Glycine to valine substitution in the short intracellular linkers of domain II enhances I1011M-mediated sodium channel resistance to Type I pyrethroids, but not Type II pyrethroids.

Pyrethroids are widely used against agricultural pests and human disease vectors due to their broad insecticidal spectrum, fast action, and low mammalian toxicity. Unfortunately, overuse of pyrethroids has led to knockdown resistance (kdr) caused by mutations in voltage-gated sodium channels. Mutation I1011M was repeatedly detected in numerous pyrethroid-resistant Aedes aegypti populations from Latin American and Brazil. In addition, mutation G923V was first reported to coexist with I1011M in permethrin/DDT-resistant Ae. aegypti, whether G923V enhances the I1011M-mediated pyrethroid resistance in sodium channels remains unclear. In this study, we introduced mutations G923V and I1011M alone or in combination into the pyrethroid-sensitive sodium channel AaNav1-1 and examined the effects of these mutations on gating properties and pyrethroid sensitivity. We found mutations I1011M and G923V + I1011M shifted the voltage dependence of activation in the depolarizing direction, and none of mutations affect the voltage-dependence of inactivation. G923V and G923V + I1011M mutations reduced the channel sensitivity to both Type I and Type II pyrethroids. However, I1011M alone conferred resistance to Type I pyrethroids, not to Type II pyrethroids. Interestingly, significant synergism effects on Type I pyrethroids were observed between mutations G923V and I1011M. The effects of all mutations on channel sensitivity to DDT were identical with those to Type I pyrethroids. Our results confirm the molecular basis of resistance mediated by mutations G923V and I1011M and may contribute to develop molecular markers for monitoring pest resistance to pyrethroids.

Increased risk of subsequent primary lung cancer among female hormone-related cancer patients: A meta-analysis based on over four million cases.

BACKGROUND: The incidence rate of lung cancer in women has significantly increased over the past decade, and previous evidence has indicated a significant relationship between the elevated levels of sex hormones and the risk of lung cancer. Therefore, we hypothesized that female hormone-related cancer (FHRC) patients, including breast, endometrial, cervical, and ovarian cancer patients, may experience a higher risk of developing subsequent lung cancer. This meta-analysis aimed to identify the risk of lung cancer among FHRC patients compared to the general population. METHODS: The PubMed, Web of Science, EMBASE, Cochrane Library, and CNKI databases were searched up to May 11, 2022. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were used to identify the risk of subsequent lung cancer after FHRC. Subgroup analyses based on the follow-up time and tumor type were also conducted. RESULTS: A total of 58 retrospective cohort studies involving 4,360,723 FHRC participants were included. The pooled results demonstrated that FHRC patients had a significantly increased risk of developing subsequent primary lung cancer (SIR = 1.61, 95% CI: 1.48-1.76, P <0.001). Subgroup analysis revealed an obvious trend of increasing lung cancer risk over time (SIRs for <5 years, ≥5 years, ≥10 years, ≥20 years, and ≥30 years after FHRC: 1.32, 1.59, 1.57, 1.68, and 1.95, respectively). In addition, subgroup analysis stratified by tumor type indicated an increased risk of developing subsequent lung cancer after breast (SIR = 1.25, P <0.001), endometrial (SIR = 1.40, P = 0.019), cervical (SIR = 2.56, P <0.001), and ovarian cancer (SIR = 1.50, P = 0.010). CONCLUSION: FHRC patients are more likely to develop lung cancer than the general population. Furthermore, the increased risk of subsequent primary lung cancer is more obvious with a longer survival time and is observed in all types of hormone-related cancer. REGISTRATION: International Platform of Registered Systematic Review and Meta-analysis Protocols: No. INPLASY202270044; https://inplasy.com/.

A facile electrochemical aptasensor for chloramphenicol detection based on synergistically photosensitization enhanced by SYBR Green I and MoS2.

