Xiaotian Ji

The Natural Product Phyllanthusmin C Enhances IFN-γ Production by Human NK Cells through Upregulation of TLR-Mediated NF-κB Signaling

Natural products are a major source for cancer drug development. NK cells are a critical component of innate immunity with the capacity to destroy cancer cells, cancer-initiating cells, and clear viral infections. However, few reports describe a natural product that stimulates NK cell IFN-γ production and unravel a mechanism of action. In this study, through screening, we found that a natural product, phyllanthusmin C (PL-C), alone enhanced IFN-γ production by human NK cells. PL-C also synergized with IL-12, even at the low cytokine concentration of 0.1 ng/ml, and stimulated IFN-γ production in both human CD56bright and CD56dim NK cell subsets. Mechanistically, TLR1 and/or TLR6 mediated PL-C’s activation of the NF-κB p65 subunit that in turn bound to the proximal promoter of IFNG and subsequently resulted in increased IFN-γ production in NK cells. However, IL-12 and IL-15Rs and their related STAT signaling pathways were not responsible for the enhanced IFN-γ secretion by PL-C. PL-C induced little or no T cell IFN-γ production or NK cell cytotoxicity. Collectively, we identify a natural product with the capacity to selectively enhance human NK cell IFN-γ production. Given the role of IFN-γ in immune surveillance, additional studies to understand the role of this natural product in prevention of cancer or infection in select populations are warranted.

Novel Anthranilic Diamide Insecticides: Design, Synthesis, and Insecticidal Evaluation

Three series of new anthranilic diamide derivatives containing sulfide, N-cyanomethylsulfilimine, and N-cyanomethylsulfoximine groups were designed and synthesized by coupling the active substructures of anthranilic diamides and sulfoxaflor. The structures of the synthesized compounds were confirmed by infrared spectroscopy, 1H and 13C NMR, and elemental analysis. Several unique structural characteristics were revealed via the crystal structure analysis of compound N-(2-(2-methyl-2-(methylthio)propylcarbamoyl)-4-chloro-6-methylphenyl)-3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide 16e. Bioassay results indicated that most of the synthesized compounds showed superior insecticidal activities against Mythimna separata and Plutella xylostella when compared with the positive control cyantraniliprole. In particular, N-(2-(2-methyl-2-(N-cyanomethylsulfideimino)propylcarbamoyl)-4-chloro-6-methylphenyl)-3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide 17e showed excellent insecticidal activity against Mythimna separata, with a mortality rate of 100 % at a concentration of 1 µg mL–1. These results indicated that sulfide, N-cyanomethylsulfilimine, and N-cyanomethylsulfoximine moieties, as important active substructures, could improve or maintain the activity of the anthranilic diamide and promote novel pesticide development.

Synthesis and biological activities of novel 1,2,4-triazole derivatives containing 1,2,3-thiadiazole ring

A series of novel 1,2,4-triazole derivatives containing 1,2,3-thiadiazole ring was designed and synthesized. Their structures were confirmed by IR, 1H NMR, high resolution mass spectrometer(HRMS) and electrospray ionization-mass spectrometer(ESI-MS) combined with melting points and elemental analysis. Preliminary bioassays indicate that these compounds exhibit good insecticidal activity against Aphis laburni at 100 μg/mL, especially compound 6b shows mortality of no less than 95%. Most of the compounds show good activities against tobacco mosaic virus(TMV) with different modes in vivo at 100 μg/mL. Compound 6d standed out, showing a good insecticidal activity and very high induction effects against TMV in vivo. Collectively, our data demonstrate a new strategy for insect and virus control.

A Synthetic Disaccharide Derivative of Diphyllin, TAARD, Activates Human Natural Killer Cells to Secrete Interferon-Gamma via Toll-Like Receptor-Mediated NF-κB and STAT3 Signaling Pathways

Natural products and their derivatives have long been used as pharmacological agents in the fight against cancer. Human natural killer (NK) cells are critical in our immune system in that they are capable of destroying tumor cells directly. However, there are few reports that elucidate the role of natural products in activating NK cells. In this study, we discovered that a synthetic disaccharide derivative of diphyllin, 4-O-{[2′′,3′′,4′′-tri-O-acetyl-α-D-arabinopyranosyl-(1′′→4′)]-2′,3′-di-O-acetyl-α-L-rhamnopyranosyl}diphyllin (TAARD), can alone stimulate interferon (IFN)-γ secretion in primary human NK cells and the NKL cell line. Additionally, it had an additive effect with IL-12 or IL-15 on IFN-γ production, but little adverse effects on NK cells. Mechanistically, TAARD induced the phosphorylation of NF-κB and STAT3, resulting in their binding on the IFNG promoter, which was dependent on TLR1 and TLR3 signaling, respectively. STAT3 and NF-κB knockdown with lentivirus shRNA as well as the NF-κB-specific inhibitor, N-tosyl-l-phenylalaninechloromethyl ketone, significantly suppressed TAARD-induced IFN-γ generation in primary NK cells. Blockade of TLR1 and TLR3 with neutralizing antibodies considerably decreased TAARD-induced activation of NF-κB and STAT3, respectively, as well as IFN-γ generation in NK cells. Collectively, our data suggest that TAARD can induce NK cell IFN-γ production through TLR1-NF-κB and TLR3-STAT3 signaling pathways, rendering its potential use as an agent for cancer prevention or treatment.

Determination of Tiadinil and Its Metabolite in Flue-Cured Tobacco

A novel and sensitive method was developed for the determination of residues of tiadinil and its metabolite, 4-methyl-l,2,3-thiadiazole-5-carboxylic acid, in flue-cured tobacco. The pesticides were extracted with acetone and purified by gel permeation chromatography and solid-phase extraction. Analysis was performed by ultra-performance liquid chromatography-tandem mass spectrometry in negative ionization mode. Two precursor-product ion transitions were monitored for both compounds in the multiple reaction monitoring mode. Quantification was conducted by using matrix-matched standard calibration. Recovery values of the proposed method for tiadinil ranged from 72.5 to 98.2%, with relative standard deviations ranging from 3.8 to 9.5%; recovery values for 4-methyl-l,2,3-thiadiazole-5-carboxylic acid ranged from 75.4 to 103.3% with RSDs ranging from 3.7 to 9.3%. The limit of quantification for both compounds was 0.01 mg/kg. This method is valuable for residual analysis, quality control and monitoring of tiadinil and its metabolite, 4-methyl-l,2,3-thiadiazole-5-carboxylic acid, in tobacco.