Discovery of Novel Pyrazole Derivatives with Improved Crop Safety as 4-Hydroxyphenylpyruvate Dioxygenase-Targeted Herbicides.

As one of the essential herbicide targets, 4-hydroxyphenylpyruvate dioxygenase (HPPD) has recently been typically used to produce potent new herbicides. In continuation with the previous work, several pyrazole derivatives comprising a benzoyl scaffold were designed and synthesized, and their inhibitory effects on Arabidopsis thaliana hydroxyphenylpyruvate dioxygenase (AtHPPD) and herbicidal activities were comprehensively evaluated in this study. Compound Z9 showed top-rank inhibitory activity to AtHPPD with an half-maximal inhibitory concentration (IC50) value of 0.05 µM, which was superior to topramezone (1.33 µM) and mesotrione (1.76 µM). Compound Z21 exhibited superior preemergence inhibitory activity against Echinochloa crusgalli, with stem and root inhibition rates of 44.3 and 69.6%, respectively, compared to topramezone (16.0 and 53.0%) and mesotrione (12.8 and 41.7%). Compounds Z5, Z15, Z20, and Z21 showed excellent postemergence herbicidal activities at a dosage of 150 g ai/ha, along with distinct bleaching symptoms and higher crop safety than topramezone and mesotrione, and they all were safe for maize, cotton, and wheat with injury rates of 0 or 10%. In addition, the molecular docking analysis also revealed that these compounds formed hydrophobic π-π interactions with Phe360 and Phe403 to AtHPPD. This study suggests that pyrazole derivatives containing a benzoyl scaffold could be used as new HPPD inhibitors to develop pre- and postemergence herbicides and be applied to additional crop fields.

The influence of in vitro gastrointestinal digestion and fecal fermentation on the flowers of Juglans regia: Changes in the active compounds and bioactivities.

The objective of the research was to investigate the digestion and fecal fermentation characteristics of the flowers of Juglans regia (FJR), by using in vitro simulated digestion model (oral, gastric, and intestine) as well as colonic fermentation. As a result, the contents of most active substances and functional activities of FJR were decreased as the digestion proceeded, and showed a trend of first increasing and then decreasing in the fecal fermentation phase. In the oral digestion phase, the total phenolic and total flavonoid contents were released most with the values of 11.43 and 9.41 µg/mg, respectively. While in the gastric digestion phase, the antioxidant abilities, α-glucosidase and α-amylase inhibitory abilities were the weakest. By using high-performance liquid chromatography, 13 phenolic acids and 3 flavonoids were detected. Of these, the highest number of identified compounds were found in the undigested and the oral digestion stages, which were mainly salicylic acid, epicatechin, 3,5-dihydroxybenoic acid, vanillic acid, and protocatechuic acid. However, great losses were observed during the gastric and intestinal digestion stages, only epicatechin, salicylic acid, and protocatechuic acid were found. Surprisingly, fecal fermentation released more abundant phenolic substances compared to gastric and intestinal digestion. Additionally, FJR reduced the pH values in the colonic fermentation system, significantly promoted the production of short-chain fatty acids, and regulated the microbe community structure by improving the community richness of beneficial microbiota. This indicated that FJR had the benefit to improve the microorganismal environment in the intestine. Further Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that FJR could suppress the metabolic pathways related to diseases, such as infectious diseases, metabolic diseases and neurodegenerative diseases. In conclusion, although the bioactivities of FJR decreased significantly after in vitro gastrointestinal digestion and fecal fermentation, it still maintained certain antioxidant and hypoglycemic ability in vitro. This study described the detailed changes in the active compounds and bioactivities of FJR during in vitro gastrointestinal digestion and fecal fermentation, and its effects on microbiota composition and SCFAs levels in feces. Our results revealed the potential health benefits of FJR, and could provide a reference for its further research and development.

Examination of the potential roles of insulin-like peptide receptor in regulating the growth of Manila clam Ruditapes philippinarum.

