Synergistic anticancer effects of ginsenoside CK and gefitinib against gefitinib-resistant NSCLC by regulating the balance of angiogenic factors through HIF-1α/VEGF.

Drug resistance is a serious problem for gefitinib in the treatment of lung cancer. Ginsenoside CK, a metabolite of diol ginsenosides, have many excellent pharmacological activities, but whether ginsenoside CK can overcome gefitinib resistance remains unclear. In our study, the sensitizing activity of ginsenoside CK on gefitinib-resistant non-small cell lung cancer (NSCLC) in vitro and in vivo was investigated. Ginsenoside CK was confirmed to enhance the anti-proliferation, pro-apoptotic and anti-migration effects of gefitinib in primary and acquired resistant NSCLC. Furthermore, the combined administration of CK and gefitinib effectively promoted the sensitivity of lung cancer xenograft to gefitinib in vivo, and the tumor inhibition rate reached 70.97% (vs. gefitinib monotherapy 32.65%). Subsequently, tubule formation experiment and western blot results showed that co-treatment of ginsenoside CK inhibited the angiogenesis ability of HUVEC cells, and inhibited the expression of HIF-1α, VEGF, FGF and MMP2/9. More interestingly, ginsenoside CK co-treatment enhanced the expression of anti-angiogenic factor PF4, increased pericellular envelope, and promoted the normalization of vascular structure. In conclusion, ginsenoside CK improved the resistance of gefitinib by regulating the balance of angiogenic factors through down-regulating the HIF-1α/VEGF signaling pathway, providing a theoretical basis for improving the clinical efficacy of gefitinib and applying combined strategies to overcome drug resistance.

Selumetinib overcomes gefitinib primary and acquired resistance by regulating MIG6/STAT3 in NSCLC.

Gefitinib, as the first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has achieved great advances in the treatment of non-small cell lung cancer (NSCLC), but drug resistance will inevitably occur. Therefore, exploring the resistance mechanism of gefitinib and developing new combination treatment strategies are of great importance. In our study, the results showed that selumetinib (AZD6244) synergistically inhibited the proliferation of NSCLC with gefitinib. Selumetinib also enhanced gefitinib-induced apoptosis and migration inhibition ability in gefitinib-resistant lung cancer cell lines. Subsequently, the negative regulation between MIG6 and STAT3 was observed and verified through the STRING database and western blotting assays. Sustained activation of STAT3 was significantly downregulated when co-treatment with selumetinib in gefitinib-resistant cells. However, the downregulation of p-STAT3, resulting from the combination of selumetinib and gefitinib was counteracted by the deletion of MIG6, suggesting that selumetinib enhanced gefitinib sensitivity by regulating MIG6/STAT3 in NSCLC. In contrast, p-STAT3 was further inhibited after treatment with gefitinib and selumetinib when MIG6 was overexpressed. Furthermore, the combined administration of selumetinib and gefitinib effectively promoted the sensitivity of lung cancer xenografts to gefitinib in vivo, and the tumor inhibition rate reached 81.49%, while the tumor inhibition rate of the gefitinib monotherapy group was only 31.95%. Overall, MIG6/STAT3 negative regulation plays an important role in the sustained activation of STAT3 and the resistance to EGFR-TKIs. Our study also suggests that EGFR-TKIs combined with MEK1/2 inhibitors, such as selumetinib, may be beneficial to those NSCLC patients who develop a primary or acquired resistance to EGFR-TKIs, providing theoretical support for combining TKIs and selumetinib in clinical cancer treatment.

Ginsenosides: a potential natural medicine to protect the lungs from lung cancer and inflammatory lung disease.

