Photoinduced Dehydrogenative Amination of Quinoxalin-2(1H)-ones with Air as an Oxidant.

A facile and eco-friendly photoinduced dehydrogenative amination of quinoxalin-2(1H)-ones with aliphatic amines without any metal, strong oxidant, and photocatalyst has been established for the first time. This reaction proceeding efficiently with air as the sole oxidant at room temperature obtains a wide range of 3-aminoquinoxaline-2(1H)-ones in high yields with excellent functional group tolerance. The mechanistic studies show an interesting involvement of quinoxalin-2(1H)-ones as a photosensitizer, which eliminates the requirement for external photocatalysts.

Ferroptosis and Preeclampsia: Genetic Analysis of Potential Biomarkers and Therapeutic Targets.

Ferroptosis is the oxidative death of cells attributed to an imbalance in intracellular lipid reactive oxygen species metabolism, a reduction in cell antioxidant capacity, and an accumulation of membrane lipid peroxides. Trophoblast cells are a group of cells susceptible to ferroptosis. The ferroptosis of trophoblast cells has a major effect on the development of preeclampsia (PE), although the impact of ferroptosis-related genes (FRGs) on PE has not been well characterized. This study obtained PE-related information from the Gene Expression Omnibus database and FRGs from the FerrDb ferroptosis database. Seventeen PE-related differentially expressed ferroptosis-related genes (DE-FRGs) that were closely associated with cellular regulation and immune response were obtained. According to the results of a subsequent functional enrichment analysis, it was found that the above marker genes may impact PE by regulating immune response, amino acid metabolism, the cell cycle, and multiple pathways correlated with PE pathogenesis. Subsequently, we used LASSO and support vector machine recursive feature elimination algorithms to help identify GOT1, CFL1, FZD7, VDR, PARP6, TMSB4X, VCP, and ENO3 as marker genes from the 17 obtained genes. According to the results of single-sample gene set enrichment analysis (ssGSEA), the immune microenvironment of PE changed, possibly due to the GOT1 and TMSB4X genes. Furthermore, 23 drugs targeting one marker gene were determined. A constructed ceRNA network revealed a complicated regulatory link based on the eight marker genes. In this study, diagnostic potency was developed, and insight into the mechanism of PE was provided. In-depth research should be conducted before clinical application to evaluate the diagnostic value of DE-FRGs in PE.

Decarboxylative Radical Sulfilimination via Photoredox, Copper, and Brønsted Base Catalysis.

Sulfilimines, the aza-variants of sulfoxides, are key structural motifs in natural products, pharmaceuticals, and agrochemicals; and sulfilimine synthesis is therefore important in organic chemistry. However, methods for radical sulfilimination remain elusive, and as a result, the structural diversity of currently available sulfilimines is limited. Herein, we report the first protocol for decarboxylative radical sulfilimination reactions between sulfenamides and N-hydroxyphthalimide esters of primary, secondary, and tertiary alkyl carboxylic acids, which were achieved via a combination of photoredox, copper, and Brønsted base catalysis. This novel protocol provided a wide variety of sulfilimines, in addition to serving as an efficient route for the synthesis of S-alkyl/S-aryl homocysteine sulfilimines and S-(4-methylphenyl) homocysteine sulfoximine. Moreover, it could be used for late-stage introduction of a sulfilimine group into structurally complex molecules, thereby avoiding the need to preserve labile organosulfur moieties through multistep synthetic sequences. A mechanism involving photocatalytic substrate transformation and copper-mediated C(sp3 )-S bond formation is proposed.

The causal role of intestinal microbiome in development of pre-eclampsia.

