Occurrence and Risk Assessment of Pesticides, Phthalates, and Heavy Metal Residues in Vegetables from Hydroponic and Conventional Cultivation.

Hydroponic cultivation of fresh produce is gaining popularity worldwide, but few studies have provided a comparative assessment of hydroponic and conventional soil-based vegetables. In this study, we analyzed a series of hazardous chemicals, including 120 pesticides, 18 phthalates (PAEs), and 2 heavy metals (lead and cadmium) in four vegetable commodities (lettuces, celeries, tomatoes, and cucumbers) from hydroponic and conventional soil-based cultivation. Our study showed that at least one pesticide was present in 84% of the conventionally grown samples, whereas only 30% of the hydroponic samples contained detectable pesticide residues. Regarding the total PAE concentrations, there was no significant difference between conventional and hydroponic vegetables. The lead and cadmium residues in conventionally cultivated vegetables were significantly higher than in those produced from hydroponic cultivation. Lead is the primary heavy metal pollutant across all vegetable samples. The hazard index (HI) values of the hydroponic and conventional vegetables were 0.22 and 0.64, respectively. Since both values are below one, the exposure to these hazardous chemicals through consumption of the studied vegetables may not pose a significant health risk. The HI values also suggested that the health risks of eating hydroponic vegetables are lower than for conventional soil-based vegetables.

Comparison of Biomarkers of Exposure in a Controlled Study of Smokers Switched from Conventional Cigarettes to Heated Tobacco Products.

The heated tobacco product (HTP) heats rather than burns tobacco to release an aerosol with significantly fewer toxicants than conventional cigarette smoke and has received global attention in recent years. To investigate whether changes in biomarkers of exposure could be detected after switching from conventional cigarettes (CCs) to HTPs, 224 subjects from four cities in China participated in this study. Nine biomarkers containing tobacco-specific nitrosamines (TSNAs), volatile organic compounds (VOCs), and the biomarkers for acrolein and crotonaldehyde were determined by UPLC-MS/MS. The levels of the sum of nine biomarkers in CCs were 5.4 and 5.2 times higher than in an Original-HTP and Menthol-HTP, respectively. Among the nine biomarkers, 3HPMA and 3HMPMA accounted for the highest proportions. Switching from CCs to HTPs is good for both men and women because the changes in each biomarker in urine samples were the same in men and women. Among all the subjects, subjects aged 20-39 years had the greatest reduction in biomarker residues in urine. The findings of the present study provided useful information for the health risk research of HTPs in China.

Advanced QuEChERS Method Using Core-Shell Magnetic Molecularly Imprinted Polymers (Fe3O4@MIP) for the Determination of Pesticides in Chlorophyll-Rich Samples.

Graphitized carbon black (GCB) in the traditional QuEChERS (quick, easy, cheap, effective, rugged, and safe) method was used to remove the interfering substance chlorophyll in vegetable and fruit samples for pesticide residues determination. However, it not only adsorbs pigments, but also adsorbs some planar and aromatic pesticides. In order to solve the shortcoming, a core-shell magnetic molecularly imprinted polymer (Fe3O4@MIP) that can specifically recognize and adsorb chlorophyll was synthesized, and an advanced QuEChERS method with the Fe3O4@MIP as a purification material was developed. This advanced method presents detection that is highly sensitive, specific, and reproducible for planar and aromatic pesticides. The limits of detection (LOD) ranged from 0.001-0.002 mg kg-1, and the limit of quantification (LOQ) was 0.005 mg kg-1. The recovery for the planar and aromatic pesticides was within 70-110% with the associated relative standard deviations < 15% in leek samples by the advanced QuEChERS method. However, in the traditional QuEChERS method with GCB, the recovery of most planar and aromatic pesticides was <60%. It may also be useful for the determination of other pesticides in vegetable samples with quick and easy sample purification.

Chromosomal-level reference genome of the moth Heortia vitessoides (Lepidoptera: Crambidae), a major pest of agarwood-producing trees.

