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1.
Biomed Pharmacother ; 126: 110104, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32224371

RESUMO

dl-Mandelic acid (MA), an alpha-hydroxycarboxylic acid, has been widely used as an intermediate of pharmaceutical and fine chemicals. Here, we evaluated the sperm-immobilizing activity of MA and its safety profiles. Spermatozoon motility was assessed by computer-aided sperm analysis, the integrity of the plasma membrane and. mitochondrial potential was assessed using fluorescein isothiocyanate-pisum sativum agglutinin and JC-1, respectively. The local tolerance of the MA-containing gel formulation was evaluated using a rabbit vaginal irritation test. We found that MA inhibited sperm motility and movement patterns in a concentration-dependent manner. Within 20 s, MA-induced spermatozoa immobilization occurred with a minimum effective concentration and a median effective concentration of 0.86 and 0.54 mg/mL, respectively. Plasma membrane disruptions of MA-treated spermatozoa were relatively mild, but mitochondrial depolarization occurred. Histopathological examination showed that MA exposure did not exert obvious effects on the integrity of spermatozoa membrane structures and only caused slight irritation to the rabbit vaginal epithelium. The vaginal irritation scores of the vehicle control and the nonoxynol -9 gel control groups were 1.38 ± 0.65 and 7.88 ± 1.67, respectively (p < 0.01), whereas those of the MA gel groups at 10, 20, and 40 mg/mL were 1.69 ± 1.04, 2.98 ± 0.77, and 4.35 ± 1.04 with p values of >0.05, >0.05, and <0.05 (vs. vehicle control), respectively, which were within the clinically acceptable range (<8). Therefore, our results confirmed that MA exhibited significant sperm-immobilizing effects and caused mild plasma membrane injury, suggesting that it has potential for development as a future non-surfactant spermicide.

2.
Cancer Med ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32168429

RESUMO

BACKGROUND: ROS1 gene fusion represents a specific subtype of non-small cell lung cancer (NSCLC). Crizotinib is recommended for ROS1-positive NSCLC due to its favorable outcome in published clinical trials. However, due to the low incidence of ROS1-positive NSCLC, there is limited information on real-world clinical outcomes in patients treated with either crizotinib or platinum-based doublet chemotherapy. METHODS: Outcomes were recorded in 102 patients with stage Ⅲb or Ⅳ NSCLC who were treated at four Chinese hospitals between April, 2010 and June, 2019. RESULTS: Of the 102 patients followed, 71.6% were females, 81.4% were non-smokers, and 98.0% had adenocarcinoma. First-line treatment with crizotinib achieved a significantly longer median progression-free survival (PFS) compared with platinum-based chemotherapy (14.9 months vs 8.5 months, respectively; P < .001). Next-generation sequencing (NGS) identified 61 patients who had ROS1 fusion variants, including CD74 (n = 33) and non-CD74 (n = 28) variants. In patients harboring CD74 fusion variants, the median PFS with first-line crizotinib treatment was significantly longer than in those harboring non-CD74 fusion variants (20.1 months vs 12.0 months, respectively; P = .046). However, in patients treated with platinum-based chemotherapy, there was no significant difference in PFS between the CD74 and non-CD74 variant groups (8.6 months vs 4.3 months, respectively; P = .115). Overall survival (OS) was not reached. CONCLUSIONS: First-line therapy with crizotinib is more beneficial than platinum-based chemotherapy in patients with advanced NSCLC with different ROS1 fusion variants. Patients harboring CD74 fusion variants appear to respond better to crizotinib.