The correlation of pre-eclampsia (PE) and intestinal microbiome has been widely demonstrated in existing research, whereas their causal relationship has been rarely explored. The causal relationship between intestinal microbiome and PE risk was examined using large-scale genome-wide association studies (GWAS) summary statistics. To be specific, the causal microbial taxa for PE were identified using the two-sample Mendelian randomization (MR) method. The results were verified to be robust through comprehensive sensitive analyses, and the independence of causal relationship was ensured through novel multivariable MR analyses. The possibility of reverse relationships was ruled out through reverse-direction MR analyses. Lastly, the biofunction was explored through enrichment analysis, and a series of validations of PE results in a second GWAS were performed to confirm the results. After correction, four microbial taxa, including Streptococcus genus for PE (FDR q = 0.085), Olsenella genus for PE (FDR q = 0.085), Enterobacteriales order for PE (FDR q = 0.0134), and Akkermansia genus for PE (FDR q = 0.015), had a causal relationship to diverse joint PE (FDR q < 0.15). Moreover, when three different methods were employed on basis of the nominal significance (P < 0.05), five suggestive microbial taxa took on significance. The effect of heterogeneity and horizontal pleiotropy was excluded through sensitive analysis, and the possibility of horizontal pleiotropy of BMI was ruled out through multivariable MR analysis. The protective mechanism of the identified taxa against PE was illustrated through GO enrichment analysis and KEGG pathways. A number of microbial taxa had a causal relationship to PE. The result of this study provides more insights into intestinal microbiome in the pathology of PE.

Design, synthesis, antiviral and fungicidal activities of novel polycarpine simplified analogues.

Fungal and viral diseases account for 70-80% of agricultural production losses caused by microbial diseases. Synthetic fungicides and antiviral agents have been used to treat plant diseases caused by plant pathogenic fungi and viruses, but their use has been criticized due to their adverse side effects. As alternative strategies, natural fungicides and antiviral agents have attracted many researchers' interest in recent years. Herein, we designed and synthesized a series of novel polycarpine simplified analogues. Antiviral activity research against tobacco mosaic virus (TMV) revealed that most of the designed compounds have good antiviral activities. The virucidal activities of 4, 6d, 6f, 6h, and 8c are higher than that of polycarpine and similar to that of ningnanmycin. The structure simplified compound 8c was selected for further antiviral mechanism research which showed that compound 8c could inhibit the formation of 20S protein discs by acting on TMV coat protein. These compounds also displayed broad-spectrum fungicidal activities against 7 kinds of plant fungi. This work lays the foundation for the application of polycarpine simplified analogues in crop protection.

CircRNA_0088196 Regulates Trophoblast Proliferation and Apoptosis in Preeclampsia Through the miR-379-5p/HSPA5 Axis.

Existing research has confirmed the dysregulation of circular RNA (circRNA) in a wide variety of human diseases. Thus, in this study, we explored the potential mechanism of circRNA_0088196 in preeclampsia (PE). We performed quantitative real-time PCR to examine circRNA_0088196 expression and verified the function of circRNA_0088196 in vitro using CCK-8, TUNEL, flow cytometry, and Western blotting analyses. Additionally, we studied the mechanism using dual-luciferase reporter gene experiments. The results of our research revealed the up-regulation of circRNA_0088196 in PE patients' placentas and Heat Shock 70 kDa Protein 5 (HSPA5)-stimulated trophoblast (HTR-8/SVneo) cells. An investigation of the mechanism also showed that there was a binding between miR-379-5p and circRNA_0088196. Additionally, circRNA_0088196 inhibited HTR-8/SVneo cell proliferation and promoted cell apoptosis via the miR-337-3p/HSPA5 axis, thereby facilitating PE. In vivo experiments indicated that circRNA_0088196 regulated HTR-8/SVneo cell production through miR-379-5p. Overall, the findings of this study illustrate that circRNA_0088196 interference promotes cell apoptosis and inhibits HTR-8/SVneo proliferation via the miR-379-5p/HSPA5 axis, thereby accelerating the development of PE.

Natural Products for Pesticides Discovery: Structural Diversity Derivation and Biological Activities of Naphthoquinones Plumbagin and Juglone.