This study reports the development of a photocatalytic electrochemical aptasensor for the purpose of detecting chloramphenicol (CAP) antibiotic residues in water by utilizing SYBR Green I (SG) and chemically exfoliated MoS2 (ce-MoS2) as synergistically signal-amplification platforms. The Au nanoparticles (AuNPs) were electrodeposited onto the surface of an indium tin oxide (ITO) electrode. After that, the thiolate-modified cDNA, also known as capture DNA, was combined with the aptamer. Subsequently, photosensitized SG molecules and ce-MoS2 nanomaterial were inserted into the groove of the resultant double-stranded DNA (dsDNA). The activation of the photocatalytic process upon exposure to light resulted in the generation of singlet oxygen. The singlet oxygen effectively split the dsDNA, resulting in significant enhancement in the current of [Fe(CN)6]3-/4-. When the CAP was present, both SG molecules and ce-MoS2 broke away from the dsDNA, which turned off the photosensitization response, leading to significant reduction in the current of [Fe(CN)6]3-/4-. Under the optimal conditions, the aptasensor exhibited a linear relationship between the current of [Fe(CN)6]3-/4- with logarithmic concentrations of CAP from 20 to 1000 nM, with a detection of limit (3σ) of 3.391 nM. The aptasensor also demonstrated good selectivity towards CAP in the presence of interfering antibiotics, such as tetracycline, streptomycin, levofloxacin, ciprofloxacin, and sulfadimethoxine. Additionally, the results obtained from the analysis of natural water samples using the proposed aptasensor were consistent with the findings acquired through the use of a liquid chromatograph-mass spectrometer. Therefore, with its simplicity and high selectivity, this aptasensor can potentially detect alternative antibiotics in environmental water samples by replacing the aptamers based on photosensitization.

Contribution of Immune Responses to the Cardiotoxicity and Hepatotoxicity of Deltamethrin in Early Life Stage Zebrafish (Danio rerio).

Deltamethrin (DM) is a widely used insecticide that has demonstrated developmental toxicity in the early life stages of fish. To better characterize the underlying mechanisms, embryos from Tg(cmlc2:RFP), Tg(apo14:GFP), and Tg(mpx:GFP) transgenic strains of zebrafish were exposed to nominal DM concentrations of 0.1, 1, 10, 25, and 50 µg/L until 120 h post-fertilization (hpf). Heart size increased 56.7%, and liver size was reduced by 17.1% in zebrafish exposed to 22.7 and 24.2 µg/L DM, respectively. RNA sequencing and bioinformatic analyses predicted that key biological processes affected by DM exposure were related to inflammatory responses. Expression of IL-1 protein was increased by 69.0% in the 24.4 µg/L DM treatment, and aggregation of neutrophils in cardiac and hepatic histologic sections was also observed. Coexposure to resatorvid, an anti-inflammatory agent, mitigated inflammatory responses and cardiac toxicity induced by DM and also restored liver biomass. Our data indicated a complex proinflammatory mechanism underlying DM-induced cardiotoxicity and hepatotoxicity which may be important for key events of adverse outcomes and associated risks of DM to early life stages of fish.

Antenna-Biased Odorant Receptor PstrOR17 Mediates Attraction of Phyllotreta striolata to (S)-Cis-Verbenol and (-)-Verbenone.

Phyllotreta striolata, the striped flea beetle, is one of the most destructive pests in Brassicaceae plants worldwide. Given the drawbacks associated with long-term use of chemical insecticides, green strategies based on chemical ecology are an effective alternative for beetle control. However, the lack of information on beetle ecology has hindered the development of effective biocontrol strategies. In this report, we identified two odorants, (S)-cis-verbenol and (-)-verbenone, which displayed significant attraction for P. striolata (p < 0.05), indicating their great potential for P. striolata management. Using the Drosophila "empty neuron" system, an antenna-biased odorant receptor, PstrOR17, was identified as responsible for the detection of (-)-verbenone and (S)-cis-verbenol. Furthermore, the interactions between PstrOR17 and (-)-verbenone or (S)-cis-verbenol were predicted via modeling and molecular docking. Finally, we used RNAi to confirm that PstrOR17 is essential for the detection of (-)-verbenone and (S)-cis-verbenol to elicit an attraction effect. Our results not only lay a foundation for the development of new and effective nonchemical insecticide strategies based on (S)-cis-verbenol and (-)-verbenone, but also provide new insight into the molecular basis of odorant recognition in P. striolata.

A potential link between aromatics-induced oviposition repellency behaviors and specific odorant receptor of Aedes albopictus.