3.
J Thorac Oncol ; 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32151779

RESUMO

INTRODUCTION: Next-generation sequencing (NGS) based on genomic DNA has been widely applied for gene rearrangement detection in patients with non-small cell lung cancer (NSCLC). However, intergenic-breakpoint fusions, in which one or both genomic breakpoints localize to intergenic regions, confound kinase fusion detection. We evaluated the function of intergenic-breakpoint fusions with multiplex molecular testing approaches. METHODS: NSCLCs with intergenic-breakpoint fusion identified by DNA-based NGS were analyzed by RNA-based NGS, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). RESULTS: Twenty-six cases with single intergenic-breakpoint fusion were identified from a large cohort of NSCLCs using DNA-based NGS. Of the 26 cases, RNA-based NGS detected expressed fusion transcripts in 11 cases, and the genomic breakpoint position did not logically predict breakpoint of the fusion transcript in these cases, possibly due to complex rearrangements (n=5), alternative splicing (n=2) and reciprocal rearrangement (n=4). Nonetheless, no expressed fusion transcript was detected in 5 cases. Moreover, positive ALK IHC was observed in 3 of the remaining 10 cases without RNA-based NGS results. Three intergenic-breakpoint ALK fusion cases with or without RNA-based NGS/IHC confirmation receiving crizotinib treatment showed partial responses. However, one intergenic-breakpoint ROS1 case, given the positive FISH result, received crizotinib but developed progressive disease within one month, possibly owing to no functional fusion transcript detected by RNA-based NGS. CONCLUSIONS: Intergenic-breakpoint fusions detected by DNA sequencing confound kinase fusion detection in NSCLC, as functional fusion transcripts may be generated or not. Additional validation testing using RNA/protein assay should be performed in intergenic-breakpoint fusion cases to guide optimal treatment.

4.
Mol Inform ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32162831

RESUMO

Epoxidation is one of the reactions in drug metabolism. Since epoxide metabolites would bind with proteins or DNA covalently, drugs should avoid epoxidation metabolism in the body. Due to the instability of epoxide, it is difficult to determine epoxidation experimentally. In silico models based on big data and machine learning methods are hence valuable approaches to predict whether a compound would undergo epoxidation. In this study, we collected 884 epoxidation data manually from various sources, and finally got 829 unique sites of epoxidation. Three types of molecular fingerprints with different lengths (1024, 2048 or 4096 bits) were used to describe the reaction sites. Six machine learning methods were used to build the classification models. The training set and test set were randomly divided into 8: 2, and 54 models were constructed and evaluated. Four best models were selected for feature selection. The features were then chosen and verified by external validation set. The resulted optimal model had the accuracy and AUC (area under the curve) values at 0.873 and 0.944 for the test set, 0.838 and 0.987 for the external validation set, respectively. The models built in this study could accurately predict whether a compound will undergo epoxidation and which part is most susceptible to epoxidation, which is of great significance for drug design.

5.
Brief Bioinform ; 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32221552

RESUMO

Drug discovery and development is a time-consuming and costly process. Therefore, drug repositioning has become an effective approach to address the issues by identifying new therapeutic or pharmacological actions for existing drugs. The drug's anatomical therapeutic chemical (ATC) code is a hierarchical classification system categorized as five levels according to the organs or systems that drugs act and the pharmacology, therapeutic and chemical properties of drugs. The 2nd-, 3rd- and 4th-level ATC codes reserved the therapeutic and pharmacological information of drugs. With the hypothesis that drugs with similar structures or targets would possess similar ATC codes, we exploited a network-based approach to predict the 2nd-, 3rd- and 4th-level ATC codes by constructing substructure drug-ATC (SD-ATC), target drug-ATC (TD-ATC) and Substructure&Target drug-ATC (STD-ATC) networks. After 10-fold cross validation and two external validations, the STD-ATC models outperformed the SD-ATC and TD-ATC ones. Furthermore, with KR as fingerprint, the STD-ATC model was identified as the optimal model with AUC values at 0.899 ± 0.015, 0.916 and 0.893 for 10-fold cross validation, external validation set 1 and external validation set 2, respectively. To illustrate the predictive capability of the STD-ATC model with KR fingerprint, as a case study, we predicted 25 FDA-approved drugs (22 drugs were actually purchased) to have potential activities on heart failure using that model. Experiments in vitro confirmed that 8 of the 22 old drugs have shown mild to potent cardioprotective activities on both hypoxia model and oxygen-glucose deprivation model, which demonstrated that our STD-ATC prediction model would be an effective tool for drug repositioning.