Plant diseases and insect pests seriously affect the yield and quality of crops and are difficult to control. Natural products are an important source for the discovery of new pesticides. In this work, naphthoquinones plumbagin and juglone were selected as parent structures, and a series of their derivatives were designed, synthesized and evaluated for their fungicidal activities, antiviral activities and insecticidal activities. We found that the naphthoquinones have broad-spectrum anti-fungal activities against 14 types of fungus for the first time. Some of the naphthoquinones showed higher fungicidal activities than pyrimethanil. Compounds I, I-1e and II-1a emerged as new anti-fungal lead compounds with excellent fungicidal activities (EC50 values: 11.35-17.70 µg/mL) against Cercospora, arachidicola Hori. Some compounds also displayed good to excellent antiviral activities against the tobacco mosaic virus (TMV). Compounds I-1f and II-1f showed similar level of anti-TMV activities with ribavirin, and could be used as new antiviral candidates. These compound also exhibited good to excellent insecticidal activities. Compounds II-1d and III-1c displayed a similar level of insecticidal activities with matrine, hexaflumuron and rotenone against Plutella xylostella. In current study, plumbagin and juglone were discovered as parent structures, which lays a foundation for their application in plant protection.

Design, Synthesis and Various Bioactivity of Acylhydrazone-Containing Matrine Analogues.

Compounds with acylhydrazone fragments contain amide and imine groups that can act as electron donors and acceptors, so they are easier to bind to biological targets and thus generally exhibit significant biological activity. In this work, acylhydrazone fragments were introduced to the C-14 or C-11 position of matrine, a natural alkaloid, aiming to enhance their biological activities. The result of this bioassay showed that many synthesized compounds exhibited excellent anti-virus activity against the tobacco mosaic virus (TMV). Seventeen out of 25 14-acylhydrazone matrine derivatives and 17 out of 20 11-butanehydrazone matrine derivatives had a higher inhibitory activity against TMV than the commercial antiviral agent Ribavirin (the in vitro activity, in vivo inactivation, curative and protection activities at 500 µg/mL were 40.9, 36.5 ± 0.9, 38.0 ± 1.6 and 35.1 ± 2.2%, respectively), and four 11-butanehydrazone matrine derivatives even had similar to or higher activity than the most efficient antiviral agent Ningnanmycin (55.4, 57.8 ± 1.4, 55.3 ± 0.5 and 60.3 ± 1.2% at 500 µg/mL for the above four test modes). Among them, the N-benzyl-11-butanehydrazone of matrine formed with 4-bromoindole-3-carboxaldehyde exhibited the best anti-TMV activity (65.8, 71.8 ± 2.8, 66.8 ± 1.3 and 69.5 ± 3.1% at 500 µg/mL; 29, 33.5 ± 0.7, 24.1 ± 0.2 and 30.3 ± 0.6% at 100 µg/mL for the above four test modes), deserving further investigation as an antiviral agent. Other than these, the two series of acylhydrazone-containing matrine derivatives were evaluated for their insecticidal and fungicidal activities. Several compounds were found to have good insecticidal activities against diamondback moth (Plutella xylostella) and mosquito larvae (Culex pipiens pallens), showing broad biological activities.

Discovery of Barakacin and Its Derivatives as Novel Antiviral and Fungicidal Agents.

Pesticides are essential for the development of agriculture. It is urgent to develop green, safe and efficient pesticides. Bisindole alkaloids have unique and concise structures and broad biological activities, which make them an important leading skeleton in the creation of new pesticides. In this work, we synthesized bisindole alkaloid barakacin in a simple seven-step process, and simultaneously designed and synthesized a series of its derivatives. Biological activity research indicated that most of these compounds displayed good antiviral activities against tobacco mosaic virus (TMV). Among them, compound 14b exerted a superior inhibitory effect in comparison to commercially available antiviral agent ribavirin, and could be expected to become a novel antiviral candidate. Molecular biology experiments and molecular docking research found that the potential target of compound 14b was TMV coat protein (CP). These compounds also showed broad-spectrum anti-fungal activities against seven kinds of plant fungi.

Prediction of programmed cell death protein 1 in hepatocellular carcinoma patients using radiomics analysis with radiofrequency-based ultrasound multifeature maps.

