Median Effective Concentration Research Articles

The median effective concentration of epidural ropivacaine with different doses of dexmedetomidine for motor blockade: an up-down sequential allocation study

Study objectiveRecent studies have shown that dexmedetomidine can be safely used in peripheral nerve blocks and spinal anesthesia. Epidural administration of dexmedetomidine produces analgesia and sedation, prolongs motor and sensory block time, extends postoperative analgesia, and reduces the need for rescue analgesia. This investigation seeks to identify the median effective concentration (EC50) of ropivacaine for epidural motor blockade, and assess how incorporating varying doses of dexmedetomidine impacts this EC50 value.DesignProspective, double-blind, up-down sequential allocation study.SettingOperating room, post-anesthesia care unit, and general ward.InterventionsOne hundred and fifty patients were allocated into five groups in a randomized, double-blinded manner as follows: NR (normal saline combined with ropivacaine) group, RD0.25 (0.25 μg/kg dexmedetomidine combined with ropivacaine) group, RD0.5 (0.5 μg/kg dexmedetomidine combined with ropivacaine) group, RD0.75 (0.75 μg/kg dexmedetomidine combined with ropivacaine) group, RD1.0 (1.0 μg/kg dexmedetomidine combined with ropivacaine) group. The concentration of epidural ropivacaine for the first patient in each group was 0.5%. Following administration, the patients were immediately placed in a supine position for observation, and the lower limb motor block was assessed every 5 min using the modified Bromage score within 30 min after drug administration. According to the sequential method, the concentration of ropivacaine in the next patient was adjusted according to the reaction of the previous patient: effective motor block was defined as the modified Bromage score > 0 within 30 min after epidural administration. If the modified Bromage score of the previous patient was >0 within 30 min after drug administration, the concentration of ropivacaine in the next patient was decreased by 1 gradient. Conversely, if the score did not exceed 0, the concentration of ropivacaine in the next patient was increased by 1 gradient. The up-down sequential allocation method and probit regression were used to calculate the EC50 of epidural ropivacaine.MeasurementsAdverse events, hemodynamic changes, demographic data and clinical characteristics.Main resultsThe EC50 of epidural ropivacaine required to achieve motor block was 0.677% (95% CI, 0.622–0.743%) in the NR group, 0.624% (95% CI, 0.550–0.728%) in the RD0.25 group, 0.549% (95% CI, 0.456–0.660%) in the RD0.5 group, 0.463% (95% CI, 0.408–0.527%) in the RD0.75 group, and 0.435% (95% CI, 0.390–0.447%) in the RD1.0 group. The EC50 of the NR group and the RD0.25 group were significantly higher than that of the RD0.75 and the RD1.0 groups, and the EC50 of the RD0.5 group was significantly higher than that of the RD1.0 group.ConclusionThe EC50 of epidural ropivacaine required to achieve motor block was 0.677% in the NR group, 0.624% in the RD0.25 group, 0.549% in the RD0.5 group, 0.463% in the RD0.75 group, and 0.435% in the RD1.0 group. Dexmedetomidine as an adjuvant for ropivacaine dose-dependently reduce the EC50 of epidural ropivacaine for motor block and shorten the onset time of epidural ropivacaine block. The optimal dose of dexmedetomidine combined with ropivacaine for epidural anesthesia was 0.5 μg/kg.

Interactions between phenanthrene exposure and historical chemical stress: Implications for fitness and ecological resilience of the sentinel species Daphnia magna