The moth Heortia vitessoides Moore (Lepidoptera: Crambidae) is a major pest of ecologically, commercially and culturally important agarwood-producing trees in the genus Aquilaria. In particular, H. vitessoides is one of the most destructive defoliating pests of the incense tree Aquilaria sinesis, which produces a valuable fragrant wood used as incense and in traditional Chinese medicine [33]. Nevertheless, a genomic resource for H. vitessoides is lacking. Here, we present a chromosomal-level assembly for H. vitessoides, consisting of a 517 megabase (Mb) genome assembly with high physical contiguity (scaffold N50 of 18.2 Mb) and high completeness (97.9% complete BUSCO score). To aid gene annotation, 8 messenger RNA transcriptomes from different developmental stages were generated, and a total of 16,421 gene models were predicted. Expansion of gene families involved in xenobiotic metabolism and development were detected, including duplications of cytosolic sulfotransferase (SULT) genes shared among lepidopterans. In addition, small RNA sequencing of 5 developmental stages of H. vitessoides facilitated the identification of 85 lepidopteran conserved microRNAs, 94 lineage-specific microRNAs, as well as several microRNA clusters. A large proportion of the H. vitessoides genome consists of repeats, with a 29.12% total genomic contribution from transposable elements, of which long interspersed nuclear elements (LINEs) are the dominant component (17.41%). A sharp decrease in the genome-wide percentage of LINEs with lower levels of genetic distance to family consensus sequences suggests that LINE activity has peaked in H. vitessoides. In contrast, opposing patterns suggest a substantial recent increase in DNA and LTR element activity. Together with annotations of essential sesquiterpenoid hormonal pathways, neuropeptides, microRNAs and transposable elements, the high-quality genomic and transcriptomic resources we provide for the economically important moth H. vitessoides provide a platform for the development of genomic approaches to pest management, and contribute to addressing fundamental research questions in Lepidoptera.

Rethinking Sesquiterpenoids: A Widespread Hormone in Animals.

The sesquiterpenoid hormone juvenile hormone (JH) controls development, reproduction, and metamorphosis in insects, and has long been thought to be confined to the Insecta. While it remains true that juvenile hormone is specifically synthesized in insects, other types or forms of sesquiterpenoids have also been discovered in distantly related animals, such as the jellyfish. Here, we combine the latest literature and annotate the sesquiterpenoid biosynthetic pathway genes in different animal genomes. We hypothesize that the sesquiterpenoid hormonal system is an ancestral system established in an animal ancestor and remains widespread in many animals. Different animal lineages have adapted different enzymatic routes from a common pathway, with cnidarians producing farnesoic acid (FA); non-insect protostomes and non-vertebrate deuterostomes such as cephalochordate and echinoderm synthesizing FA and methyl farnesoate (MF); and insects producing FA, MF, and JH. Our hypothesis revolutionizes the current view on the sesquiterpenoids in the metazoans, and forms a foundation for a re-investigation of the roles of this important and yet neglected type of hormone in different animals.

Myriapod genomes reveal ancestral horizontal gene transfer and hormonal gene loss in millipedes.

Animals display a fascinating diversity of body plans. Correspondingly, genomic analyses have revealed dynamic evolution of gene gains and losses among animal lineages. Here we sequence six new myriapod genomes (three millipedes, three centipedes) at key phylogenetic positions within this major but understudied arthropod lineage. We combine these with existing genomic resources to conduct a comparative analysis across all available myriapod genomes. We find that millipedes generally have considerably smaller genomes than centipedes, with the repeatome being a major contributor to genome size, driven by independent large gains of transposons in three centipede species. In contrast to millipedes, centipedes gained a large number of gene families after the subphyla diverged, with gains contributing to sensory and locomotory adaptations that facilitated their ecological shift to predation. We identify distinct horizontal gene transfer (HGT) events from bacteria to millipedes and centipedes, with no identifiable HGTs shared among all myriapods. Loss of juvenile hormone O-methyltransferase, a key enzyme in catalysing sesquiterpenoid hormone production in arthropods, was also revealed in all millipede lineages. Our findings suggest that the rapid evolution of distinct genomic pathways in centipede and millipede lineages following their divergence from the myriapod ancestor, was shaped by differing ecological pressures.