BACKGROUND: This study explored the feasibility of radiofrequency (RF)-based radiomics analysis techniques for the preoperative prediction of programmed cell death protein 1 (PD-1) in patients with hepatocellular carcinoma (HCC). METHODS: The RF-based radiomics analysis method used ultrasound multifeature maps calculated from the RF signals of HCC patients, including direct energy attenuation (DEA) feature map, skewness of spectrum difference (SSD) feature map, and noncentrality parameter S of the Rician distribution (NRD) feature map. From each of the above ultrasound maps, 345 high-throughput radiomics features were extracted. Then, the useful radiomics features were selected by the sparse representation method and input into support vector machine (SVM) classifier for PD-1 prediction. RESULTS AND CONCLUSION: Among all the RF-based prediction models and the ultrasound grayscale comparative model, the RF-based model using all of the three ultrasound feature maps had the highest prediction accuracy (ACC) and area under the curve (AUC), which were 92.5% and 94.23%, respectively. The method proposed in this paper is effective for the meaningful feature extraction of RF signals and can effectively predict PD-1 in patients with HCC.

Digital RNA-seq analysis of the cardiac transcriptome response to thermal stress in turbot Scophthalmus maximus.

The hearts of fish play a major role in their physiological plasticity and acclimation to different thermal conditions. To understand the precise mechanism and the pathways activated by thermal cardiac stress in fish, we sampled cardiac tissue from juvenile turbot (Scophthalmus maximus) exposed to control (14°C) and test (20°C, 24°C, and 28°C) conditions, and performed digital RNA sequencing (RNA-seq). A total of 3359 differentially expressed genes (DEGs) were identified. The results of an expression tendency analysis and KEGG annotation analysis of the DEGs demonstrated that energy metabolism played a core role in thermal stress in turbot for the majority of the up-regulated genes. This was followed by lipid metabolism, mitochondrial function, glycolysis, and carbohydrate metabolism. RNA modifications are gaining the interest of biologists worldwide. In this study, at the transcriptome level, our results showed that 246 m6A-containing genes were detected in the DEGs, which were related to EIF3C, EIF3D, EIF3J, METTL16, RBM15B, VIRMA, and YTHDC1. This indicates that m6A is involved in the regulation of heat stress in turbot. This study is an important step towards understanding the cardiac adaptive response to thermal stress. Importantly, the plasticity of cardiac tissue could predict the adaptability of fish species to environmental temperature.

Synthesis and Evaluation of 11-Butyl Matrine Derivatives as Potential Anti-Virus Agents.

Matrine derivatives were reported to have various biological activities, especially the ester, amide or sulfonamide derivatives of matrine deriving from the hydroxyl or carboxyl group at the end of the branch chain after the D ring of matrine is opened. In this work, to investigate whether moving away all functional groups from the C-11 branch chain could have an impact on the bioactivities, such as anti-tobacco mosaic virus (TMV), insecticidal and fungicidal activities, a variety of N-substituted-11-butyl matrine derivatives were synthesized. The obtained bioassay result showed that most N-substituted-11-butyl matrine derivatives had obviously enhanced anti-TMV activity compared with matrine, especially many compounds had good inhibitory activity close to that of commercialized virucide Ningnanmycin (inhibition rate 55.4, 57.8 ± 1.4, 55.3 ± 0.5 and 60.3 ± 1.2% at 500 µg/mL; 26.1, 29.7 ± 0.2, 24.2 ± 1.0 and 27.0 ± 0.3% at 100 µg/mL, for the in vitro activity, in vivo inactivation, curative and protection activities, respectively). Notably, N-benzoyl (7), N-benzyl (16), and N-cyclohexylmethyl-11-butyl (19) matrine derivatives had higher anti-TMV activity than Ningnanmycin at both 500 and 100 µg/mL for the four test modes, showing high potential as anti-TMV agent. Furthermore, some compounds also showed good fungicidal activity or insecticidal activity.

Discovery of Hyrtinadine A and Its Derivatives as Novel Antiviral and Anti-Phytopathogenic-Fungus Agents.