The role of insulin/insulin-like growth factor (IGF) signaling pathway in the growth regulation of marine invertebrates has not been fully studied. In this study, the economically important species Ruditapes philippinarum was sacrificed to clarify the role of IGF system in the growth regulation of R. philippinarum by real-time quantitative PCR. Systematic bioinformatics analysis can identify the major genes of IGF signaling pathway and insulin-like peptide receptor (ILPR) - mediated signaling pathway in R. philippinarum. The expression levels of IGF and its downstream signaling pathway genes in larger clams were significantly higher than those in small clams, indicating that they were involved in the growth regulation of R. philippinarum. These results suggest that IGF signaling pathway and ILPR mediated signaling pathway to regulate the growth of R. philippinarum.

Design, synthesis, antiviral activity, and mechanisms of novel ferulic acid derivatives containing amide moiety.

To explore the novel compounds with high antiviral activity, three series ferulic acid derivatives containing amide moiety were gradually designed and synthesized based on antiviral activity tracking. The bioassay results exhibited that some target compounds had notable antiviral activities against tomato spotted wilt virus (TSWV) and cucumber mosaic virus (CMV). Compounds Y1, Y2, Y8, Z1 and Z2 presented splendid curative, protective, and inactivating activities to TSWV and CMV at 500 µg/mL. Especially, these compounds displayed outstanding inactivating effects on TSWV with the EC50 values of 225.9, 126.1, 224.6, 216.1, and 147.3 µg/mL, which were superior to ningnanmycin (249.1 µg/mL) and ribavirin (315.7 µg/mL). Furthermore, the antiviral mechanisms of compound Y2 were investigated by conducting microscale thermophoresis experiment and molecular docking experiment. The results suggested that compound Y2 performed excellent binding affinity to TSWV coat protein (TSWV CP) with the binding constant of 2.14 µM, which due to two strong hydrogen bonds of compound Y2 to the key amino acids ARG94 of TSWV CP. Therefore, compound Y2 can be regarded as a leading structure for development of the potential antiviral agent.

Novel Pyrazole Amides as Potential 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for the development of new herbicides. HPPD inhibitors can hinder photosynthesis and induce weed death with bleaching symptoms. To explore the novel skeleton of HPPD inhibitors, a series of novel pyrazole amide derivatives were synthesized and evaluated for their inhibitory effects on Arabidopsis thaliana HPPD (AtHPPD) and herbicidal activities. Some compounds had excellent inhibitory activities against AtHPPD. Among them, compound B5 displayed top-rank inhibitory activity against AtHPPD with an IC50 value of 0.04 µM, which was obviously superior to that of topramezone (IC50 value of 0.11 µM). Furthermore, compounds B2 and B7 had 100% herbicidal activities in Petri dish assays against Portulaca oleracea and Amaranthus tricolor at 100 µg/mL. In particular, compound B7 not only possessed strong AtHPPD inhibitory activity but also exhibited significant preemergence herbicidal activity. However, compound B7 was completely harmless to soybean, cotton, and wheat. In addition, the molecular docking and microscale thermophoresis measurement experiment verified that compounds can bind well with AtHPPD via π-π interactions. The present work provides a new approach for the rational design of more effective HPPD inhibitors, and pyrazole amides could be used as useful substructures for the development of new HPPD inhibitors and preemergence herbicidal agents.

Design, Synthesis and Antifungal/Nematicidal Activity of Novel 1,2,4-Oxadiazole Derivatives Containing Amide Fragments.