BACKGROUND: The Asian tiger mosquito, Aedes albopictus, is a competent vector for the spread of several viral arboviruses including dengue, chikungunya, and Zika. Several vital mosquito behaviors linked to survival and reproduction are primarily dependent on a sophisticated olfactory system for semiochemical perception. However, a limited number of studies has hampered our understanding of the relationship between the A. albopictus acute olfactory system and the complex chemical world. RESULTS: Here, we performed a qRT-PCR assay on antennae from A. albopictus of differing sex, age and physiological states, and found that AalbOr10 was enriched in blood-fed female mosquitoes. We then undertook single sensillum recording to de-orphan AalbOr10 using a panel of physiologically and behaviorally relevant odorants in a Drosophila 'empty neuron' system. The results indicated that AalbOr10 was activated by seven aromatic compounds, all of which hampered egg-laying in blood-fed mosquitoes. Furthermore, using a post-RNA interference oviposition assay, we found that reducing the transcript level of AalbOr10 affected repellent activity mediated by 2-ethylphenol at low concentrations (10-4 vol/vol). Computational modeling and molecular docking studies suggested that hydrogen bonds to Y68 and Y150 mediated the interaction of 2-ethylphenol with AalbOr10. CONCLUSION: We reveal a potential link between aromatics-induced oviposition repellency behaviors and a specific odorant receptor in A. albopictus. Our findings provide a foundation for identifying active semiochemicals for the monitoring or controlling of mosquito populations. © 2024 Society of Chemical Industry.

On-site rapid detection of multiple pesticide residues in tea leaves by lateral flow immunoassay.

The application of pesticides (mostly insecticides and fungicides) during the tea-planting process will undoubtedly increase the dietary risk associated with drinking tea. Thus, it is necessary to ascertain whether pesticide residues in tea products exceed the maximum residue limits. However, the complex matrices present in tea samples comprise a major challenge in the analytical detection of pesticide residues. In this study, nine types of lateral flow immunochromatographic strips (LFICSs) were developed to detect the pesticides of interest (fenpropathrin, chlorpyrifos, imidacloprid, thiamethoxam, acetamiprid, carbendazim, chlorothalonil, pyraclostrobin, and iprodione). To reduce the interference of tea substrates on the assay sensitivity, the pretreatment conditions for tea samples, including the extraction solvent, extraction time, and purification agent, were optimized for the simultaneous detection of these pesticides. The entire testing procedure (including pretreatment and detection) could be completed within 30 min. The detected results of authentic tea samples were confirmed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which suggest that the LFICS coupled with sample rapid pretreatment can be used for on-site rapid screening of the target pesticide in tea products prior to their market release.

Aquatic and sediment ecotoxicity data of difenoconazole and its potential environmental risks in ponds bordering rice paddies.

Difenoconazole has a widespread agricultural use to control fungal diseases in crops, including rice. In edge-of-field surface waters the residues of this lipophilic fungicide may be toxic to both pelagic and benthic organisms. To allow an effect assessment we mined the regulatory and open literature for aquatic toxicity data. Since published sediment toxicity data were scarce we conducted 28 d sediment-spiked toxicity test with 8 species of benthic macroinvertebrates. Ecotoxicological threshold levels for effects were assessed by applying the species sensitivity distribution approach. Based on short-term L(E)C50's for aquatic organisms from water-only tests an acute Hazardous Concentration to 5% of the species (HC5) of 100 µg difenoconazole/L was obtained, while the HC5 based on chronic NOEC values was a factor of 104 lower (0.96 µg difenoconazole/L). For benthic macroinvertebrates the chronic HC5, based on 28d-L(E)C10 values, was 0.82 mg difenoconazole/kg dry weight sediment. To allow a risk assessment for water- and sediment-dwelling organisms, exposure concentrations were predicted for the water and sediment compartment of an edge-of-field pond bordering rice paddies treated with difenoconazole using the Chinese Top-Rice modelling approach, the Chinese Nanchang exposure scenario and the Equilibrium Partitioning theory. It appeared that in the vast majority of the 20 climate years simulated, potential risks to aquatic and sediment organisms cannot be excluded. Although the HC5 values based on laboratory toxicity data provide one line of evidence only, our evaluation suggests population- and community-level effects on these organisms due to chronic risks in particular.