Plant diseases caused by viruses and fungi have a serious impact on the quality and yield of crops, endangering food security. The use of new, green, and efficient pesticides is an important strategy to increase crop output and deal with the food crisis. Ideally, the best pesticide innovation strategy is to find and use active compounds from natural products. Here, we took the marine natural product hyrtinadine A as the lead compound, and designed, synthesized, and systematically investigated a series of its derivatives for their antiviral and antifungal activities. Compound 8a was found to have excellent antiviral activity against the tobacco mosaic virus (TMV) (inactivation inhibitory effect of 55%/500 µg/mL and 19%/100 µg/mL, curative inhibitory effect of 52%/500 µg/mL and 22%/100 µg/mL, and protection inhibitory effect of 57%/500 µg/mL and 26%/100 µg/mL) and emerged as a novel antiviral candidate. These compound derivatives displayed broad-spectrum fungicidal activities against 14 kinds of phytopathogenic fungi at 50 µg/mL and the antifungal activities of compounds 5c, 5g, 6a, and 6e against Rhizoctonia cerealis are higher than that of the commercial fungicide chlorothalonil. Therefore, this study could lay a foundation for the application of hyrtinadine A derivatives in plant protection.

Design, Synthesis, and Bioactivity Study of Novel Tryptophan Derivatives Containing Azepine and Acylhydrazone Moieties.

Based on the scaffolds widely used in drug design, a series of novel tryptophan derivatives containing azepine and acylhydrazone moieties have been designed, synthesized, characterized, and evaluated for their biological activities. The bioassay results showed that the target compounds possessed moderate to good antiviral activities against the tobacco mosaic virus (TMV), among which compounds 5c, 6a, 6h, 6t, 6v, and 6y exhibited higher inactivation, curative, and protection activities in vivo than that of ribavirin (40 ± 1, 37 ± 1, 39 ± 2% at 500 mg/L). Especially, 6y showed comparable activities to that of ningnanmycin (57 ± 2, 55 ± 3, 58 ± 1% at 500 mg/L). Meanwhile, we were pleased to find that almost all these derivatives showed good larvicidal activities against Plutella xylostella. Meanwhile, these derivatives also showed a broad spectrum of fungicidal activities.

Promoting Efficacy and Environmental Safety of Pesticide Synergists via Non-Ionic Gemini Surfactants with Short Fluorocarbon Chains.

Improving the utilization rate of pesticides is key to achieve a reduction and synergism, and adding appropriate surfactant to pesticide preparation is an effective way to improve pesticide utilization. Fluorinated surfactants have excellent surface activity, thermal and chemical stability, but long-chain linear perfluoroalkyl derivatives are highly toxic, obvious persistence and high bioaccumulation in the environment. Therefore, new strategies for designing fluorinated surfactants which combine excellent surface activity and environmental safety would be useful. In this study, four non-ionic gemini surfactants with short fluorocarbon chains were synthesized. The surface activities of the resulting surfactants were assessed on the basis of equilibrium surface tension, dynamic surface tension, and contact angle. Compared with their monomeric counterparts, the gemini surfactants had markedly lower critical micelle concentrations and higher diffusivities, as well as better wetting abilities. We selected a single-chain surfactant and a gemini surfactant with good surface activities as synergists for the glyphosate water agent. Both surfactants clearly improved the efficacy of the herbicide, but the gemini surfactant had a significantly greater effect than the single-chain surfactant. An acute toxicity test indicated that the gemini surfactant showed slight toxicity to rats.

Design, Synthesis, and Bioactivities of Novel Tryptophan Derivatives Containing 2,5-Diketopiperazine and Acyl Hydrazine Moieties.