Genome of the ramshorn snail Biomphalaria straminea-an obligate intermediate host of schistosomiasis.

BACKGROUND: Schistosomiasis, or bilharzia, is a parasitic disease caused by trematode flatworms of the genus Schistosoma. Infection by Schistosoma mansoni in humans results when cercariae emerge into water from freshwater snails in the genus Biomphalaria and seek out and penetrate human skin. The snail Biomphalaria straminea is native to South America and is now also present in Central America and China, and represents a potential vector host for spreading schistosomiasis. To date, genomic information for the genus is restricted to the neotropical species Biomphalaria glabrata. This limits understanding of the biology and management of other schistosomiasis vectors, such as B. straminea. FINDINGS: Using a combination of Illumina short-read, 10X Genomics linked-read, and Hi-C sequencing data, our 1.005 Gb B. straminea genome assembly is of high contiguity, with a scaffold N50 of 25.3 Mb. Transcriptomes from adults were also obtained. Developmental homeobox genes, hormonal genes, and stress-response genes were identified, and repeat content was annotated (40.68% of genomic content). Comparisons with other mollusc genomes (including Gastropoda, Bivalvia, and Cephalopoda) revealed syntenic conservation, patterns of homeobox gene linkage indicative of evolutionary changes to gene clusters, expansion of heat shock protein genes, and the presence of sesquiterpenoid and cholesterol metabolic pathway genes in Gastropoda. In addition, hormone treatment together with RT-qPCR assay reveal a sesquiterpenoid hormone responsive system in B. straminea, illustrating that this renowned insect hormonal system is also present in the lophotrochozoan lineage. CONCLUSION: This study provides the first genome assembly for the snail B. straminea and offers an unprecedented opportunity to address a variety of phenomena related to snail vectors of schistosomiasis, as well as evolutionary and genomics questions related to molluscs more widely.

Concentrations and Related Health Risk Assessment of Pesticides, Phthalates, and Heavy Metals in Strawberries from Shanghai, China.

ABSTRACT: In the present study, a risk assessment of pesticides, phthalates, and heavy metals in strawberries (n = 335) in recent years was conducted by determining the estimated daily intake, target hazard quotient, and hazard index. The study used 128 pesticides, 18 phthalates, and three heavy metals in this determination. It detected 51 pesticide residues in the strawberry samples, and 97.91% samples had levels of at least 1 of the 51 pesticides above the limit of detection. In addition, 2.39% of samples had pesticides higher than the Chinese maximum residue limit. Multiple pesticide residues were detected in most samples. Bis-2-ethylhexyl phthalate, diisobutyl phthalate, and dibutyl phthalate were detected in the strawberry samples, with a high frequency of detection. Their detectable rates were 100, 100, and 89.9%, respectively. In most samples, lead, cadmium, and nickel were detected, with detectable rates 75.76, 92.93, and 92.93%, respectively. The estimated daily intake of analyzed pesticide, phthalate, and heavy metal residues appears to be relatively low compared with the acceptable daily intake. The average target hazard quotients and hazard indices were less than 1. That means that customers who are exposed to the average contaminant levels may not pose a significant health risk. Our results show that the strawberries may be polluted by many kinds of contaminants. Therefore, monitoring of pesticide, phthalate, and heavy metal residues in strawberries should be increasingly developed to fully protect the health of the consumer.

Effects of fragrance compounds on growth of the silkworm Bombyx mori.