Polycyclic aromatic hydrocarbons (PAHs) arise from incomplete combustion of oil, coal, and gasoline, with lipophilic properties facilitating their widespread distribution and persistence. Due to their biochemical attributes, PAHs can accumulate in animal tissues, potentially causing mutagenic and carcinogenic effects. Since the industrial revolution, PAH concentrations in the environment have risen, with lakes showing levels from 0.159 to 33,090 μg/kg sediment. Despite acute toxicity studies showing adverse effects on freshwater organisms, the long-term impacts and synergistic interactions with other pollutants remain largely unexplored.This study investigates the impact of phenanthrene (PHE), a prominent PAH found in aquatic environments, on Daphnia magna, a species of significant ecological importance in freshwater ecosystems globally, being both a sentinel species for chemical pollution and a keystone organism in freshwater aquatic ecosystems. Leveraging the dormancy of D. magna, which spans decades or even centuries, we exposed strains with diverse histories of chemical contaminant exposure to environmentally relevant concentrations of PHE. Initially, acute exposure experiments were conducted in accordance with OECD guidelines across 16 Daphnia strains, revealing substantial variation in acute toxic responses, with strains naïve to chemical pollutants showing the lowest toxicity. Utilizing the median effect concentration EC10 derived from acute exposures, we assessed the impacts of chronic PHE exposure on life history traits and ecological endpoints of the 16 strains. To elucidate how historical exposure to other environmental stressors may modulate the toxicity of PHE, temporal populations of D. magna resurrected from a lake with a well-documented century-spanning history of environmental impact were utilized. Our findings demonstrate that PHE exposure induces developmental failure, delays sexual maturation, and reduces adult size in Daphnia. Populations of Daphnia historically exposed to chemical stress exhibited significantly greater fitness impacts compared to naïve populations. This study provides crucial insights into the augmented effects of PAHs interacting with other environmental stressors.

Design, synthesis and biological activity evaluation of eco-friendly rosin-based fungicides for sustainable crop protection.

Utilizing fungicides to protect crops from diseases is an effective method, and novel eco-friendly plant-derived fungicides with high efficiency and low toxicity are urgent requirements for sustainable crop protection. Two series of rosin-based fungicides (totally 35) were designed and synthesized. In vitro fungicidal activity revealed that Compound 6a (Co. 6a) effectively inhibited the growth of Valsa mali [median effective concentration (EC50) = 0.627 μg mL-1], and in vivo fungicidal activity suggested a significant protective efficacy of Co. 6a in protecting both apple branches (35.12% to 75.20%) and apples (75.86% to 90.82%). Quantum chemical calculations (via density functional theory) results indicated that the primary active site of Co. 6a lies in its amide structure. Mycelial morphology and physiology were investigated to elucidate the mode-of-action of Co. 6a, and suggested that Co. 6a produced significant cell membrane damage, accelerated electrolyte leakage, decreased succinate dehydrogenase (SDH) protein activity, and impaired physiological and biochemical functions, culminating in mycelial mortality. Molecular docking analysis revealed a robust binding energy (ΔE = -7.29 kcal mol-1) between Co. 6a and SDH. Subsequently, biosafety evaluations confirmed the environmentally-friendly nature of Co. 6a via the zebrafish model, yet toxicological results indicated that Co. 6a at median lethal concentration [LC50(96)] damaged the gills, liver and intestines of zebrafish. The above research offers a theoretical foundation for exploiting eco-friendly rosin-based fungicidal candidates in sustainable crop protection. © 2024 Society of Chemical Industry.

Biocontrol Mechanisms of Three Plant Essential Oils Against Phytophthora infestans Causing Potato Late Blight.

Late blight, caused by the notorious pathogen Phytophthora infestans, poses a significant threat to potato (Solanum tuberosum) crops worldwide, impacting their quality as well as yield. Here, we aimed to investigate the potential use of cinnamaldehyde, carvacrol, and eugenol as control agents against P. infestans and to elucidate their underlying mechanisms of action. To determine the pathogen-inhibiting concentrations of these three plant essential oils (PEOs), a comprehensive evaluation of their effects using gradient dilution, mycelial growth rate, and spore germination methods was carried out. Cinnamaldehyde, carvacrol, and eugenol were capable of significantly inhibiting P. infestans by hindering its mycelial radial growth, zoospore release, and sporangium germination; the median effective inhibitory concentration of the three PEOs was 23.87, 8.66, and 89.65 μl/liter, respectively. Scanning electron microscopy revealed that PEOs caused the irreversible deformation of P. infestans, resulting in hyphal shrinkage, distortion, and breakage. Moreover, propidium iodide staining and extracellular conductivity measurements demonstrated that all three PEOs significantly impaired the integrity and permeability of the pathogen's cell membrane in a time- and dose-dependent manner. In vivo experiments confirmed the dose-dependent efficacy of PEOs in reducing the lesion diameter of potato late blight. Altogether, these findings provide valuable insight into the antifungal mechanisms of PEOs vis-à-vis late blight-causing P. infestans. By utilizing the inherent capabilities of these natural compounds, we could effectively limit the harmful impacts of late blight on potato crops, thereby enhancing agricultural practices and ensuring the resilience of global potato food production.