Plant diseases that are caused by fungi and nematodes have become increasingly serious in recent years. However, there are few pesticide chemicals that can be used for the joint control of fungi and nematodes on the market. To solve this problem, a series of novel 1,2,4-oxadiazole derivatives containing amide fragments were designed and synthesized. Additionally, the bioassays revealed that the compound F15 demonstrated excellent antifungal activity against Sclerotinia sclerotiorum (S. sclerotiorum) in vitro, and the EC50 value of that was 2.9 µg/mL, which is comparable with commonly used fungicides thifluzamide and fluopyram. Meanwhile, F15 demonstrated excellent curative and protective activity against S. sclerotiorum-infected cole in vivo. The scanning electron microscopy results showed that the hyphae of S. sclerotiorum treated with F15 became abnormally collapsed and shriveled, thereby inhibiting the growth of the hyphae. Furthermore, F15 exhibited favorable inhibition against the succinate dehydrogenase (SDH) of the S. sclerotiorum (IC50 = 12.5 µg/mL), and the combination mode and binding ability between compound F15 and SDH were confirmed by molecular docking. In addition, compound F11 showed excellent nematicidal activity against Meloidogyne incognita at 200 µg/mL, the corrected mortality rate was 93.2%, which is higher than that of tioxazafen.

Ferulic acid derivatives with piperazine moiety as potential antiviral agents.

BACKGROUND: Plant virus diseases are difficult to control and severely threaten the productivity of crops, which leads to huge financial losses. To discover the new antiviral drugs, 34 novel ferulic acid derivatives with piperazine moiety were synthesized, and the antiviral activities were systematically screened as well. RESULTS: Bioassay results indicated that most of the target compounds had outstanding antiviral activities against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) in vivo. In particular, compound E2 exhibited remarkable curative activities to TMV and CMV with EC50 values of 189.0 and 401.7 µg/mL compared to those for ningnanmycin (387.0, 519.3 µg/mL) and ribavirin (542.1, 721.5 µg/mL). And then the mechanisms of compound E2 were studied by chlorophyll content, differentially expressed proteins and genes tests. CONCLUSION: The excellent antiviral activity of compound E2 was closely associated with the increase in host photosynthesis, which was confirmed by chlorophyll content, differentially expressed proteins and genes assays. Compound E2 can be considered as a lead structure for the discovery of new antiviral agents. © 2022 Society of Chemical Industry.

Synthesis of Novel Antiviral Ferulic Acid-Eugenol and Isoeugenol Hybrids Using Various Link Reactions.

To develop novel antiviral agents, some novel conjugates between ferulic acid and eugenol or isoeugenol were designed and synthesized by the link reaction. The antiviral activities of compounds were evaluated using the half leaf dead spot method. Bioassay results showed acceptable antiviral activities of some conjugates against the tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV). Compounds A9, A10, E1, and E4 showed remarkable curative, protective, and inactivating effects on TMV and CMV at 500 µg mL-1. Notably, these compounds exhibited excellent protective effects on TMV and CMV. The EC50 values of compounds A9, A10, E1, and E4 against TMV were 180.5, 169.5, 211.4, and 135.5 µg mL-1, respectively, and those against CMV were 210.5, 239.1, 218.4, and 178.6 µg mL-1, respectively, which were superior to those of ferulic acid (471.5 and 489.2 µg mL-1), eugenol (456.3 and 463.2 µg mL-1), isoeugenol (478.4 and 487.5 µg mL-1), and ningnanmycin (246.5 and 286.6 µg mL-1). Then, the antiviral mechanisms of compound E4 were investigated by determining defensive enzyme activities and multi-omics analysis. The results indicated that compound E4 resisted the virus infection by enhancing defensive responses via inducing the accumulation of secondary metabolites from the phenylpropanoid biosynthesis pathway in tobacco.

Transcriptomic analysis provides insights into candidate genes and molecular pathways involved in growth of Manila clam Ruditapes philippinarum.