Lung cancer is the malignancy with the highest morbidity and mortality. Additionally, pulmonary inflammatory diseases, such as pneumonia, acute lung injury, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF), also have high mortality rates and can promote the development and progression of lung cancer. Unfortunately, available treatments for them are limited, so it is critical to search for effective drugs and treatment strategies to protect the lungs. Ginsenosides, the main active components of ginseng, have been shown to have anti-cancer and anti-inflammatory activities. In this paper, we focus on the beneficial effects of ginsenosides on lung diseases and their molecular mechanisms. Firstly, the molecular mechanism of ginsenosides against lung cancer was summarized in detail, mainly from the points of view of proliferation, apoptosis, autophagy, angiogenesis, metastasis, drug resistance and immunity. In in vivo and in vitro lung cancer models, ginsenosides Rg3, Rh2 and CK were reported to have strong anti-lung cancer effects. Then, in the models of pneumonia and acute lung injury, the protective effect of Rb1 was particularly remarkable, followed by Rg3 and Rg1, and its molecular mechanism was mainly associated with targeting NF-κB, Nrf2, MAPK and PI3K/Akt pathways to alleviate inflammation, oxidative stress and apoptosis. Additionally, ginsenosides may also have a potential health-promoting effect in the improvement of COPD, asthma and PF. Furthermore, to overcome the low bioavailability of CK and Rh2, the development of nanoparticles, micelles, liposomes and other nanomedicine delivery systems can significantly improve the efficacy of targeted lung cancer treatment. To conclude, ginsenosides can be used as both anti-lung cancer and lung protective agents or adjuvants and have great potential for future clinical applications.

Development of Flowers Buds and Mixed Buds in the Dichasial Inflorescence of Geranium koreanum Kom. (Geraniaceae).

Flower bud differentiation is of great significance for understanding plant evolution and ecological adaptability. The development of flower buds and mixed buds in the dichasial inflorescence of Geranium koreanum was described in this paper. The morphogenesis, surface structure, and organ morphology at different growth stages of G. koreanum buds were examined in detail using scanning electron microscope and stereo microscope. The development of mixed buds started from the flattened apical meristem. The stipule and leaf primordia arose first. Subsequently, the hemispherical meristem was divided into two hemispheres, forming a terminal bud and floral bud primordia, followed by lateral bud differentiation. The formation of the terminal and lateral buds of G. koreanum was sequential and their differentiation positions were also different. The floral bud primordia would develop into two flower units and four bracts. The primordia of a flower bud first formed the sepal primordia, then the stamen and petal primordia, and finally the pistil primordia. Compared to the stamen primordia, the growth of the petal primordia was slower. Finally, all organs, especially the petals and pistil, grew rapidly. When the pistil and petals exceeded the stamens and the petals changed color, the flower bud was ready to bloom.

Engineering the Electronic Interaction between Atomically Dispersed Fe and RuO2 Attaining High Catalytic Activity and Durability Catalyst for Li-O2 Battery.

It is significant to develop catalysts with high catalytic activity and durability to improve the electrochemical performances of lithium-oxygen batteries (LOBs). While electronic metal-support interaction (EMSI) between metal atoms and support has shown great potential in catalytic field. Hence, to effectively improve the electrochemical performance of LOBs, atomically dispersed Fe modified RuO2 nanoparticles are designed to be loaded on hierarchical porous carbon shells (FeSA -RuO2 /HPCS) based on EMSI criterion. It is revealed that the Ru-O-Fe1 structure is formed between the atomically dispersed Fe atoms and the surrounding Ru sites through electron interaction, and this structure could act as the ultra-high activity driving force center of oxygen reduction/evolution reaction (ORR/OER). Specifically, the Ru-O-Fe1 structure enhances the reaction kinetics of ORR to a certain extent, and optimizes the morphology of discharge products by reducing the adsorption energy of catalyst for O2 and LiO2 ; while during the OER process, the Ru-O-Fe1 structure not only greatly enhances the reaction kinetics of OER, but also catalyzes the efficient decomposition of the discharge products Li2 O2 by the favorable electron transfer between the active sites and the discharge products. Hence, LOBs based on FeSA-RuO2 /HPCS cathodes show an ultra-low over-potential, high discharge capacity and superior durability.

Constructing a Redox-Active Cu(I)-Pyridyltriazine Framework for Catalytic Photoreduction of Nitrobenzenes and Carboxylic Cyclization of Alkynol with CO2.

A redox-active metal-organic framework, Cu(I)-TPT, was synthesized by combination of Cu(I), the halogenoid cyanide group (CN), and redox-active organic bridging ligand 2,4,6-tri(4-pyridyl)-1,3,5-triazine (TPT) into one single framework. Cu(I)-TPT displays a two-dimensional (2D) plane structure by 1D -Cu(I)-CN- chains connected with TPT ligands. Cu(I)-TPT exhibits intrinsic semiconductive features with a moderate bandgap energy (1.97 eV). Under irradiation, Cu(I)-TPT has an electrical conductivity of 2 × 10-7 S cm-1 in the presence of the sacrificial electron donor ethanol under the ambient test conditions, which is owing to the π-π stacking interactions between TPT moieties, the d-π conjugation between the Cu(I) ion and the CN ligands, and the permanent microporosity. Cu(I)-TPT displayed highly efficient hole-electron separation and ordered electron transfer, which is beneficial for the photoreduction of nitrobenzene. In addition, Cu(I)-TPT displays high efficiency in carboxylic cyclization of alkynol with CO2 because it possesses highly decentralized Cu(I) catalytic sites to the active C≡C bond of alkynol and affluent N atoms on the 2D sheets to facilitate the trapping and activation of CO2.