Biological Evaluation of Lysionotin: a Novel Inhibitor of 5-Lipoxygenase for Anti-glioma.

To explore the potential mechanism of lysionotin in treating glioma. First, target prediction based on Bernoulli Naïve Bayes profiling and pathway enrichment was used to predict the biological activity of lysionotin. The binding between 5-lipoxygenase (5-LO) and lysionotin was detected by surface plasmon resonance (SPR) and molecular docking, and the inhibitory effects of lysionotin on 5-LO and proliferation of glioma were determined using enzyme inhibition assay in vitro and cell viability analysis, respectively. Furthermore, the pharmaceutical effect of lysionotin was explored by cell survival rate analysis and liquid chromatography with tandem mass spectrometry (LC-MS/MS). The protein expression, intracellular calcium ion concentration and cytoskeleton detection were revealed by Western blot, flow cytometry and fluorescence labeling, respectively. Target prediction and pathway enrichment revealed that lysionotin inhibited 5-LO, a key enzyme involved in the arachidonic acid metabolism pathway, to inhibit the proliferation of glioma. Molecular docking results demonstrated that 5-LO can be binding to lysionotin through hydrogen bonds, forming bonds with His600, Gln557, Asn554, and His372. SPR analysis further confirmed the interaction between 5-LO and lysionotin. Furthermore, enzyme inhibition assay in vitro and cell survival rate analysis revealed that 50% inhibition concentration of lysionotin and the median effective concentration of lysionotin were 90 and 16.58 µmol/L, respectively, and the results of LC-MS/MS showed that lysionotin inhibited the production of 5S-hydroperoxy-eicosatetraenoic acid (P<0.05), and moreover, the LC-MS/MS results indicated that lysionotin can enter glioma cells well (P<0.01) and inhibit their proliferation. Western blot analysis demonstrated that lysionotin can inhibit the expression of 5-LO (P<0.05) and downstream leukotriene B4 receptor (P<0.01). In addition, the results showed that lysionotin affected intracellular calcium ion concentration by inhibiting 5-LO to affect the cytoskeleton, as determined by flow cytometry and fluorescence labeling. Lysionotin binds to 5-LO could suppress glioma by inhibiting arachiodonic acid metabolism pathway.

A novel nitrogenous coumarin: The promising antiviral therapy against white spot syndrome virus in the culture of shrimp seedlings

White spot disease (WSD), attributed to the white spot syndrome virus (WSSV), represents a substantial danger to the international shrimp sector, resulting in considerable losses in both production and economic terms. Nevertheless, there are currently no approved therapeutic measures to control the outbreak. This study involved the synthesis of 15 new compounds for the assessment of their anti-WSSV efficacy in Litopenaeus vannamei post-larvae. Among these compounds, N-(4-methyl-2-oxo-2H-chromen-7-yl)acetamide (P13) exhibited a maximum antiviral response of > 90 %, with a median effective concentration (EC50) < 12 mg/L, making P13 the most promising antiviral compound. In the cases where the larvae were simultaneously incubated with WSSV and P13, as well as where the larvae were first infected with WSSV and then treated with P13, the replication of WSSV was significantly inhibited. However, pre-treatment with P13 had minimal impact on WSSV multiplication, suggesting a potential therapeutic effect. Simultaneously, the cumulative mortality rate of WSSV-infected post-larvae decreased in the presence of P13. After the shrimp larvae were infected with WSSV, continuously changing the aquacultural water containing DMSO resulted in a mortality rate of 80 % at 120 hours post-infection (hpi); whereas continuously changing the aquaculture water containing P13 resulted in a mortality rate of 45 %. Given that P13 remains stable in farmed water for up to two days, it is recommended to regularly replace the medication to eliminate the virus threat. In conclusion, P13 demonstrates a positive anti-WSSV activity and holds potential for further development as an antiviral therapy against WSSV infection.

Effect of Insecticide Exposure Across Multiple Generations of the Earthworm Eisenia andrei.