6.
Bioinspir Biomim ; 15(3): 036008, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32196482

RESUMO

Inspired by a scallop's strong underwater propulsion mechanism, we designed and prototyped a scallop robot capable of clapping and swimming. In this work, an artificial velum was used to work as a check valve to stimulate the robot's swimming. A couple of supporting plates were fixed on the robot shells to achieve the modulation of clapping process of the shells. The scallop robot can move at a maximum average and instantaneous speed of 3.4 and 4.65 body lengths per second, respectively. The effect of the supporting plates, the artificial velum, as well as the clapping frequency and amplitude on the swimming performance of the scallop robot was also experimentally evaluated. By tuning the sizes of the jet apertures, the scallop robot is capable of achieving high mobility actions such as turning. We also obtained the aperture ratio with the corresponding turning radius. This scallop robot provides a new propulsion mechanism in underwater bionic robots; it is also of help to understand the swimming principle of scallops in terms of jet propulsion and clapping motion.

7.
Zhongguo Fei Ai Za Zhi ; 23(3): 150-155, 2020 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-32209183

RESUMO

BACKGROUND: Pembrolizumab, an immunotherapy for advanced non-small cell lung cancer (NSCLC), needs to predict treatment response based on test results including immunohistochemistry (IHC), which detects the expression of programmed death ligand 1 (PD-L1). The aim of this study was to evaluate the feasibility of immunocytochemistry (ICC) in NSCLC cytology to detect PD-L1 and to investigate the correlation between PD-L1 expression and clinical pathology and molecular features. METHODS: Sixty cases of lung adenocarcinoma pleural cytology were collected and PD-L1 sp263 reagent was used for immunocytochemical staining according to the manufacturer's instructions. Next-generation sequencing (NGS) was performed on pleural cytology specimens to explore its correlation. RESULTS: Of the 60 cases of lung adenocarcinoma pleural effusion cell block, 35 cases were positive for PD-L1 expression, and the positive expression rate was 58.3%. The positive rate of PD-L1 expression in the specimens of our hospital was 33.3%, and there was no significant difference between the cytological specimens and the histological specimens (P>0.05). Of the 60 cytological specimens, 26 were tested for NGS, and 15 (57.7%) were found to have epidermal growth factor receptor (EGFR) mutations. No correlation was found between PD-L1 expression and EGFR mutation. The positive expression rate of PD-L1 were not correlated with the age and gender in the study population (P>0.05). CONCLUSIONS: When no surgical specimens are available, pleural cytology cell block specimens can be used for immunocytochemical detection of PD-L1, and the results are feasible.

8.
Chem Res Toxicol ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32091207

RESUMO

Structural alerts are a simple and easy way to identify toxic compounds being widely used in environmental toxicology research and drug discovery. With the emergence of big data techniques in recent years and their applications in chemistry and toxicology, computational approaches have become a promising method to identify structural alerts. In this Review, we describe the recent progress in computational methods for identification of structural alerts and their applications in toxicology. Two major computational approaches, namely frequency analysis and interpretable machine learning models, are reviewed. Recent studies have shown that both approaches are superior to expert systems with respect to predictive capability. Methodologies for defining the applicability domain of such approaches are also reviewed, with their importance stemming from their ability to not only improve the predictive performance of structural alert models but also ensure the confidence of a prediction. In addition to toxicity prediction, structural alerts could be also used to explain quantitative structure-activity relationship models and guide lead optimization in drug discovery. Nevertheless, there are still some challenges to be solved, such as how to address the co-existence of several structural alerts in one molecule, how to directly compare computationally derived structural alerts with expert systems, and how to explore new mechanisms of toxicity.