Dysbiosis of lower respiratory tract microbiome are associated with proinflammatory states in non-small cell lung cancer patients.

BACKGROUND: The lung has a sophisticated microbiome, and respiratory illnesses are greatly influenced by the lung microbiota. Despite the fact that numerous studies have shown that lung cancer patients have a dysbiosis as compared to healthy people, more research is needed to explore the association between the microbiota dysbiosis and immune profile within the tumor microenvironment (TME). METHODS: In this study, we performed metagenomic sequencing of tumor and normal tissues from 61 non-small cell lung cancer (NSCLC) patients and six patients with other lung diseases. In order to characterize the impact of the microbes in TME, the cytokine concentrations of 24 lung tumor and normal tissues were detected using a multiple cytokine panel. RESULTS: Our results showed that tumors had lower microbiota diversity than the paired normal tissues, and the microbiota of NSCLC was enriched in Proteobacteria, Firmicutes, and Actinobacteria. In addition, proinflammatory cytokines such as IL-8, MIF, TNF- α, and so on, were significantly upregulated in tumor tissues. CONCLUSION: We discovered a subset of bacteria linked to host inflammatory signaling pathways and, more precisely, to particular immune cells. We determined that lower airway microbiome dysbiosis may be linked to the disruption of the equilibrium of the immune system causing lung inflammation. The spread of lung cancer may be linked to specific bacteria.

Nanomedicine Combats Drug Resistance in Lung Cancer.

Lung cancer is the second most prevalent cancer and the leading cause of cancer-related death worldwide. Surgery, chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy are currently available as treatment methods. However, drug resistance is a significant factor in the failure of lung cancer treatments. Novel therapeutics have been exploited to address complicated resistance mechanisms of lung cancer and the advancement of nanomedicine is extremely promising in terms of overcoming drug resistance. Nanomedicine equipped with multifunctional and tunable physiochemical properties in alignment with tumor genetic profiles can achieve precise, safe, and effective treatment while minimizing or eradicating drug resistance in cancer. Here, this work reviews the discovered resistance mechanisms for lung cancer chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy, and outlines novel strategies for the development of nanomedicine against drug resistance. This work focuses on engineering design, customized delivery, current challenges, and clinical translation of nanomedicine in the application of resistant lung cancer.

Dual-target inhibitors based on COX-2: a review from medicinal chemistry perspectives.

Inhibitors of COX-2 constitute a class of anti-inflammatory analgesics, showing potential against certain types of cancer. However, such inhibitors are associated with cardiovascular toxicity. Moreover, although single-target molecules possess specificity for particular targets, they often lead to poor safety, low efficacy and drug resistance due to compensatory mechanisms. A new generation of dual-target drugs that simultaneously inhibit COX-2 and another target is showing strong potential to treat cancer or reduce adverse cardiac effects. The present perspective focuses on the structure and functions of COX-2, and its role as a therapeutic target. It also explores the current state and future possibilities for dual-target strategies from a medicinal chemistry perspective.

Leucine to tryptophane substitution in the pore helix IIP1 confer sodium channel resistance to pyrethroids and DDT.

Aedes aegypti is responsible for transmitting a variety of arboviral infectious diseases such as dengue and chikungunya. Insecticides, particularly pyrethroids, are used widely for mosquito control. However, intensive used of pyrethroids has led to the selection of kdr mutations on sodium channels. L982W, locating in the PyR1 (Pyrethroid receptor site 1), was first reported in Ae. aegypti populations collected from Vietnam. Recently, the high frequency of L982W was detected in pyrethroid-resistant populations of Vietnam and Cambodia, and also concomitant mutations L982W + F1534C was detected in both countries. However, the role of L982W in pyrethroid resistance remains unclear. In this study, we examined the effects of L982W on gating properties and pyrethroid sensitivity in Xenopus oocytes. We found that mutations L982W and L982W + F1534C shifted the voltage dependence of activation in the depolarizing direction, however, neither mutations altered the voltage dependence of inactivation. L982W significantly reduced channel sensitivity to Type I pyrethroids, permethrin and bifenthrin, and Type II pyrethroids, deltamethrin and cypermethrin. No enhancement was observed when synergized with F1534C. In addition, L982W and L982W + F1534C mutations reduced the channel sensitivity to DDT. Our results illustrate the molecular basis of resistance mediates by L982W mutation, which will be helpful to understand the interacions of pyrethroids or DDT with sodium channels and develop molecular markers for monitoring pest resistance to pyrethroids and DDT.