The toxicity of neonicotinoids and many of their replacement insecticides to nontarget soil invertebrates such as earthworms has previously been established. However, the long-term effects of these substances on these organisms are largely unknown. In the field of soil ecotoxicology, lumbricid earthworms such as Eisenia andrei are used extensively due to the availability of standardized test methods and their adaptability to laboratory culture and testing. Multigenerational studies have gained popularity and attention in recent years, with a shift toward the use of long-term assays and lower concentrations of test chemicals. The use of exposure concentrations that include those measured in a monitoring program carried out by the Government of Ontario presents a realistic exposure scenario that may not show significant effects in contemporary, shorter term studies. We used current standardized test methods as a basis for the development of multigenerational studies on E. andrei. The effects of exposure to a single application of the insecticides thiamethoxam and cyantraniliprole on the survival and reproduction of E. andrei were observed over three (thiamethoxam) or two (cyantraniliprole) generations using consecutive reproduction tests. No significant impacts on adult survival were reported in any generation for either insecticide, whereas reproduction decreased between the first and second generations in the thiamethoxam test, with median effective concentration (EC50) values of 0.022 mg/kg dry weight reported for the first generation compared with 0.002 mg/kg dry weight in the second generation. For cyantraniliprole, an EC50 of 0.064 was determined for the first generation compared with 0.016 mg/kg dry weight in the second generation. A third generation was completed for the thiamethoxam test, and a significant decrease in reproduction was observed in all treatments and controls compared with previous generations. No significant difference between thiamethoxam treatments and the control treatment was reported for the third generation. Collectively, these data indicate that exposure of oligochaetes to these two insecticides at concentrations representative of field conditions may result in long-term stresses. Environ Toxicol Chem 2024;00:1-13. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Effect of Combining Wuyiencin and Pyrimethanil on Controlling Grape Gray Mold and Delaying Resistance Development in Botrytis cinerea.

By screening the compounding combination of Wuyiencin and chemical agents, this study aims to delay the emergence of chemical agent resistance, and provide a technical reference for scientific and rational fungicides technology. This study investigated the impacts of the antibiotic wuyiencin derived from Streptomyces albulus var. wuyiensis and its combination with pyrimethanil on the inhibition of Botrytis cinerea. Treatment with wuyiencin (≥80 µg mL-1) strongly inhibited the pathogenicity of B. cinerea and activated the plant defense response against B. cinerea. Application of 80-100 µg mL-1 wuyiencin effectively controlled grape gray mold (by 57.6-88.1% on leaves and 46.7-96.6% on fruits). Consequently, the application of 80-100 µg mL-1 wuyiencin effectively mitigated grape gray mold incidence, leading to a substantial reduction in disease symptoms to nearly imperceptible levels. When wuyiencin (at the median effective concentration [EC50]) was combined with pyrimethanil (EC50) at a ratio of 7:3, it exhibited the highest efficacy in inhibiting B. cinerea growth. This combination was significantly more potent (p < 0.05) than using wuyiencin or pyrimethanil alone in controlling gray mold on grape leaves and fruits. Furthermore, the combination effectively delayed resistance development in gray mold. The experimental results show that wuyiencin can delay resistance development by affecting the expression of methionine biosynthesis genes and reducing the activity of the cell wall-degrading enzyme activity.

Physiological and transcriptome level responses of Microcystis aeruginosa and M. viridis to environmental concentrations of triclosan

The toxicity of triclosan (TCS) to various aquatic organisms has been demonstrated at environmental concentrations. However, the effects and mechanisms of TCS on toxic cyanobacteria remains largely unexplored. This study investigated the physiological and molecular variations in two representative toxic Microcystis species (M. aeruginosa and M. viridis) under exposure to TCS for 12 d. Our findings demonstrated that the median effective concentration (EC50) of TCS for both Microcystis species were close to the levels detected in the environment (M. aeruginosa: 9.62 μg L−1; M. viridis: 27.56 μg L−1). An increased level of reactive oxygen species (ROS) was observed in Microcystis, resulting in oxidative damage when exposed to TCS at concentrations ranging from 10 μg L−1 to 50 μg L−1. The photosynthetic activity of Microcystis had a certain degree of recovery capability at low concentrations of TCS. Compared to M. aeruginosa, the higher recovery capability of the photosynthetic system in M. viridis would be mainly attributed to the increased ability for PSII repair and phycobilisome synthesis. Additionally, the synthesis of microcystins in the two species and the release rate in M. viridis significantly increased under 10–50 μg L−1 TCS. At the molecular level, exposure to TCS at EC50 for 12 d induced the dysregulation of genes associated with photosynthesis and antioxidant system. The upregulation of genes associated with microcystin synthesis and nitrogen metabolism further increased the potential risk of microcystin release. Our results revealed the aquatic toxicity and secondary ecological risks of TCS at environmental concentrations, and provided theoretical data with practical reference value for TCS monitoring.

