrations of antibiotics in STP effluent were significantly higher (p < 0.05) than those in the water. Norfloxacin (NOR) was the most predominant antibiotic, with low removal efficiency (-38%-51%), in STPs; the concentration of NOR in the STP effluent was 4-6 orders of magnitude higher than that in the water. Moreover, the concentrations of antibiotics and their corresponding ARG abundance in downstream were higher than those in upstream, suggesting that STPs with high concentration levels might be an important source of river contamination. Additionally, the concentrations of antibiotics and the abundance of ARGs might increase after the sewage treatment process. The results also showed the prevalence of sul1 and sul2 in all the sampling sites. Significant correlations (p < 0.0001) were detected between int1 and sul1 and sul2, which resulted from the contribution of int1 to the propagation of ARGs. Overall, this study demonstrated the prevalence of antibiotics and ARGs and their inconsistent correlations in the Yangtze River (Jiangsu section) and provides support for further investigation of the occurrence and spread of antibiotics and ARGs.

12.
Chem Commun (Camb) ; 56(2): 217-220, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31803869

RESUMO

Herein, we evaluate the suitablity of polystyrenes with thiol, dithioester and trithiocarbonate end-groups for the synthesis of Al nanocrystals. Both the end-groups and molecular weight of the polymer ligands play important roles for controlling the size and shape of the Al nanocrystals. A general criterion for evaluating polymers as the ligand for the synthesis of Al nanocrystals is proposed.


Assuntos
Nanopartículas/química , Poliestirenos/química , Alumínio/química , Cristalização , Teoria da Densidade Funcional , Ligantes , Modelos Químicos , Peso Molecular , Tamanho da Partícula , Compostos de Sulfidrila/química
13.
Adv Exp Med Biol ; 1163: 65-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707700

RESUMO

An allosteric mechanism refers to the biological regulation process wherein macromolecules propagate the effect of ligand binding at one site to a spatially distant orthosteric locus, thus affecting activity. The theory has remained a trending topic in biology research for over 50 years, since the understanding of allostery is fundamental for gleaning numerous biological processes and developing new drug therapies. In the past two decades, the allosteric paradigm has evolved into more descriptive models, with ever-expanding amounts of experimental data pertaining to newly identified allosteric molecules. The AlloSteric Database (ASD, accessible at http://mdl.shsmu.edu.cn/ASD ), which is a comprehensive knowledge repository, has provided the public with integrated information encompassing allosteric proteins, modulators, sites, pathways, and networks to investigate allostery since 2009. In this chapter, we introduce the history and usage of the ASD and give attention to specific applications that have benefited from the ASD.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Proteínas , Regulação Alostérica , Bases de Dados de Proteínas , Descoberta de Drogas/tendências , Proteínas/química
14.
Adv Exp Med Biol ; 1163: 107-139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707702

RESUMO

Allostery is considered one of the most direct and efficient ways to regulate biological macromolecule functions. Allostery is increasingly receiving attention in the field of drug discovery because of the unique advantages of allosteric modulators such as high selectivity and low toxicity. Because of technical breakthroughs in the allosteric studies, the understanding of the characteristics of allosteric entities such as allosteric proteins and their allosteric sites and modulators has made great strides. These features play a critical role in both the evolution of the allosteric concept and the prediction of allosteric interactions. In this chapter, we highlight the fundamental characteristics of allosteric proteins, allosteric sites, and allosteric modulators. Importantly, the applications of such principles in real cases are depicted in detail. Collectively, these characteristics are beneficial in aiding allosteric drug design and allosteric mechanism research.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Proteínas , Regulação Alostérica , Proteínas/química
15.
Environ Pollut ; 255(Pt 2): 113225, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31557558

RESUMO

Cadmium (II) can potentially alter the microbial community structure and molecular ecological network in activated sludge systems. In this study, we used Illumina sequencing combined with an RMT-based network approach to show the response of the microbial community and its network structure to Cd (II) in activated sludge systems. The results demonstrated that 1 mg/L Cd (II) did not have chronic negative effects on chemical oxygen demand (COD) reduction and denitrification processes, but negatively affected the nitrification process and phosphorus removal. In contrast, 10 mg/L Cd (II) adversely affected both COD and nutrient removal, and reduced the microbial diversity and changed the overall microbial community structure. The relative abundances of Nitrosomonadaceae, Nitrospira, Accumulibacter and Acinetobacter, which are involved in nitrogen removal, significantly decreased with increases in the Cd (II) concentration. In addition, molecular ecological network analysis showed that the networks sizes in the presence of higher levels of Cd (II) were smaller than in the control, but the nodes were more closely connected with neighbors. These shifts in bacterial abundance and the bacterial network structure may be responsible for the deterioration of COD and nutrient removal. Overall, this study provides new insights into the effects of Cd (II) on the bacterial community and its interactions in activated sludge systems.