Insights into the Binding Profile of Anti-chlorpyrifos Recombinant Antibodies: From Computational Simulation to Immunoassay Validation.

A novel virtual screening strategy was proposed for the profiling and discovery of active variable regions (VRs) that encode hapten-specific recombinant antibodies (rAbs). Chlorpyrifos, a hazardous organophosphorus pesticide, was selected as the target. First, a VR model-14G4 from anti-chlorpyrifos hybridoma was built via homology modeling. Its binding pattern toward seven organophosphorus analogues was assessed through virtual screening by performing molecular docking. Based on energy scoring, visual examination, and molecular interaction analysis, chlorpyrifos-methyl was also inferred as the high-affinity target for model-14G4 and was then confirmed via a non-competitive surface plasmon resonance (SPR) assay. Subsequently, we attempted to discover hapten-specific VRs by creating a collection of VR models for anonymous testing. Chlorpyrifos and model-14G4 were employed as the known hit and active VRs, respectively. After molecular docking, a novel anti-chlorpyrifos VR (model-1) was identified due to its satisfactory energy scoring and a similar binding pattern to the reference model-14G4. Expressed by HEK293(F) mammalian cells, the newly prepared full-length rAb-model-1 and rAb-14G4 exhibited high sensitivities for detecting chlorpyrifos by the indirect competitive enzyme-linked immunosorbent assay (ic-ELISA), with IC50 of 3.01 ng/mL and 42.82 ng/mL, respectively. They recognized chlorpyrifos-methyl with a cross-reactivity (CR) of 2.5-17.3%. Moreover, the binding properties of rAb-model-1 for recognizing chlorpyrifos and chlorpyrifos-methyl were confirmed via a non-competitive microscale thermophoresis (MST) method. Thus, the experimental results showed good agreement with computational outputs on antibody profiling. Furthermore, the recognition diversity of rAb-model-1 for chlorpyrifos and chlorpyrifos-methyl was studied via molecular dynamics simulation. Overall, the proposed study provides a versatile and economical strategy for antibody characterization and promotes the in vitro production of rAbs for pesticide monitoring.

Interaction between neutrophil extracellular traps and cardiomyocytes contributes to atrial fibrillation progression.

Atrial fibrillation (AF) is a frequent arrhythmia associated with cardiovascular morbidity and mortality. Neutrophil extracellular traps (NETs) are DNA fragments with cytoplasm proteins released from neutrophils, which are involved in various cardiovascular diseases. To elucidate the role of NETs in AF, we investigated the effect of NETs on AF progression and the secretion of NETs in AF. Results showed that: NETs induced the autophagic apoptosis of cardiomyocytes, and NETs also led to mitochondrial injury by promoting mitochondrial depolarization and ROS production. Ongoing tachy-pacing led to the structural loss of cardiomyocytes and provided potent stimuli to induce NETs secretion from neutrophils. In the meanwhile, increased Ang II in AF facilitated NETs formation through the upregulation of AKT phosphorylation, while it could not directly initiate NETosis as the autophagy was not induced. In vivo, DNase I was administrated to abrogate NETs formation, and AF-related fibrosis was ameliorated as expected. Correspondingly, the duration of the induced AF was reduced. Our study addresses the formation mechanism of NETs in AF and demonstrates the lethal effects of NETs on cardiomyocytes through the induction of mitochondrial injury and autophagic cell death, which comprehensively describes the positive feedback comprised of NETs and stimuli secreted by cardiomyocytes that sustains the progression of AF and AF related fibrosis.

Single-cell transcriptome analysis reveals cellular and molecular alterations in small cell lung cancer tumors following chemotherapy.