9.
Chemistry ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32049373

RESUMO

The hydroxylation of non-reactive C-H bonds can be easily catalyzed by a variety of metalloenzymes, especially cytochromes P450 (P450s). The mechanism of P450 mediated hydroxylation has been intensively studied, both experimentally and theoretically. However, understanding the regio- and stereoselectivities of substrates hydroxylated by P450s remains a great challenge. Here, we use a multi-scale modeling approach to investigate the selectivity of testosterone (TES) and dihydrotestosterone (DHT) hydroxylation catalyzed by two important P450s, CYP3A4 and CYP19A1. For CYP3A4, two distinct binding modes for TES/DHT were predicted by dockings and molecular dynamics simulations, in which the experimentally identified sites of metabolism of TES/DHT can access to the catalytic center. The regio- and stereoselectivities of TES/DHT hydroxylation were further evaluated by quantum mechanical and ONIOM calculations. For CYP19A1, we found that sites 1ß, 2ß and 19 can access to the catalytic center, with the intrinsic reactivity 2ß > 1ß > 19. However, our ONIOM calculation results indicate that the hydroxylation is favored at site 19 for both TES and DHT, which is in agreement with the experiments and reflects the importance of the catalytic environment in determining the selectivity. Our study unravels the mechanism underlying the selectivity of TES/DHT hydroxylation mediated by CYP3A4 and CYP19A1 and is helpful for understanding the selectivity of other substrates hydroxylated by P450s.

10.
J Chem Inf Model ; 60(3): 1540-1550, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32097559

RESUMO

The farnesoid X receptor (FXR) is a bile acid-sensing transcription factor with indispensable roles in regulating metabolic processes. Nowadays, FXR has become a highly promising drug target for severe liver disorders, especially nonalcoholic steatohepatitis (NASH). A recent study showed that imatinib and its analogues were able to allosterically enhance agonist-induced FXR activation and its target gene expression. However, the allosteric modulation mechanism of FXR by these compounds remains unclear. In this work, the most effective imatinib analogue, P16, was used as a probe to explore this issue by computational approaches. Our results identified one potential allosteric site surrounded by residues Ile335, Phe336, Lys338, Glu339, Leu340, and Leu348, which could efficiently accommodate P16. In addition, the long-time molecular dynamics simulations indicated that the binding of P16 could significantly decrease the fluctuation of the co-activator and enhance the communications between the endogenous ligand chenodeoxycholic acid (CDCA) and FXR. By analyzing the residue interaction network, we observed two unique communication pathways connecting P16 and CDCA through three key residues, Arg331, Ser332, and Phe336. The communications of network organization in the P16-bound complex may allow the synergistic effect of the two compounds via robust signal transmission between the binding sites and global network bridges, which coordinate allosteric transitions and modulate the receptor activity. Our study offers insights into the allosteric modulation occurring in FXR and would be helpful for discovery of new allosteric modulators targeting FXR for further clinical research.

11.
Biomolecules ; 10(2)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32023953

RESUMO

Inflammation-induced angiogenesis is closely related to many diseases and has been regarded as a therapeutic target. Caspase-8 has attracted increasing attention for its immune properties and therapeutic potential in inflammatory disorders. The aim of our study is to investigate the clinical application of pharmacological inhibition of caspase-8 and the underlying molecular mechanisms in inflammation-induced angiogenesis in the cornea. A model of alkali burn (AB)-induced corneal neovascularization (CNV) in C57BL/6 wild-type (WT) mice and toll-like receptor 4 knockout (Tlr4-/-) mice was used. We found that AB increased caspase-8 activity and the pharmacological inhibition of caspase-8 exerted substantial inhibitory effects on CNV, with consistent decreases in caspase-8 activity, inflammatory cell infiltration, macrophage recruitment and activation, VEGF-A, TNF-α, IL-1ß, MIP-1, and MCP-1 expression in the cornea. In vitro, caspase-8 mediated TLR4-dependent chemokines and VEGF-A production by macrophages. The TLR4 knockout significantly alleviated CNV, suppressed caspase-8 activity and downregulated expression of inflammatory cytokines and chemokines after AB. Taken together, these findings provide the first demonstration that the pharmacological inhibition of caspase-8 suppresses inflammation-induced angiogenesis and support the use of a pharmacological caspase-8 inhibitor as a novel clinical treatment for CNV and other angiogenic disorders.