Physiological and transcriptome level responses of Microcystis aeruginosa and M. viridis to environmental concentrations of Triclosan

The toxicity of triclosan (TCS) to various aquatic organisms has been demonstrated at environmental concentrations. However, the effects and mechanisms of TCS on toxic cyanobacteria remains largely unexplored. This study investigated the physiological and molecular variations in two representative toxic Microcystis species (M. aeruginosa and M. viridis) under exposure to TCS for 12 d. Our findings demonstrated that the median effective concentration (EC50) of TCS for both Microcystis species were close to the levels detected in the environment (M. aeruginosa: 9.62 μg L-1; M. viridis: 27.56 μg L-1). An increased level of reactive oxygen species (ROS) was observed in Microcystis, resulting in oxidative damage when exposed to TCS at concentrations ranging from 10 μg L-1 to 50 μg L-1. The photosynthetic activity of Microcystis had a certain degree of recovery capability at low concentrations of TCS. Compared to M. aeruginosa, the higher recovery capability of the photosynthetic system in M. viridis would be mainly attributed to the increased ability for PSII repair and phycobilisome synthesis. Additionally, the synthesis of microcystins in the two species and the release rate in M. viridis significantly increased under 10-50 μg L-1 TCS. At the molecular level, exposure to TCS at EC50 for 12 d induced the dysregulation of genes associated with photosynthesis and antioxidant system. The upregulation of genes associated with microcystin synthesis and nitrogen metabolism further increased the potential risk of microcystin release. Our results revealed the aquatic toxicity and secondary ecological risks of TCS at environmental concentrations, and provided theoretical data with practical reference value for TCS monitoring.

Toxicity of rare earth elements (REEs) to marine organisms: Using species sensitivity distributions to establish water quality guidelines for protecting marine life

A lack of chronic rare earth element (REE) toxicity data for marine organisms has impeded the establishment of numerical REE water quality benchmarks (e.g., guidelines) to protect marine life and assess ecological risk. This study determined the chronic no (significant) effect concentrations (N(S)ECs) and median-effect concentrations (EC50s) of eight key REEs (yttrium (Y), lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), gadolinium (Gd), dysprosium (Dy) and lutetium (Lu)) for 30 coastal marine organisms (encompassing 22 phyla and five trophic levels from temperate and tropical habitats). Organisms with calcifying life stages were most vulnerable to REEs, which competitively inhibit calcium uptake. The most sensitive organism was a sea urchin, with N(S)ECs ranging from 0.64 μg/L for Y to 1.9 μg/L for La and Pr, and EC50s ranging from 4.3 μg/L for Y to 14.4 μg/L for Pr. Conversely, the least sensitive organism was a cyanobacterium, with N(S)ECs ranging from 21 μg/L for Y to 73 μg/L for Pr, and EC50s ranging from 153 μg/L for Y to 535 μg/L for La. Median sensitivity varied 215-fold across all organisms. The two-fold difference in median toxicity (μmol/L EC50) among REEs (Y∼Gd > Lu∼Nd∼Dy∼Ce > La∼Pr) was attributed to offset differences in binding affinity (log K) to cell surface receptors and the percentage of free metal ion (REE3+) in the test waters. The toxicity (EC50) of the remaining REEs (samarium, europium, terbium, holmium, thulium and ytterbium) was predicted using a combination of physicochemical data and measured EC50s for the eight tested REEs, with good agreement between predicted and measured EC50s for selected organisms. Numerical REE water quality guidelines to protect marine life were established using species sensitivity distributions (e.g., for 95 % species protection, values ranged from 1.1 μg/L for Y to 3.0 μg/L for La, Pr or Lu).