Due to the contamination and biological toxicity of some fragrance compounds, the environmental and ecological problems of such compounds have attracted more and more attention. However, studies of the toxicity of fragrance compounds for insects have been limited. The toxicity of 48 fragrance compounds for the silkworm Bombyx mori were investigated in this study. All of the fragrance compounds examined had no acute toxicity for B. mori larvae, but eight of them (menthol, maltol, musk xylene, musk tibeten, dibutyl sulfide, nerolidol, ethyl vanillin, and α-amylcinnamaldehyde) exhibited chronic and lethal toxicity with LC50 values from 20 to 120 µM. In a long-term feeding study, musk tibeten, nerolidol, and musk xylene showed significant growth regulatory activity. They were also extremely harmful to the cocooning of B. mori, resulting in small, thin, and loose cocoons. Two important insect hormones, namely, juvenile hormone (JH) and 20-hydroxyecdysone (20-E), were quantified in hemolymph following chronic exposure to musk tibeten, nerolidol, and musk xylene, respectively. Musk tibeten significantly increased JH titer and decreased the 20-E titer in hemolymph, and musk xylene had a significant inhibitory effect on JH titer and increased 20-E titer. Although nerolidol had no effect on hormone levels, exogenous JH mimic nerolidol increased the physiological effects of JH and significantly slowed the growth rate of B. mori larvae. The results showed that these fragrance compounds could interfere with the insect endocrine system, leading to death and abnormal growth. The risk to insects of residual fragrance compounds in the environment is worthy of attention.

Enzymes in the juvenile hormone biosynthetic pathway can be potential targets for pest control.

BACKGROUND: Discovery of novel insecticides and targets has received global attention in recent years. Ten genes coding for enzymes involved in the juvenile hormone biosynthetic pathway of Manduca sexta were studied as potential insecticide targets. RESULTS: We determined the expression of genes encoding some critical enzymes in the JH biosynthetic pathway. Farnesol dehydrogenase (FOLD), Juvenile hormone acid O-methyltransferase (JHAMT) and Juvenile hormone epoxidase (CYP15C1) were selected as the candidate targets based on gene expression results. RNAi silencing and enzyme inhibitor tests were performed to validate whether these candidate genes could be the potential insecticide targets. The down-regulation of FOLD, JHAMT and CYP15C1 resulted in a 68%, 82% and 79% reduction in the rates of JH biosynthesis in vitro, respectively. In addition, RNA interference and inhibitor studies of these enzymes following oral administration demonstrated the potential application in pest management, with respect to high mortality and effects on growth. CONCLUSION: Based on our study, FOLD, JHAMT and CYP15C1 could be potential targets for pest control as a consequence of their important roles in insect development. © 2019 Society of Chemical Industry.

3D-QSAR based optimization of insect neuropeptide allatostatin analogs.

Allatostatins (AST) are neuropeptides originally described as inhibitors of juvenile hormone (JH) synthesis in insects. Consequently, they have been considered as potential lead compounds for the discovery of new insect growth regulators (IGRs). In the present work, receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) was studied with 48 AST analogs, and a general approach for novel potent bioactive AST analogs is proposed. Hence, six novel AST analogs were designed and synthesized. Bioassays indicated that the majority novel analogs exhibited potent JH inhibitory activity, especially analog A6 (IC50: 3.79 nmol/L), which can be used as lead compound to develop new IGRs.

Discovery of a Manduca sexta Allatotropin Antagonist from a Manduca sexta Allatotropin Receptor Homology Model.

Insect G protein coupled receptors (GPCRs) have important roles in modulating biology, physiology and behavior. They have been identified as candidate targets for next-generation insecticides, yet these targets have been relatively poorly exploited for insect control. In this study, we present a pipeline of novel Manduca sexta allatotropin (Manse-AT) antagonist discovery with homology modeling, docking, molecular dynamics simulation and structure-activity relationship. A series of truncated and alanine-replacement analogs of Manse-AT were assayed for the stimulation of juvenile hormone biosynthesis. The minimum sequence required to retain potent biological activity is the C-terminal amidated octapeptide Manse-AT (6-13). We identified three residues essential for bioactivity (Thr4, Arg6 and Phe8) by assaying alanine-replacement analogs of Manse-AT (6-13). Alanine replacement of other residues resulted in reduced potency but bioactivity was retained. The 3D structure of the receptor (Manse-ATR) was built and the binding pocket was identified. The binding affinities of all the analogs were estimated by calculating the free energy of binding. The calculated binding affinities corresponded to the biological activities of the analogs, which supporting our localization of the binding pocket. Then, based on the docking and molecular dynamics studies of Manse-AT (10-13), we described it can act as a potent Manse-AT antagonist. The antagonistic effect on JH biosynthesis of Manse-AT (10-13) validated our hypothesis. The IC50 value of antagonist Manse-AT (10-13) is 0.9 nM. The structure-activity relationship of antagonist Manse-AT (10-13) was also studied for the further purpose of investigating theoretically the structure factors influencing activity. These data will be useful for the design of new Manse-AT agonist and antagonist as potential pest control agents.