A derivant of ginsenoside CK and its inhibitory effect on hepatocellular carcinoma.

Epidemiological studies have shown that hepatocellular carcinoma (HCC) is a main cause of tumor death worldwide. Accumulating data indicate that ginsenoside CK is an effective compound for preventing HCC growth and development. However, improvement of pharmaceutical effect of the ginsenoside CK is still needed. In our study, we performed acetylation of ginsenoside CK (CK-3) and investigated the antitumor effects of the derivative in vitro and in vivo. The cytotoxicity analysis revealed that compared with CK, CK-3 could inhibit the proliferation of multiple tumor cell lines at a lower concentration. Treating with CK-3 on HCC cells arrested cell cycle in G2/M phase and induced cell apoptosis through AO/EB staining, TUNEL analysis and flow cytometry. Meanwhile, CK-3 significantly inhibited tumor growth in an HCC xenograft model and showed no side effect on the function of the main organs. Mechanistically, whole transcriptome analysis revealed that the antitumor effect of CK-3 was involved in the Hippo signaling pathway. The immunoblotting and immunofluorescence results illustrated that CK-3 directly facilitated the phosphorylation of YAP1 and decreased the expression of the main transcription factor TEAD2 in HCC cell lines and tumor tissue sections. Collectively, our results demostrate the formation of a new derivative of ginsenoside CK and its regulatory mechanism in HCC, which could activate the Hippo-YAP1-TEAD2 signaling pathway to regulate HCC progression. This research could provide a new direction for traditional Chinese medicine in the therapy of tumors.

Efficient Modulation of Electron Pathways by Constructing a MnO2-x@CeO2 Interface toward Advanced Lithium-Oxygen Batteries.

A major challenge for Li-O2 batteries is to facilely achieve the formation and decomposition of the discharge product Li2O2, and the development of an active and synergistic cathode is of great significance to efficiently accelerate its formation/decomposition kinetics. Herein, a novel strategy is presented by constructing a MnO2-x@CeO2 heterostructure on the porous carbon matrix. When it was used as a cathode for Li-O2 batteries, excellent electrochemical performances, including low overpotential, large discharge capacity, and superior cycling stability were obtained. Series theoretical calculations were conducted to reveal the mechanism for the reversible battery reactions and explain how Li2O2 interacts with the MnO2-x@CeO2 interface. Apart from the electronic ladders formed between MnO2-x 3d and CeO2 4f orbitals, which can act as a highly efficient "electron transfer expressway", the specific adsorption of MnO2-x and CeO2 with Li2O2 molecules contributes to the enhanced anchoring force of Li2O2 and delocalization of the electron cloud on the Li-O bond. Thanks to the constructed heterostructure and synergistic effect, filmlike Li2O2 can be formed through a surface pathway, and when charging, it accelerates the separation of electrons and Li+ in Li2O2, thus achieving fast redox kinetics and low overpotential.

Insight on structural modification, biological activity, structure-activity relationship of PPD-type ginsenoside derivatives.

Ginsenosides, characterized by triterpenoid, are one of the active components of ginseng. Among them, PPD-type ginsenosides have potent and diverse pharmacological activities, while the effective applications and clinical studies are limited by the poor stability, water solubility and oral bioavailability. In this review, we have attempted to demonstrate the structural-activity relationship of chemical modifications on the dammarane-type skeleton and the C-17 side chain, noting that certain structurally modified derivatives exhibit satisfactory pharmacological activity. This review will provide ideas for the design and synthesis of novel PPD derivatives, and valuable help for the further study of PPD derivatives to make it realize clinical application.

Transfer learning-based highway crash risk evaluation considering manifold characteristics of traffic flow.