Understanding the Role of Low-Dose Polystyrene Microplastic in Copper Toxicity to Rice Seed (Oryza sativa L.).

There is still much to learn with respect to the potential for microplastics (MPs) to interact with environmental toxins and biota. In the present study, we investigated the effect of MPs on the toxicity of copper (Cu) to rice seeds (Oryza sativa L.). The 7-day median effective concentration (EC50) value of MPs on rice seed germination was 864 mg/L (95% confidence interval [CI] 839 to 897 mg/L). We found that MPs slightly reduced Cu toxicity to rice seeds. The 7-day EC50 of Cu on rice seed germination increased from 7.29 mg/L (95% CI 7.10-7.52 mg/L) to 7.93 mg/L (95% CI 7.58-8.08 mg/L) in the presence of 20 mg/L MPs. We examined this toxicity reduction phenomenon by investigating the role of MPs in the process of Cu transport, Cu accumulation, and metabolic responses. Further investigation found that the MPs used in the present study hardly adsorbed Cu, but these MPs accumulated on the coats of rice seeds and significantly reduced Cu accumulation in rice seedlings. When Cu concentration was 10 mg/L, the presence of MPs reduced the accumulation of Cu in rice seedlings by 34%. We also found that, compared with only Cu present, the addition of MPs resulted in lower reactive oxygen species accumulation and higher catalase activity and glutathione levels in rice seedlings, which also contributed to Cu toxicity reduction. Collectively, the present study shows that polystyrene MPs have the potential to form associations with plant structures which can ultimately impact heavy metal bioaccessibility and therefore toxicity. Environ Toxicol Chem 2024;00:1-10. © 2024 SETAC.

Synthesis, fungicidal activity and molecular docking of novel pyrazole-carboxamides bearing a branched alkyl ether moiety

Succinate dehydrogenase inhibitors are essential fungicides used in agriculture. To explore new pyrazole-carboxamides with high fungicidal activity, a series of N-substitutedphenyl-3-di/trifluoromethyl-1-methyl-1H-pyrazole-4-carboxamides bearing a branched alkyl ether moiety were designed and synthesized. The in vitro bioassay indicated that some target compounds displayed appreciable fungicidal activity. For example, compounds 5d and 5e showed high efficacy against S. sclerotiorum with EC50 values of 3.26 and 1.52 μg/mL respectively, and also exhibited excellent efficacy against R. solani with EC50 values of 0.27 and 0.06 μg/mL respectively, which were comparable or superior to penflufen. The further in vivo bioassay on cucumber leaves demonstrated that 5e provided strong protective activity of 94.3 % against S. sclerotiorum at 100 μg/mL, comparable to penflufen (99.1 %). Cytotoxicity assessment against human renal cell lines (239A cell) revealed that 5e had low cytotoxicity within the median effective concentrations. Docking study of 5e with succinate dehydrogenase illustrated that R-5e formed one hydrogen bond and two π-π stacking interactions with amino acid residues of target enzyme, while S-5e formed only one π-π stacking interaction with amino acid residue. This study provides a valuable reference for the design of new succinate dehydrogenase inhibitor.

Assessment of the effects of 2,4-D-dichlorophenoxyacetic acid-based herbicide exposure in eggs and embryos of golden apple snails using OCT

This study aimed to evaluate the effects of herbicide 2, 4-D-dichlorophenoxy acetic acid on golden apple snail eggs and embryos. Additionally, the study assessed the applicability of optical coherence tomography (OCT), a non-invasive depth cross-sectional microscopic imaging technique, as a novel method, to the best of our knowledge, for studying morphological changes in golden apple snail eggs and embryos, in comparison to the conventional approach of using white light microscopy. The study revealed that the herbicide 2,4-D-dichlorophenoxy acetic acid affected the hatchery rate and morphological changes of the eggs and embryos. The lethal concentration (LC50), representing the concentration of a substance that is expected to cause death in half of the population being studied, of the golden apple eggs and embryos increased with longer exposure time and higher concentrations. The estimated median effective concentration (EC50), which denotes the concentration producing the desired effect in 50% of the exposed golden apple embryos, exhibited a similar trend of change as the LC50. When compared to the microscopic study, it was observed that OCT could be employed to investigate morphological changes of golden apple snail eggs and embryos, enabling evaluation of alterations in both 2D and 3D structures.

