Design, synthesis, and biological evaluation of novel protopanoxadiol derivatives based PROTACs technology for the treatment of lung cancer.

Protopanoxadiol is a key active ingredient derived from Panax ginseng that is well-known to exhibit anti-tumor activity. Previous research focused on the natural protopanaxadiol derivative AD-1 has demonstrated that it possesses broad spectrum anti-tumor activities in vitro and in vivo. However, its limited activity, selectivity, and cell permeability have impeded its therapeutic application. Herein, a series of novel AD-1 derivatives were designed and synthesized based on proteolysis-targeting chimera (PROTAC) technology by linking AD-1 at the C-3 and C-12 positions with pomalidomide through linkers of alkyl chain of differing lengths to achieve the goal of improving the efficacy of the parent compound. Among these synthesized PROTACs, the representative compound A05 exhibited the most potent anti-proliferative activity against A549 cells. Furthermore, mechanistic studies revealed that compound A05 was able to suppress MDM2 expression, disrupt interactions between p53 and MDM2 and readily induce apoptotic death via the mitochondrial apoptosis pathway. Moreover, the in vivo assays revealed that compound A05 exhibited both anti-proliferative and anti-metastatic activities in the zebrafish tumor xenograft model with A549 cells. Together, our findings suggest that AD-1 based PROTACs associated with the degradation of MDM2 may have promising effects for the treatment of lung cancer and this work provide a foundation for future efforts to develop novel anti-tumor agents from natural products.

Potential to Reduce Chemical Fertilizer Application in Tea Plantations at Various Spatial Scales.

Tea is the main commercial crop grown in China, and excessive application of chemical fertilizers in tea plantations is common. However, the potential to reduce chemical fertilizer use in tea plantations is unclear. In this study, Zhejiang Province was selected as the research object to systematically analyze the potential for tea plantation chemical-fertilizer reduction at different spatial scales. The geographic information system-based analytic hierarchy process method and Soil and Water Assessment Tool model were used to determine the chemical fertilizer reduction potential at the province scale and watershed scale, respectively. At the field scale, two consecutive years of field experiments were conducted on a tea plantation. Province-level analysis showed that 51.7% of the area had an average total fertilization intensity greater than 350 kg/hm2 and a high reduction potential. Watershed analysis revealed that chemical fertilizer reduction had better potential in reducing total nitrogen and total phosphorus inputs to runoff in the short term, whereas 50% organic fertilizer substitution was the best strategy to achieve long-term effects. The field experiments further proved that organic fertilizer substitution balanced tea growth and environmental protection. This study provides a useful method to investigate strategies to reduce chemical fertilizer use in tea-growing areas.

A versatile luminescent resonance energy transfer (LRET)-based ratiometric upconversion nanoprobe for intracellular miRNA biosensing.

Rational design and fabrication of bio-nanoprobes for intracellular miRNA biosensing are highly desired for early clinical diagnosis and prognosis. Herein, we have developed a versatile LRET-based ratiometric (LBRU) nanoprobe of NaYF4:Yb,Er@NaYF4@NH2-mSiO2/rhodamine B/C-DNA sandwich-structured nanocomposites for intracellular miRNA biosensing. The nanoprobe was composed of NaYF4:Yb,Er@NaYF4 upconversion nanoparticles (energy donor) with an amino functionalized mesoporous silica shell (NH2-mSiO2), rhodamine B (acceptor) loaded into the mesopores of NH2-mSiO2, and the complementary sequences of target miRNA (denoted as C-DNA) acting as recognition species wrapped on the nanocomposite. Due to the LRET behavior between donors and acceptors, the loaded rhodamine B can quench the green upconversion emission of NaYF4:Yb,Er@NaYF4 at 540 nm completely. Moreover, it can be released from the nanocomposite in the presence of target miRNA, which blocked the LRET behavior to "turn on" the green upconversion luminescence. Besides, as the unaffected red upconversion luminescence (at 660 nm) can be used as an internal standard to provide built-in correction for environmental effects, the intensity ratio of upconversion luminescence at 540 and 660 nm (I540/I660) was employed as the output signal to afford an accurate detection of target miRNA. Due to the biocompatibility, high photostability and low auto-fluorescence background, the nanoprobe was successfully utilized to diagnose the intracellular miRNA-21 expression in MCF-7 cells via upconversion fluorescence imaging. We envision that the proposed LBRU nanoprobe has great potential applications in early cancer diagnosis.