12.
Int J Cancer ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32030746

RESUMO

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) predisposition syndrome. We performed a large-scale study to assess a screening strategy for identifying LS in Chinese CRC patients in routine clinical testing. A total of 4,195 eligible CRCs were universally screened. Then, 8.7% of CRCs were detected with dMMR. The incidence of LS was 2.7% (115 of 4,195) in this cohort; among patients over 70 years of age, only 0.3% (2 of 678) were diagnosed as LS. Then, 17.4% of LS cases showed large genomic deletions/duplications. LS probands developed CRCs predominantly at proximal colon location. The frequency of BRAF V600E mutation among Chinese CRCs was significantly lower than that among Western populations, and MLH1 promoter methylation significantly improved the efficiency of genetic screening for LS among MLH1-deficient patients. A comprehensive molecular testing strategy that includes detection of large genomic rearrangements is imperative for the diagnosis of LS. Among CRC patients aged 70 years or younger, a selective strategy for LS screening might be considered for routine clinical testing.

13.
Nat Immunol ; 21(3): 355, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32034311

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32037788

RESUMO

Gallium-based room-temperature liquid metals have enormous potential for realizing various applications in electronic devices, heat flow management, and soft actuators. Filling narrow spaces with a liquid metal is of great importance in rapid prototyping and circuit printing. However, it is relatively difficult to stretch or spread liquid metals into desired patterns because of their large surface tension. Here, we propose a method to fabricate a particle-based porous material which can enable the rapid and spontaneous diffusion of liquid metals within the material under a capillary force. Remarkably, such a method can allow liquid metal to diffuse along complex structures and even overcome the effect of gravity despite their large densities. We further demonstrate that the developed method can be utilized for prototyping complex three-dimensional (3D) structures via direct casting and connecting individual parts or by 3D printing. As such, we believe that the presented technique holds great promise for the development of additive manufacturing, rapid prototyping, and soft electronics using liquid metals.

15.
Chem Res Toxicol ; 33(2): 640-650, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-31957435

RESUMO

Renal clearance (CLr) plays an essential role in the elimination of drugs. In this study, 636 compounds were obtained from various sources to develop in silico models for the prediction of CLr. Stepwise multiple linear regression and random forest regression methods were employed to build global models and local models according to ionization state or net elimination pathways. The local models toward compounds undergoing different net elimination pathways showed good predictive power: the geometric mean fold error was close to 2, indicating the clearance of most compounds could be predicted within a 2-fold error range. Six classification methods were used to construct classification models. However, the performance of these classification models was less than satisfactory, and the mean accuracy of the top five models in test sets was 0.65. Moreover, qualitative analysis of physicochemical profiles between compounds undergoing different net elimination pathways revealed that compounds with higher lipophilicity tended to be reabsorbed more easily and showed lower CLr, while compounds with higher values of polar descriptors tended to secrete more easily and showed higher CLr.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31958968

RESUMO

Traditional Chinese medicine can improve the immune reconstruction of HIV/AIDS patients.