Design, synthesis, antifungal evaluation and mechanism study of novel norbornene derivatives as potential laccase inhibitors.

To discover novel fungicide candidates, five series of novel norbornene hydrazide, bishydrazide, oxadiazole, carboxamide and acylthiourea derivatives (2a-2t, 3a-3f, 4a-4f, 5a-5f and 7a-7f) were designed, synthesized and assayed for their antifungal activity toward seven representative plant fungal pathogens. In the in vitro antifungal assay, some title norbornene derivatives presented good antifungal activity against Botryosphaeria dothidea, Sclerotinia sclerotiorum and Fusarium graminearum. Especially, compound 2b exhibited the best inhibitory activity toward B. dothidea with the median effective concentration (EC50) of 0.17 mg L-1, substantially stronger than those of the reference fungicides boscalid and carbendazim. The in vivo antifungal assay on apples revealed that 2b had significant curative and protective effects, both of which were superior to boscalid. In the preliminary antifungal mechanism study, 2b was able to injure the surface morphology of hyphae, destroy the cell membrane integrity and increase the intracellular reactive oxygen species (ROS) level of B. dothidea. In addition, 2b could considerably inhibit the laccase activity with the median inhibitory concentration (IC50) of 1.02 μM, much stronger than that of positive control cysteine (IC50 = 35.50 μM). The binding affinity and interaction mode of 2b with laccase were also confirmed by molecular docking. This study presented a promising lead compound for the study of novel laccase inhibitors as fungicidal agrochemicals, which demonstrate significant anti-B. dothidea activity and laccase inhibitory activity. © 2024 Society of Chemical Industry.

Why Certain Repurposed Drugs Are Unlikely to Be Effective Antivirals to Treat SARS-CoV-2 Infections.

Most repurposed drugs have proved ineffective for treating COVID-19. We evaluated median effective and toxic concentrations (EC50, CC50) of 49 drugs, mostly from previous clinical trials, in Vero cells. Ratios of reported unbound peak plasma concentrations, (Cmax)/EC50, were used to predict the potential in vivo efficacy. The 20 drugs with the highest ratios were retested in human Calu-3 and Caco-2 cells, and their CC50 was determined in an expanded panel of cell lines. Many of the 20 drugs with the highest ratios were inactive in human Calu-3 and Caco-2 cells. Antivirals effective in controlled clinical trials had unbound Cmax/EC50 ≥ 6.8 in Calu-3 or Caco-2 cells. EC50 of nucleoside analogs were cell dependent. This approach and earlier availability of more relevant cultures could have reduced the number of unwarranted clinical trials.

Prediction of acute toxicity for Chlorella vulgaris caused by tire wear particle-derived compounds using quantitative structure-activity relationship models

Tire wear particles (TWPs) enter aquatic ecosystems through various pathways, such as rainwater and urban runoff. Additives in TWPs can harm aquatic organisms in these ecosystems. Therefore, it is essential to investigate their toxicity to aquatic organisms. In our study, we initially recorded the median effective concentrations of 21 TWP-derived compounds on Chlorella vulgaris growth, ranging from 0.04 to 8.60 mg/L. Subsequently, through an extensive review of the literature, we incorporated 112 compounds with specific toxicity endpoints to construct the QSAR model using genetic algorithm and multiple linear regression techniques, followed by the construction of the consensus model and the quantitative read-across structure-activity relationship (q-RASAR) model. Meanwhile, we employed rigorous internal and external validation measures to assess the performance of the model. The results indicated that the developed q-RASAR model exhibited strong adaptation, robustness, and reliable prediction, with q-RASAR indicators of Q2LOO = 0.7673, R2tr = 0.8079, R2test = 0.8610, Q2Fn = 0.8285−0.8614, and CCCtest = 0.9222. Based on an external dataset containing 128 emerging TWP-derived compounds, the model's applicability domain coverage was 90.6 %. The q-RASAR model predicted that the structure of diphenylamine was associated with higher toxicity, possibly liked to the SpMax2_Bhm and LogBCF descriptors. The established model reliably provides prediction and fills a critical data gap. These findings highlight the potential risks posed by emerging TWP-derived compounds to aquatic organisms.