Chemotherapy is the standard therapy for small cell lung cancer (SCLC), but relapse is common and the 2-year survival rate remains low. Given the contribution of the tumor microenvironment (TME) to cancer development and response to treatment, we analyzed here how chemotherapy alters the TME in SCLC using single-cell RNA sequencing. The comparison between neuroendocrine cells and other epithelial cells in five chemotherapy-naive patients identified upregulation of Notch-inhibiting genes, such as DLL3 and HES6. Analysis of genes differentially expressed between five patients receiving chemotherapy and five treatment-naive patients in cells in the TME showed that chemotherapy promoted antigen presentation and senescence in neuroendocrine cells, upregulated ID1 to enhance angiogenic activities of stalk-like endothelial cells and strengthened vascular endothelial growth factor signaling in lymphatic endothelial cells. Chemotherapy also promoted the remodeling of extracellular matrix by fibroblasts and upregulated interferon-mediated antitumor immune responses by B and T cells. Our single-cell transcriptome analysis provides insights into how chemotherapy affects the TME in SCLC, which may guide efforts to make therapy more effective.

Early detection and stratification of lung cancer aided by a cost-effective assay targeting circulating tumor DNA (ctDNA) methylation.

BACKGROUND: Detection of lung cancer at earlier stage can greatly improve patient survival. We aim to develop, validate, and implement a cost-effective ctDNA-methylation-based plasma test to aid lung cancer early detection. METHODS: Case-control studies were designed to select the most relevant markers to lung cancer. Patients with lung cancer or benign lung disease and healthy individuals were recruited from different clinical centers. A multi-locus qPCR assay, LunaCAM, was developed for lung cancer alertness by ctDNA methylation. Two LunaCAM models were built for screening (-S) or diagnostic aid (-D) to favor sensitivity or specificity, respectively. The performance of the models was validated for different intended uses in clinics. RESULTS: Profiling DNA methylation on 429 plasma samples including 209 lung cancer, 123 benign diseases and 97 healthy participants identified the top markers that detected lung cancer from benign diseases and healthy with an AUC of 0.85 and 0.95, respectively. The most effective methylation markers were verified individually in 40 tissues and 169 plasma samples to develop LunaCAM assay. Two models corresponding to different intended uses were trained with 513 plasma samples, and validated with an independent collection of 172 plasma samples. In validation, LunaCAM-S model achieved an AUC of 0.90 (95% CI: 0.88-0.94) between lung cancer and healthy individuals, whereas LunaCAM-D model stratified lung cancer from benign pulmonary diseases with an AUC of 0.81 (95% CI: 0.78-0.86). When implemented sequentially in the validation set, LunaCAM-S enables to identify 58 patients of lung cancer (90.6% sensitivity), followed by LunaCAM-D to remove 20 patients with no evidence of cancer (83.3% specificity). LunaCAM-D significantly outperformed the blood test of carcinoembryonic antigen (CEA), and the combined model can further improve the predictive power for lung cancer to an overall AUC of 0.86. CONCLUSIONS: We developed two different models by ctDNA methylation assay to sensitively detect early-stage lung cancer or specifically classify lung benign diseases. Implemented at different clinical settings, LunaCAM models has a potential to provide a facile and inexpensive avenue for early screening and diagnostic aids for lung cancer.

An oral phenylacrylic acid derivative suppressed hepatic stellate cell activation and ameliorated liver fibrosis by blocking TGF-ß1 signalling.

BACKGROUND AND AIMS: Liver fibrosis is an excessive wound-healing response governed by activated hepatic stellate cells (HSCs). To date, there is no drug available for liver fibrosis. Although ferulic acid (FA) has multiple pharmacological functions, its anti-hepatic fibrosis activity is weak. Based on the activity modification of the FA structure, we synthesized a series of phenylacrylic derivatives and found a superior compound, FA11. In this study, we investigated its antifibrotic effect and mechanism. METHODS: Activated HSC and CCl4 -induced mouse liver fibrosis were established and followed by FA11 treatment. Cell viability was measured by CCK-8 assay. Apoptosis and cell cycle analysis were conducted by flow cytometry. Western blot and Real-time qPCR were used to examine the expression of fibrotic and M1/M2-type macrophages markers. Degree of liver fibrosis was shown by histological staining. RESULTS: In vitro, FA11 inhibited TGF-ß1-induced LX-2 proliferation and led to apoptosis and cycle arrest. Furthermore, elevation of fibrotic markers in TGF-ß1-induced LX-2 and primary activated HSC was reversed by FA11. In vivo, FA11 administration alleviated collagen deposition and blocked HSC activation and epithelial-mesenchymal transition (EMT). Additionally, FA11 reduced macrophage infiltration in fibrotic liver and prevented macrophage polarization to a profibrotic phenotype. Meanwhile, the systemic toxicity of CCl4 was also ameliorated by FA11. Mechanistically, FA11 reversed the phosphorylation of canonical and noncanonical TGF-ß1 signalling, as well as FGFR1 signalling. CONCLUSIONS: We reported an oral phenylacrylic acid derivative, FA11, which showed excellent antifibrotic activity and was expected to be an anti-hepatic fibrosis candidate.