Assuntos
Cádmio/toxicidade , Microbiota/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Bactérias/efeitos dos fármacos , Análise da Demanda Biológica de Oxigênio , Reatores Biológicos/microbiologia , Desnitrificação , Sistemas de Liberação de Medicamentos , Ecologia , Nitrificação , Nitrogênio/metabolismo , Fósforo/metabolismo , Esgotos/química , Eliminação de Resíduos Líquidos
16.
Environ Pollut ; 254(Pt A): 112996, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31400665

RESUMO

Pollution caused by antibiotics has been highlighted in recent decades as a worldwide environmental and health concern. Compared to traditional physical, chemical and biological treatments, constructed wetlands (CWs) have been suggested to be a cost-efficient and ecological technology for the remediation of various kinds of contaminated waters. In this review, 39 antibiotics removal-related studies conducted on 106 treatment systems from China, Spain, Canada, Portugal, etc. were summarized. Overall, the removal efficiency of CWs for antibiotics showed good performance (average value = over 50%), especially vertical flow constructed wetlands (VFCWs) (average value = 80.44%). The removal efficiencies of sulfonamide and macrolide antibiotics were lower than those of tetracycline and quinolone antibiotics. In addition, the relationship between the removal efficiency of antibiotics and chemical oxygen demand (COD), total suspended solids (TSS), total nitrogen (TN), total phosphorus (TP) and ammonia nitrogen (NH3-N) concentrations showed an inverted U-shaped curve with turning points of 300 mg L-1, 57.4 mg L-1, 40 mg L-1, 3.2 mg L-1 and 48 mg L-1, respectively. The coexistence of antibiotics with nitrogen and phosphorus slightly reduced the removal efficiency of nitrogen and phosphorus in CWs. The removal effect of horizontal subsurface flow constructed wetlands for antibiotic resistance genes (ARGs) had better performance (over 50%) than that of vertical wetlands, especially for sulfonamide resistance genes. Microorganisms are highly sensitive to antibiotics. In fact, microorganisms are one of the main responsible for antibiotic removal. Moreover, due to the selective pressure induced by antibiotics and drug-resistant gene transfer from resistant bacteria to other sensitive strains through their own genetic transfer elements, decreased microbial diversity and increased resistance in sewage have been consistently reported. This review promotes further research on the removal mechanism of antibiotics and ARGs in CWs.


Assuntos
Resistência Microbiana a Medicamentos/genética , Genes Microbianos , Eliminação de Resíduos Líquidos/métodos , Águas Residuárias/microbiologia , Áreas Alagadas , Amônia , Biodegradação Ambiental , Análise da Demanda Biológica de Oxigênio , Nitrogênio , Fósforo/análise , Águas Residuárias/química , Poluentes Químicos da Água/análise
17.
Environ Technol ; : 1-12, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31446846

RESUMO

The purpose of this study was to investigate the effects of increasing salinity on the performance and microbial community structure in a sequencing batch reactor (SBR) treating low C/N ratio wastewater. The SBR was subjected to a gradual increased salinity from 0 wt% to3.0 wt% under low Chemical Oxygen Demand (COD)/N ratio, operating for 80 days. The study results indicated that high salinity decreased the removal efficiency of ammonium ( NH4+-N ) from 77.09% (1.0 wt%) to 45.7% (3.0wt%). The organic matter removal are not significantly affected by the high salinity. Non-metric Multi-Dimensional Scaling (NMDS) analysis showed that the gradual increased salinity altered the overall bacterial community structure, and low salinity (1wt%) promoted the bacterial diversity, while high salinity (2 and 3 wt%) significantly decreased the bacterial diversity in low C/N ratio activated sludge system. Further analysis revealed that two genera related to nitrification process (unclassified-Nitrosomonadales and g-Nitrospira) were inhibited, while a genus related to organic removal (Piscicoccus) and three genera related to denitrification (Rodobacteraceae, Denitromonas and Hyphomicrobium) increased significantly at a salinity of 3 wt%. This study provides insights of shifts in the bacteria community under the stress of high salinity in low C/N ratio of activated sludge systems.