Toxicity of individual and mixture of organic compounds to P. Phosphoreum and S. Capricornutum using interpretable simple structural parameters

Human and environmental ecosystem beings are exposed to multicomponent compound mixtures but the toxicity nature of compound mixtures is not alike to the individual chemicals. This work introduces four models for the prediction of the negative logarithm of median effective concentration (pEC50) of individual chemicals to marine bacteria Photobacterium Phosphoreum (P. Phosphoreum) and algal test species Selenastrum Capricornutum (S. Capricornutum) as well as their mixtures to P. Phosphoreum, and S. Capricornutum. These models provide the simplest approaches for the forecast of pEC50 of some classes of organic compounds from their interpretable structural parameters. Due to the lack of adequate toxicity data for chemical mixtures, the largest available experimental data of individual chemicals (55 data) and their mixtures (99 data) are used to derive the new correlations. The models of individual chemicals are based on two simple structural parameters but chemical mixture models require further interaction terms. The new model's results are compared with the outputs of the best accessible quantitative structure–activity relationships (QSARs) models. Various statistical parameters are done on the new and comparative complex QSAR models, which confirm the higher reliability and simplicity of the new correlations.

Chronic toxic effects of erythromycin and its photodegradation products on microalgae Chlorella pyrenoidosa

The photodegradation products (PDPs) of antibiotics in the aquatic environment received increasing concern, but their chronic effects on microalgae remain unclear. This study initially focused on examining the acute effects of erythromycin (ERY), then explored the chronic impacts of ERY PDPs on Chlorella pyrenoidosa. ERY of 4.0 − 32 mg/L ERY notably inhibited the cell growth and chlorophyll synthesis. The determined 96 h median effective concentration of ERY to C. pyrenoidosa was 11.78 mg/L. Higher concentrations of ERY induced more serious oxidative damage, antioxidant enzymes alleviated the oxidative stress. 6 PDPs (PDP749, PDP747, PDP719, PDP715, PDP701 and PDP557) were identified in the photodegradation process of ERY. The predicted combined toxicity of PDPs increased in the first 3 h, then decreased. Chronic exposure showed a gradual decreasing inhibition on microalgae growth and chlorophyll content. The acute effect of ERY PDPs manifested as growth stimulation, but the chronic effect manifested as growth inhibition. The malonaldehyde contents decreased with the degradation time of ERY at 7, 14 and 21 d. However, the malonaldehyde contents of ERY PDPs treatments were elevated compared to those in the control group after 21 d. Risk assessment still need to consider the potential toxicity of degradation products under long-term exposure.

Generation and characterization of a nanobody against the avian influenza virus H7 subtype

Avian influenza virus (AIV) H7N9 diseases have been recently reported, raising concerns about a potential pandemic. Thus, there is an urgent need for effective therapeutics for AIV H7N9 infections. Herein, camelid immunization and yeast two-hybrid techniques were used to identify potent neutralizing nanobodies (Nbs) targeting the H7 subtype hemagglutinin. First, we evaluated the binding specificity and hemagglutination inhibition activity of the screened Nbs against the H7 subtype hemagglutinin. Nb-Z77, with high hemagglutination inhibition activity was selected from the screened Nbs to optimize the yeast expression conditions and construct oligomeric forms of Nb-Z77 using various ligation methods. The oligomers Nb-Z77-DiGS, Nb-Z77-TriGS, Nb-Z77-Fc and Nb-Z77-Foldon were successfully constructed and expressed. Nb-Z77-DiGS and Nb-Z77-Foldon exhibited considerably greater activity than did Nb-Z77 against H7 subtype hemagglutinin, with median effective concentrations of 384.7 and 27.33 pM and binding affinity values of 213 and 5.21 pM, respectively. Nb-Z77-DiGS and Nb-Z77-Foldon completely inhibited the hemagglutination activity of the inactivated virus H7-Re1 at the lowest concentration of 0.938 μg/mL. This study screened a strain of Nb with high hemagglutination inhibition activity and enhanced its antiviral activity through oligomerization, which may have great potential for developing effective agents for the prevention, diagnosis, and treatment of AIV H7 subtype infection.