Based on the scaffolds widely used in drug design, a series of novel tryptophan derivatives containing 2,5-diketopiperazine and acyl hydrazine moieties have been designed, synthesized, characterized, and evaluated for their biological activities. The bioassay results showed that the target compounds possessed moderate to good antiviral activities against tobacco mosaic virus (TMV), among which compounds 4, 9, 14, 19, and 24 showed higher inactivation, curative, and protection activities in vivo than that of ribavirin (39 ± 1, 37 ± 1, 39 ± 1 at 500 mg/L) and comparable to that of ningnanmycin (58 ± 1, 55 ± 1, 57 ± 1% at 500 mg/L). Thus, these compounds are a promising candidate for anti-TMV development. Most of these compounds showed broad-spectrum fungicidal activities against 13 kinds of phytopathogenic fungi and selective fungicidal activities against Alternaria solani, Phytophthora capsica, and Sclerotinia sclerotiorum. Additionally, some of these compounds exhibited larvicidal activities against Tetranychus cinnabarinus, Plutella xylostella, Culex pipiens pallens, Mythimna separata, Helicoverpa armigera, and Pyrausta nubilalis.

Dehalogenative Cross-Coupling of gem-Difluoroalkenes with Alkyl Halides via a Silyl Radical-Mediated Process.

Herein, we describe a convenient general protocol for monofluoroalkenylation reactions of alkyl bromides involving cooperative visible-light photoredox catalysis and halogen abstraction. Mechanistic experiments showed that the products were generated by selective cross-coupling of aliphatic radicals with fluoroalkenyl radicals. Silyl radical-mediated halogen abstraction enabled the protocol to be used for the monofluoroalkenylation of a broad range of alkyl and heteroaryl halides. The protocol could be carried out on a gram scale and was applied to cholesterol, indicating its utility for late-stage monofluoroalkenylation reactions.

Visible-light-mediated alkylation of 4-alkyl-1,4-dihydropyridines with alkenyl sulfones.

Herein we report a mild, general protocol for visible-light-mediated alkylation of 4-alkyl-1,4-dihydropyridines with alkenyl sulfones. The protocol permits efficient functionalization of sulfones with a broad range of cyclic and acyclic secondary and tertiary alkyl groups and is scalable to the gram level. Its excellent functional group tolerance and mildness make it suitable for late-stage functionalization of natural products and drug molecules.

Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents.

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood-brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.

Transfer learning radiomics based on multimodal ultrasound imaging for staging liver fibrosis.

OBJECTIVES: To propose a transfer learning (TL) radiomics model that efficiently combines the information from gray scale and elastogram ultrasound images for accurate liver fibrosis grading. METHODS: Totally 466 patients undergoing partial hepatectomy were enrolled, including 401 with chronic hepatitis B and 65 without fibrosis pathologically. All patients received elastography and got liver stiffness measurement (LSM) 2-3 days before surgery. We proposed a deep convolutional neural network by TL to analyze images of gray scale modality (GM) and elastogram modality (EM). The TL process was used for liver fibrosis classification by Inception-V3 network which pretrained on ImageNet. The diagnostic performance of TL and non-TL was compared. The value of single modalities, including GM and EM alone, and multimodalities, including GM + LSM and GM + EM, was evaluated and compared with that of LSM and serological indexes. Receiver operating characteristic curve analysis was performed to calculate the optimal area under the curve (AUC) for classifying fibrosis of S4, ≥ S3, and ≥ S2. RESULTS: TL in GM and EM demonstrated higher diagnostic accuracy than non-TL, with significantly higher AUCs (all p < .01). Single-modal GM and EM both performed better than LSM and serum indexes (all p < .001). Multimodal GM + EM was the most accurate prediction model (AUCs are 0.950, 0.932, and 0.930 for classifying S4, ≥ S3, and ≥ S2, respectively) compared with GM + LSM, GM and EM alone, LSM, and biomarkers (all p < .05). CONCLUSIONS: Liver fibrosis can be staged by a transfer learning modal based on the combination of gray scale and elastogram ultrasound images, with excellent performance. KEY POINTS: • Transfer learning consists in applying to a specific deep learning algorithm that pretrained on another relevant problem, expected to reduce the risk of overfitting due to insufficient medical images. • Liver fibrosis can be staged by transfer learning radiomics with excellent performance. • The most accurate prediction model of transfer learning by Inception-V3 network is the combination of gray scale and elastogram ultrasound images.