Structure-Based Discovery of Nonpeptide Allatostatin Analogues for Pest Control.

FGLamide allatostatins (ASTs) are regarded as possible insecticide candidates, although their lack of in vivo effects, rapid degradation, poor water solubility, and high production costs preclude their practical use in pest control. In contrast to previous research, the C-terminal tripeptide (FGLa) was selected as the lead compound in this study. Five nonpeptide AST analogues (2-amino-1-[3-oxo-3-(substituted-anilino)propyl]pyridinium nitrate derivatives) were designed on the basis of the structure-activity relationship and docking results of FGLa. All of the nonpeptide analogues (S1-S5) were more potent against juvenile-hormone (JH) biosynthesis than the lead compound. They significantly inhibited the biosynthesis of JH in vivo following injection. A pest-control application demonstrated that S1 and S3 have larvicidal effects following oral administration (the IC50 values were 0.020 and 0.0016 mg/g, respectively). The good oral toxicities and excellent water solubilities of S1 and S3 suggest that they have considerable potential as insecticides for pest management.

A rapid quantitative assay for juvenile hormones and intermediates in the biosynthetic pathway using gas chromatography tandem mass spectrometry.

A method for rapid quantitation of insect juvenile hormones (JH) and intermediates in the biosynthetic pathway, both in vitro and in vivo (hemolymph and whole body), has been developed using GC-MS/MS. This method is as simple as the radiochemical assay (RCA), the most commonly used method for measurement of JH biosynthesis in vitro, without need for further purification and derivatization, or radioactive precursors or ligands. It shows high sensitivity, accuracy and reproducibility. Linear responses were obtained the range of 1-800 ng/mL (approximately 4-3000 nM). Recovery efficiencies for farnesol, farnesal, methyl farnesoate and JH III were approximately 100% in vitro and over 90% in vivo, with excellent reproducibility at three different spike levels. Titer of JH III in the hemolymph was relatively low at day 0 (adult female emergence) (79.68 ±â€¯5.03 ng/mL) but increased to a maximum of 1717 ng/mL five days later. In whole body, JH III quantity reached a maximum on day 4 (845.5 ±â€¯87.9 ng/g) and day 5 (679.7 ±â€¯164.6 ng/g) and declined rapidly thereafter. It is in agreement with the hemolymph titer changes and biosynthetic rate of JH in vitro. Comparison with the results of inhibition of JH biosynthesis by two known inhibitors (allatostatin (AST) mimic H17 and pitavastatin) using RCA and GC-MS/MS, showed that there was little difference between the two methods In contrast to other methods, the present method with GC-MS/MS can be used to elucidate the mechanism of inhibition by inhibitors of JH biosynthesis without any derivatization and purification. This method is applicable to screening of JH inhibitors and the study of inhibitory mechanisms with high sensitivity and accurate quantification. It may also be useful for the determination of JH titer in other Arthropods.

MicroRNAs regulate the sesquiterpenoid hormonal pathway in Drosophila and other arthropods.