17.
Nat Commun ; 11(1): 340, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953413

RESUMO

Mikania micrantha is one of the top 100 worst invasive species that can cause serious damage to natural ecosystems and substantial economic losses. Here, we present its 1.79 Gb chromosome-scale reference genome. Half of the genome is composed of long terminal repeat retrotransposons, 80% of which have been derived from a significant expansion in the past one million years. We identify a whole genome duplication event and recent segmental duplications, which may be responsible for its rapid environmental adaptation. Additionally, we show that M. micrantha achieves higher photosynthetic capacity by CO2 absorption at night to supplement the carbon fixation during the day, as well as enhanced stem photosynthesis efficiency. Furthermore, the metabolites of M. micrantha can increase the availability of nitrogen by enriching the microbes that participate in nitrogen cycling pathways. These findings collectively provide insights into the rapid growth and invasive adaptation.

18.
J Environ Manage ; 258: 110021, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31929062

RESUMO

Coking wastewater is highly concentrated and extremely toxic, greatly challenging the treatment technologies. Conventional biological technology such as anaerobic-anoxic-oxic (A2O) system is inefficient, since various biological reactions are inhibited by toxicants in coking wastewater. In this work, a pilot-scale three-dimensional electrochemical reactor (3DER) is integrated into the A2O system as a pretreatment unit to improve the treatment efficiency of coking wastewater. The results indicate that 3DER pretreatment increased the biodegradability of coking wastewater, promoting the degradation of coking wastewater in A2O system. The integrated 3DER-A2O system can remove 94.4% of COD and 76.2% of TN from coking wastewater, and the energy consumption was only 0.22 kWh/kg COD and 4.69 kWh/kg TN. The components of coking wastewater were significantly simplified and the acute toxicity was reduced from 99% to 12% after the treatment. The integrated 3DER-A2O system provides a new solution for coking wastewater treatment, showing a promising application potential.


Assuntos
Coque , Águas Residuárias , Anaerobiose , Reatores Biológicos , Eliminação de Resíduos Líquidos
19.
BMC Plant Biol ; 20(1): 5, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900117

RESUMO

BACKGROUND: In strawberry cultivation, continuous cropping (CC) obstacles seriously threaten production. A patented soil amendment (SA) can effectively relieve the CC obstacles to strawberry cultivation, but knowledge of the recovery mechanisms underlying this phenomenon is limited. RESULTS: In this study, transcriptomic profiling of strawberry roots in soil with and without the SA was conducted using RNA-Seq technology to reveal gene expression changes in response to SA treatment. In total, 188 differentially expressed genes (DEGs), including 144 upregulated and 44 downregulated DEGs, were identified. SA treatment resulted in genotype-dependent responses, and the response pattern, including an overall increase in the expression of nutrient transport genes and a decrease in the expression of defense response genes, may be a possible mechanism underlying recovery strategies in strawberry roots after the application of the SA to CC soil. We also found that 9 Hsp genes involved in plant defense pathways were all downregulated in the SA-treated roots. CONCLUSIONS: This research indicated that strawberry plants reallocated defense resources to development when SA treatment alleviated the stress caused by a CC soil environment. The present study provides an opportunity to reveal the fundamental mechanisms of the tradeoff between growth and defense in strawberry.

20.
Mol Cancer ; 19(1): 1, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31901224

RESUMO

Hepatocellular carcinoma (HCC) is the most commonmalignancy. Exsome plays a significant role in the elucidation of signal transduction pathways between hepatoma cells, angiogenesis and early diagnosis of HCC. Exosomes are small vesicular structures that mediate interaction between different types of cells, and contain a variety of components (including DNA, RNA, and proteins). Numerous studies have shown that these substances in exosomes are involved in growth, metastasis and angiogenesis in liver cancer, and then inhibited the growth of liver cancer by blocking the signaling pathway of liver cancer cells. In addition, the exosomal substances could also be used as markers for screening early liver cancer. In this review, we summarized to reveal the significance of exosomes in the occurrence, development, diagnosis and treatment of HCC, which in turn might help us to further elucidate the mechanism of exosomes in HCC, and promote the use of exosomes in the clinical diagnosis and treatment of HCC.

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