Silencing of dre4 Contributes to Mortality of Phyllotreta striolata.

The striped flea beetle, Phyllotreta striolata, is one of the most destructive pests of Cruciferae crops worldwide. RNA interference (RNAi) is a promising alternative strategy for pest biological control, which overcomes the weakness of synthetic insecticides, such as pest resistance, food safety problems and toxicity to non-target insects. The homolog of Spt16/FACT, dre4 plays a critical role in the process of gene transcription, DNA repair, and DNA replication; however, the effects of dre4 silencing in P. striolata remain elusive. In this study, we cloned and characterized the full-length dre4 from P. striolata and silenced Psdre4 through microinjection and oral delivery; it was found that the silencing of dre4 contributed to the high mortality of P. striolata in both bioassays. Moreover, 1166 differentially regulated genes were identified after Psdre4 interference by RNA-seq analysis, which might have been responsible for the lethality. The GO analysis indicated that the differentially regulated genes were classified into three GO functional categories, including biological process, cellular component, and molecular function. The KEGG analysis revealed that these differentially regulated genes are related to apoptosis, autophagy, steroid hormone biosynthesis, cytochrome P450 and other signaling pathways. Our results suggest that Psdre4 is a fatal RNAi target and has significant potential for the development of RNA pesticides for P. striolata management.

A fluorogenic probe for predicting treatment response in non-small cell lung cancer with EGFR-activating mutations.

Therapeutic responses of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) are known to be associated with EGFR mutations. However, a proportion of NSCLCs carrying EGFR mutations still progress on EGFR-TKI underlining the imperfect correlation. Structure-function-based approaches have recently been reported to perform better in retrospectively predicting patient outcomes following EGFR-TKI treatment than exon-based method. Here, we develop a multicolor fluorescence-activated cell sorting (FACS) with an EGFR-TKI-based fluorogenic probe (HX103) to profile active-EGFR in tumors. HX103-based FACS shows an overall agreement with gene mutations of 82.6%, sensitivity of 81.8% and specificity of 83.3% for discriminating EGFR-activating mutations from wild-type in surgical specimens from NSCLC patients. We then translate HX103 to the clinical studies for prediction of EGFR-TKI sensitivity. When integrating computed tomography imaging with HX103-based FACS, we find a high correlation between EGFR-TKI therapy response and probe labeling. These studies demonstrate HX103-based FACS provides a high predictive performance for response to EGFR-TKI, suggesting the potential utility of an EGFR-TKI-based probe in precision medicine trials to stratify NSCLC patients for EGFR-TKI treatment.

Trace Immunosensing of Multiple Neonicotinoid Insecticides by a Novel Broad-Specific Antibody Obtained from a Rational Screening Strategy.

Residues of neonicotinoid pesticides have potential risks to food, environmental and biological safety. In this study, the hapten toward imidacloprid was adopted to gain antibodies. After molecular modeling, the electrostatic potentials of eight commonly-used neonicotinoid pesticides were individually calculated to analyze the structural similarity. Two representative compounds (imidacloprid and acetamiprid) with moderate similarity were rationally selected for hybridoma screening. Using this strategy, four clones of broad-specific monoclonal antibodies (mAbs) against multiple neonicotinoids were obtained, and the clone 6F11 exhibited the broadest spectrum to six neonicotinoid pesticides and two metabolites, with half-maximal inhibitory concentrations (IC50) ranging from 0.20 to 5.92 ng/mL. Then, the novel antibody gene was sequenced and successfully expressed in full-length IgG form using mammalian cells. Based on the sensitive recombinant antibody, a gold lateral-flow immunosensing strip assay was developed and it was qualified for rapid detection of imidacloprid, clothianidin or imidaclothiz residues in food samples.