Arthropods comprise the majority of all described animal species, and understanding their evolution is a central question in biology. Their developmental processes are under the precise control of distinct hormonal regulators, including the sesquiterpenoids juvenile hormone (JH) and methyl farnesoate. The control of the synthesis and mode of action of these hormones played important roles in the evolution of arthropods and their adaptation to diverse habitats. However, the precise roles of non-coding RNAs, such as microRNAs (miRNAs), controlling arthropod hormonal pathways are unknown. Here, we investigated the miRNA regulation of the expression of the juvenile hormone acid methyltransferase gene (JHAMT), which encodes a rate-determining sesquiterpenoid biosynthetic enzyme. Loss of function of the miRNA bantam in the fly Drosophila melanogaster increased JHAMT expression, while overexpression of the bantam repressed JHAMT expression and resulted in pupal lethality. The male genital organs of the pupae were malformed, and exogenous sesquiterpenoid application partially rescued the genital deformities. The role of the bantam in the regulation of sesquiterpenoid biosynthesis was validated by transcriptomic, qPCR and hormone titre (JHB3 and JH III) analyses. In addition, we found a conserved set of miRNAs that interacted with JHAMT, and the sesquiterpenoid receptor methoprene-tolerant (Met) in different arthropod lineages, including insects (fly, mosquito and beetle), crustaceans (water flea and shrimp), myriapod (centipede) and chelicerate (horseshoe crab). This suggests that these miRNAs might have conserved roles in the post-transcriptional regulation of genes in sesquiterpenoid pathways across the Panarthropoda. Some of the identified lineage-specific miRNAs are potential targets for the development of new strategies in aquaculture and agricultural pest control.

Discovery and quantitative structure-activity relationship study of lepidopteran HMG-CoA reductase inhibitors as selective insecticides.

BACKGROUND: In a previous study we have demonstrated that insect 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) can be a potential selective insecticide target. Three series of inhibitors were designed on the basis of the difference in HMGR structures from Homo sapiens and Manduca sexta, with the aim of discovering potent selective insecticide candidates. RESULTS: An in vitro bioassay showed that gem-difluoromethylenated statin analogues have potent effects on JH biosynthesis of M. sexta and high selectivity between H. sapiens and M. sexta. All series II compounds {1,3,5-trisubstituted [4-tert-butyl 2-(5,5-difluoro-2,2-dimethyl-6-vinyl-4-yl) acetate] pyrazoles} have some effect on JH biosynthesis, whereas most of them are inactive on human HMGR. In particular, the IC50 value of compound II-12 (37.8 nm) is lower than that of lovastatin (99.5 nm) and similar to that of rosuvastatin (24.2 nm). An in vivo bioassay showed that I-1, I-2, I-3 and II-12 are potential selective insecticides, especially for lepidopteran pest control. A predictable and statistically meaningful CoMFA model of 23 inhibitors (20 as training sets and three as test sets) was obtained with a value of q2 and r2 of 0.66 and 0.996 respectively. The final model suggested that a potent insect HMGR inhibitor should contain suitable small and non-electronegative groups in the ring part, and electronegative groups in the side chain. CONCLUSION: Four analogues were discovered as potent selective lepidopteran HMGR inhibitors, which can specifically be used for lepidopteran pest control. The CoMFA model will be useful for the design of new selective insect HMGR inhibitors that are structurally related to the training set compounds. © 2017 Society of Chemical Industry.

Lepidopteran HMG-CoA reductase is a potential selective target for pest control.

As a consequence of the negative impacts on the environment of some insecticides, discovery of eco-friendly insecticides and target has received global attention in recent years. Sequence alignment and structural comparison of the rate-limiting enzyme HMG-CoA reductase (HMGR) revealed differences between lepidopteran pests and other organisms, which suggested insect HMGR could be a selective insecticide target candidate. Inhibition of JH biosynthesis in vitro confirmed that HMGR inhibitors showed a potent lethal effect on the lepidopteran pest Manduca sexta, whereas there was little effect on JH biosynthesis in Apis mellifera and Diploptera punctata. The pest control application of these inhibitors demonstrated that they can be insecticide candidates with potent ovicidal activity, larvicidal activity and insect growth regulatory effects. The present study has validated that Lepidopteran HMGR can be a potent selective insecticide target, and the HMGR inhibitors (especially type II statins) could be selective insecticide candidates and lead compounds. Furthermore, we demonstrated that sequence alignment, homology modeling and structural comparison may be useful for determining potential enzymes or receptors which can be eco-friendly pesticide  targets.