Does dual reduction in chemical fertilizer and pesticides improve nutrient loss and tea yield and quality? A pilot study in a green tea garden in Shaoxing, Zhejiang Province, China.

Tea tree (Camellia sinensis) is a valuable and popular cash crop widely planted in tropical and subtropical areas of China. To increase tea yield and quality, high rates of chemical fertilizer and pesticide application have generally been used; however, increasing usage of fertilizers and pesticides does not always proportionally increase tea yield. Indeed, excessive nutrient inputs may cause serious agricultural non-point source pollution. A pilot study on dual reduction in fertilizers and pesticides was conducted in a green tea plantation in Shaoxing, Zhejiang Province, to explore the environmental effects of different fertilizer and pesticide managements (e.g., changes in soil properties and nutrient accumulation, nutrient inputs in runoff water) and to reveal the potential effects of the interaction of these two managements on tea yield and quality. Traditional formulas and rates of chemical fertilizers and pesticides were used as the baselines (100% usage); replacement with different proportions of organic fertilizer (i.e., 20%, 50% and 80%) and direct pesticide reductions of 30%, 50%, and 80% were tested. The results showed that proper management with organic fertilizer replacement can effectively mitigate soil acidification and nutrient deficiency in tea plantations, increase soil organic matter (OM) and ammonium nitrogen (NH4-N) contents, and promote tea yield and quality. Moreover, managements with organic fertilizer replacement can markedly reduce the inputs of ammonium nitrogen (NH4-N), nitrate nitrogen (NO3-N), total phosphorus (TP), and total potassium (TK) in runoff water. Soil nutrient accumulation was the highest while the runoff nutrient input was the lowest at 20% organic fertilizer replacement. Experimental spraying of bifenthrin and chlorfenapyr revealed that these pesticides were mainly trapped by the tea leaves and rarely entered the soil or water bodies. Although pesticide reduction treatments can effectively decrease pesticide residues in tea leaves, differences in pesticide residue between various treatments were not obvious due to the rapid degradation of pesticides. Multivariate analysis of variance showed that 50% of the variation in tea yield, bud density, polyphenols, and caffeine can be explained by interactions between fertilizers and pesticides. Combinations of 20% or 50% organic fertilizer replacement and 30% or 50% pesticide application reduction are appropriate for both mitigating nutrient loss and balancing tea yield and quality, especially the combination of 50% organic fertilizer replacement and 50% pesticide reduction, which produced the best results. This study demonstrates the feasibility of dual reductions in fertilizers and pesticides for mitigating environmental hazards while maintaining the yield and quality of tea.

Porous Magnetic Pseudo-Carbon Paste Electrode Electrochemical Biosensor for DNA Detection.

A novel and sensitive electrochemical sensor based on magnetic porous pseudo-carbon paste electrode (MPPCPE) for DNA detection was described in this study. The MPPCPE was fabricated by mixing polymethyl methacrylate (PMMA) microspheres, as template, graphite powders, as filler, pyrrole, as precursor of polymer and magnetic powder. It was demonstrated that the fabricated MPPCPE had more sensitivity for detecting DNA when compared with magnetic carbon paste electrode (MPCPE). Results from anodic stripping voltammetry (ASV) experiments showed that the Ag peak current versus concentration of complementary DNA at MPPCPE had two linear regions. The first region demonstrated linearity over a concentration range from 0.5 to 20 nM, with correlation coefficient of 0.992, while the second linear region had concentration of complementary DNA at 0.005 to 0.1 nM range, with correlation coefficient of 0.957. The detection limit was as low as 0.005 nM and the electrochemical sensor was easy to preserve for a long time, and had good reusability and stability.