18.
Environ Sci Pollut Res Int ; 26(28): 28796-28807, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377929

RESUMO

The pharmaceutical and personal care product (PPCP) residues in freshwater lakes are being highlighted around the world. The occurrence and ecological risk of 34 PPCPs classified as antibiotics, non-steroidal anti-inflammatory drugs (NSAID), cardiovascular drugs, psychotropic drugs, anti-inflammatory drugs, psychostimulants, and pesticides during rainstorm period in surface water of the Dongting Lake, China, were studied. Twenty-six out of thirty-four PPCPs were detected, and the total concentrations of antibiotics ranged from 0.15 to 214.75 ng L-1 in surface water. The highest average concentration was observed for diclofenac, followed by diethyltoluamide (DEET). The PPCP concentrations were much lower in Dongting Lake compared to other rivers and lakes due to the strong dilution effect of rainstorm, while the detection rate remains high. Caffeine and DEET were detected with 100% frequency in Dongting Lake, and the detection rates of diclofenac, mefenamic acid, and roxithromycin were above 90%. The pollution levels of antibiotics decreased in the order of East Dongting Lake > South Dongting Lake > West Dongting Lake, which may be related to the distribution of aquaculture plants, sewage treatment plants, and population density. The risk quotient (RQ) method was used to evaluate ecological environment risk under the worst case and the results suggested that clarithromycin, diclofenac, roxithromycin, and erythromycin might pose a significant risk to aquatic organisms in Dongting Lake, especially clarithromycin. This study can provide data support for further research on the dilutive effect and mechanism of rainwater runoff on PPCPs in lakes on a large scale.


Assuntos
Antibacterianos/análise , Lagos/análise , Roxitromicina/análise , Poluentes Químicos da Água/análise , Antibacterianos/química , Organismos Aquáticos , China , Ecologia , Rios , Roxitromicina/química , Água , Poluentes Químicos da Água/química
19.
Pharmacol Ther ; 202: 1-17, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31233765

RESUMO

Ras, whose mutants are present in approximately 30% of human tumours, is one of the most important oncogenes. Drugging Ras is thus regarded as the quest for the Holy Grail in cancer therapeutics development. Despite more than three decades of efforts, drug discovery targeting Ras constantly fails, rendering Ras undruggable, due to its smooth surface and picomolar affinity towards guanosine substrates. The most frequently mutated isoform of Ras is K-Ras, accounting for >85% of Ras-driven cancers, and one majority of them is the G12C mutation. Recent advances in structural biology shed light on drugging Ras, and one of the cutting-edge breakthroughs is the design of covalent G12C-specific inhibitors targeting the mutated cysteine. This type of inhibitor can be classified into substrate-competitive orthosteric inhibitors and non-competitive allosteric inhibitors. They display improved selectivity and enhanced potency due to their G12-specific and irreversible covalent binding nature. Thus, they represent a new hope for revolutionizing the conventional characterization of Ras as "undruggable" and pave a promising avenue for further drug discovery. Here, we provide comprehensive structural and medicinal chemical insights into K-Ras covalent inhibitors specific for the G12C mutant. We first present an in-depth analysis of the conformations of the inhibitor binding pockets. Then, all the latest covalent ligands selectively inhibiting K-RasG12C are reviewed. Finally, we examine the current challenges faced by this new class of anti-Ras inhibitors.

20.
Nucleic Acids Res ; 47(W1): W315-W321, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31069394

RESUMO

Identifying the variants that alter protein function is a promising strategy for deciphering the biological consequences of somatic mutations during tumorigenesis, which could provide novel targets for the development of cancer therapies. Here, based on our previously developed method, we present a strategy called AlloDriver that identifies cancer driver genes/proteins as possible targets from mutations. AlloDriver utilizes structural and dynamic features to prioritize potentially functional genes/proteins in individual cancers via mapping mutations generated from clinical cancer samples to allosteric/orthosteric sites derived from three-dimensional protein structures. This strategy exhibits desirable performance in the reemergence of known cancer driver mutations and genes/proteins from clinical samples. Significantly, the practicability of AlloDriver to discover novel cancer driver proteins in head and neck squamous cell carcinoma (HNSC) was tested in a real case of human protein tyrosine phosphatase, receptor type K (PTPRK) through a L1143F driver mutation located at the allosteric site of PTPRK, which was experimentally validated by cell proliferation assay. AlloDriver is expected to help to uncover innovative molecular mechanisms of tumorigenesis by perturbing proteins and to discover novel targets based on cancer driver mutations. The AlloDriver is freely available to all users at http://mdl.shsmu.edu.cn/ALD.

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