Growth is one of the most important traits of aquaculture breeding programs. Understanding the mechanisms underlying growth differences between individuals can contribute to improving growth rates through more efficient breeding schemes. Ruditapes philippinarum is an economically important marine bivalve. In order to gain insights into the molecular mechanisms to growth variability in marine shellfish, we conducted the transcriptome sequencing and examined the expression differences in growth-related gene and molecular pathways involved in growth trait of R. philippinarum. In this study, we investigated the molecular and gene expression differences in fast-growing and slow-growing Manila clam and focused on the analysis of the differential expression patterns of specific genes associated with growth by RNA-seq and qPCR analysis. A total of 61 differentially expressed genes (DEGs) were captured significantly differentially expressed, and were categorized into Ras signaling pathway, hedgehog signaling pathway, AMPK signaling pathway, p53 signaling pathway, regulation of actin cytoskeleton, focal adhesion, mTOR signaling pathway, VEGF signaling pathway, and TGF-beta signaling pathway. A total of 34 growth-related genes were validated significantly and up/downregulated at fast growing and slow growing of R. philippinarum. Functional enrichment analysis revealed the insulin signaling pathway, PI3K-Akt signaling pathway, and mTOR signaling pathway play pivotal roles in molecular function and regulation of growth trait in R. philippinarum. The growth-related genes and pathways obtained here provide important insights into the molecular basis of physiological acclimation, metabolic activity, and growth variability in marine bivalves.

Molecular mechanisms of wound healing and regeneration of siphon in the Manila clam Ruditapes philippinarum revealed by transcriptomic analysis.

Ruditapes philippinarum is an economically important marine shellfish aquaculture species, and it has the ability to regenerate its siphons. To gain a greater understanding of the molecular mechanisms at work during siphon regeneration and to provide evidence for morphological regeneration, we examined transcriptome responses of siphon tissue of R. philippinarum during regeneration and observed regenerative siphons under the stereomicroscope. The overall process of siphon regeneration was dissected based on the morphological changes of siphon and the identification of up-regulated key differentially expressed genes (DEGs). The protein biosynthesis and metabolism played important roles in wound healing and siphon regeneration of R. philippinarum. Transcriptomic analysis identified the Wnt and TGF-ß signaling pathways by focusing on the function and expression pattern of genes in these pathways during siphon regeneration. In addition, we carried out a genome-wide identification and phylogenetic analysis of TGF-ß superfamily in R. philippinarum. The expression profiles of the TGF-ß superfamily genes were analyzed in eight adult tissues (adductor muscle, mantle, foot, gill, siphon, digestive gland, gonad, and labial palp) and regenerative siphon. This study shed new light on the process of morphological regeneration and regenerative mechanism of siphon of R. philippinarum.

Single image super-resolution via Image Quality Assessment-Guided Deep Learning Network.

In recent years, deep learning (DL) networks have been widely used in super-resolution (SR) and exhibit improved performance. In this paper, an image quality assessment (IQA)-guided single image super-resolution (SISR) method is proposed in DL architecture, in order to achieve a nice tradeoff between perceptual quality and distortion measure of the SR result. Unlike existing DL-based SR algorithms, an IQA net is introduced to extract perception features from SR results, calculate corresponding loss fused with original absolute pixel loss, and guide the adjustment of SR net parameters. To solve the problem of heterogeneous datasets used by IQA and SR networks, an interactive training model is established via cascaded network. We also propose a pairwise ranking hinge loss method to overcome the shortcomings of insufficient samples during training process. The performance comparison between our proposed method with recent SISR methods shows that the former achieves a better tradeoff between perceptual quality and distortion measure than the latter. Extensive benchmark experiments and analyses also prove that our method provides a promising and opening architecture for SISR, which is not confined to a specific network model.

Genome-wide identification and transcriptome-based expression profiling of Wnt gene family in Ruditapes philippinarum.

The Wnt genes encode a set of conserved glycoproteins regulating early development, cell proliferation and differentiation, and tissue regeneration in metazoans. In some mollusks, the knowledge of Wnt gene family has been limited because of the short of the genomic and transcriptomic resources. Ruditapes philippinarum is an economically important bivalve with a variety of shell coloration patterns and ability to regenerate its siphon. To gain a greater understanding of the evolutionary dynamics of Wnt gene family, we carried out a genome-wide identification and phylogenetic analysis of Wnt gene family in R. philippinarum and other four mollusks. A total of 12 Wnt genes were identified in the genome of R. philippinarum, and the dynamic patterns of gene conservation, loss and duplication of Wnt genes were analyzed in mollusks and model organisms. Furthermore, the transcriptome analyses demonstrated the expression profiles of the Wnt genes at different developmental stage, in adult tissues, during siphon regeneration, in four different shell color strains, and at uncolored and colored developmental stages in two different shell color strains. These findings suggest that the expansion of Wnt genes may play vital roles in the larval development, the formation of shell color pattern and siphon regeneration in R. philippinarum. This study provides a valuable insight into Wnt function and evolution in mollusks.