The discovery of a novel antagonist - Manduca sexta allatotropin analogue - as an insect midgut active ion transport inhibitor.

BACKGROUND: The midgut is an important site for both nutrient absorption and ionic regulation in lepidopteran larvae, major pests in agriculture. The larval lepidopteran midgut has become a potent insecticide target over the past few decades. Recent studies have shown that an insect neuropeptide, Manduca sexta allatotropin (Manse-AT), exhibits inhibition of active ion transport (AIT) across the larval midgut epithelium. The full characteristic of the AIT inhibition capacity of Manse-AT is essential to assay. In this study, AIT inhibition across the M. sexta midgut by Manse-AT and its analogues in a range of concentrations was assayed. The structure-activity relationship of Manse-AT was also studied by truncated and alanine-replacement strategies. RESULTS: Our results identified three residues, Thr4, Arg6 and Phe8, as the most important components for activity on the midgut. Replacement of Glu1, Met2 and Met3 reduced the potency of the analogues. The conservative substitution of Gly7 with alanine had little effect on the potency of the analogues. We demonstrated for the first time that Manse-AT (10-13) behaves as a potent antagonist in vitro on active ion transport across the epithelium of the posterior midgut in M. sexta. CONCLUSION: Structure-activity studies of Manse-AT are useful in developing lead compounds for the design and testing of synthetic antagonists, ultimately to develop potent and specific pest control strategies. Manse-AT (10-13) has been discovered as the first Manse-AT antagonist, with a significant effect and a short sequence compared with other insect neuropeptides. It may be a new potential pest control agent in the future. © 2016 Society of Chemical Industry.

Combretastatin A-4 and Derivatives: Potential Fungicides Targeting Fungal Tubulin.

Combretastatin A-4, first isolated from the African willow tree Combretum caffrum, is a tubulin polymerization inhibitor in medicine. It was first postulated as a potential fungicide targeting fungal tubulin for plant disease control in this study. Combretastatin A-4 and its derivatives were synthesized and tested against Rhizoctonia solani and Pyricularia oryzae. Several compounds have EC50 values similar to or better than that of isoprothiolane, which is widely used for rice disease control. Structure-activity relationship study indicated the the cis configuration and hydroxyl group in combretastatin A-4 are crucial to the antifungal effect. Molecular modeling indicated the binding sites of combretastatin A-4 and carbendazim on fungal tubulin are totally different. The bioactivity of combretastatin A-4 and its derivatives against carbendazim-resistant strains was demonstrated in this study. The results provide a new approach for fungicide discovery and fungicide resistance management.

Molecular modeling studies of atorvastatin analogues as HMGR inhibitors using 3D-QSAR, molecular docking and molecular dynamics simulations.

3-Hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) is generally regarded as targets for the treatment of hypercholesterolemia. HMGR inhibitors (more commonly known as statins) are discovered as plasma cholesterol lowering molecules. In this work, 120 atorvastatin analogues were studied using a combination of molecular modeling techniques including three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulation. The results show that the best CoMFA (comparative molecular field analysis) model has q(2)=0.558 and r(2)=0.977, and the best CoMSIA (comparative molecular similarity indices analysis) model has q(2)=0.582 and r(2)=0.919. Molecular docking and MD simulation explored the binding relationship of the ligand and the receptor protein. The calculation results indicated that the hydrophobic and electrostatic fields play key roles in QSAR model. After MD simulation, we found four vital residues (Lys735, Arg590, Asp690 and Asn686) and three hydrophobic regions in HMGR binding site. The calculation results show that atorvastatin analogues obtained by introduction of F atoms or gem-difluoro groups could obviously improve the inhibitory activity. The new HMGR inhibitor analogues design in this Letter had been submitted which is being currently synthesized by our laboratories.