Benzoquinone-Based Polyimide Derivatives as High-Capacity and Stable Organic Cathodes for Lithium-Ion Batteries.

Multicarbonyl polyimide derivatives were synthesized by a facial condensation polymerization of dianhydrides with a new diamine monomer containing a benzoquinone unit that was prepared according to the Michael addition reaction. The ingenious combination of dedicated carbonyl groups from the benzoquinone and dianhydride with an aniline structure linkage not only provided stable polymeric chains with a high number of carbonyl groups per unit but also guaranteed their large π-conjugated main chains, which is favorable to their long cycle life and fast kinetics. When explored as cathode materials for lithium-ion batteries, the polyimide derivatives based on naphthalic dianhydride delivered a reversible specific capacity of 145 mAh/g at 0.1 C, a high rate performance with a capacity of 108 mAh/g at 1 C, and an ultralong stable cyclic performance with a capacity retention of 80.3% after 1000 cycles at 0.5 C. Based on the theoretical calculations and the exploration of the electrochemical behaviors, sensible predictions for the reversible ion-insertion reaction of the as-prepared sample were proposed to deeply understand the charge storage mechanisms. Moreover, a stable solid electrolyte interphase film formed in the ether-based electrolyte was confirmed to improve the electrochemical properties.

Tim-1-Fc suppresses chronic cardiac allograft rejection and vasculopathy by reducing IL-17 production.

Previously, we demonstrated that Tim-1-Fc prevents acute cardiac graft rejection by inhibiting Th1 response. In the present report, we tackled the impact of Tim-1-Fc on Th17 cells in a model of cardiac chronic rejection. Administration of Tim-1-Fc did not result in a detectable impact on innate immunity and regulatory T cells, while it provided protection for Bm12-derive cardiac grafts against chronic rejection in B6 recipients, as manifested by the reduction of inflammatory infiltration along with less severity of vasculopathy. Studies in T-bet(-/-) recipients by implanting Bm12-derived cardiac grafts further revealed that Tim-1-Fc significantly protected cardiac grafts from chronic rejection along with attenuated production of IL-17 producing T cells. Depletion of CD4 and CD8 T cells or blockade of IL-17 in T-bet(-/-) recipients demonstrated that Tim-1-Fc selectively suppresses Th17 differentiation along with attenuated IL-17 secretion. Together, our data suggest that Tim-1-Fc protects cardiac grafts from chronic rejection by suppressing CD4 Th17 development and functionality. Therefore, Tim-1-Fc might be a potential immunosuppressive agent in the setting of cardiac transplantation.

[Identification of a highly conserved domain that suppresses the DNA-binding domain-DNA interactions in the androgen receptor].

OBJECTIVE: To determine the gene regulation of androgen receptor (AR). METHODS: Gel shift assay, protein-protein pull down assay, western blot and technique of site-directed mutagenesis were used to study the gene regulation of AR. RESULTS: The N terminal of AR contained an inhibitory domain located in an 81-amino acid segment lying upstream of the DNA-binding domain (DBD). The inhibitory domain interacted directly with DBD and repressed DBD binding to the ARE. Mutations of the conserved amino acid residues (K520E and R538E) within the inhibitory domain decreased its inhibiting ability in vitro and increased AR trans-activation in vivo. CONCLUSION: These data demonstrated the existence of a novel inhibitory domain in the N-terminal part of AR, which might play important role in the regulation of AR trans-activation.