The main objective of this study is to evaluate highway crash risk and improve the spatial and temporal transferability of crash risk models. The predictive performance is affected by the difficulty of existing models to quantify crash risk from historical traffic flow data at different locations and times and may not fully capture the complex nonlinear relationships between high-dimensional factors in traffic flow states. Oregon US26W freeway data from 2016 and 2017 and I5N freeway data from 2017 were used. Raw detector data collected from two consecutive detector stations upstream-downstream detector stations were converted into 30 traffic variables. The averages, standard deviations, and coefficients of variation were obtained by aggregating traffic values using each lane. Candidate variables for traffic flow were extracted, and the importance of each variable was calculated using LightGBM, which reveals that variable differences between lanes contributed more. The manifold distance was then applied to quantify the crash risk and classify traffic crashes or not. When the manifold distance is 0.4, it could effectively distinguish traffic crashes. TransferBoost was further employed to build a crash risk model. Modeling using 2016 and 2017 data from the US26W freeway revealed a significant decrease in AUC and a gradual decrease in the model's sensitivity. However, the crash risk prediction performance of TransferBoost improved by 5.2% when modeling using 2017 data from US26W and I5N freeways. The results show that the model developed for one time period cannot be directly used to predict crash risk for another period on the same freeway. However, the model developed for one highway cannot be directly used to predict the crash risk of another highway either, maintaining some transferability at low false alarm rates. TransferBoost provides a fresh perspective on the transferability of the model. The findings of this study could facilitate more accurate proactive safety management and improvement countermeasure development.

Enhanced Electrochemical O2 -to-H2 O2 Synthesis Via Cu-Pb Synergistic Interplay.

Electrocatalytic reduction of oxygen (O2 ) to produce hydrogen peroxide (H2 O2 ) frequently suffers from the low activity and poor selectivity of catalysts owing to the lack of systematic strategies. The resulting enhancement to enable the further design of a new bimetallic catalyst with the synergistic interplay, as exemplified by Cu-Pb catalyst for two-electron oxygen reduction reaction (2e- ORR), is reported here. Critically, in-depth evidence, including density functional theory (DFT) calculations, electrochemical signals, in-situ Raman, and H2 O2 -proof work, allude to a catalytic favor to the 2e- ORR of Cu-Pb.

Three-dimensional carbon dots/Prussian blue analogues nanocubes /nickel foams as self-standing electrodes for high-performance hybrid electrochemical capacitors.

Developing the high-performance supercapacitors is overwhelmingly dependent on the composition design and structure tailoring of electrode materials. By a one-step solution method, the composite of carbon dots/Prussian blue analogues nanocubes-incorporated three-dimensional Ni foams was prepared and used as a self-standing positive electrode for hybrid electrochemical capacitors (HEC). Aside from the role of Ni source for Prussian blue analogues (PBA), Ni foams acts as 3D conductive supports, making electrolytes more accessible to the internal surface of electrode. Meanwhile, carbon dots can be absorbed for the formation of carbon dots/PBA nanocubes on Ni foams surfaces, offering optimized interfaces for the interactions between electrodes and electrolytes and relieving the decomposition of PBA in alkaline electrolyte. With these merits, the carbon dots/Prussian blue analogues nanocubes-Ni foams electrode in the hybrid electrolyte of 0.5 M KOH and 1.3 M Na2SO4 exhibits a maximum specific capacity of 659 C g-1 at current density of 0.5 A g-1 and 344 C g-1 even under large current density of 5 A g-1. An extended working potential window of 1.8 V, high energy density of 65 Wh kg-1 and high power density of 4.052 kW kg-1 as well as improved cyclic stability are also achieved in the assembled HEC. This study builds a boulevard to improve the application potential of PBA in HEC, which will be beneficial for the development of supercapacitors.

Tagging Peptides with a Redox Responsive Fluorescent Probe Enabled by Photoredox Difunctionalization of Phenylacetylenes with Sulfinates and Disulfides.

Herein, we describe a photoredox three-component atom-transfer radical addition (ATRA) reaction of aryl alkynes directly with dialkyl disulfides and alkylsulfinates, circumventing the utilization of chemically unstable and synthetically challenging S-alkyl alkylthiosulfonates as viable addition partners. A vast array of (E)-ß-alkylsulfonylvinyl alkylsulfides was prepared with great regio- and stereoselectivity. Moreover, this powerful tactic could be employed to tag cysteine residues of complex polypeptides in solution or on resin merging with solid phase peptide synthesis (SPPS) techniques. A sulfonyl-derived redox responsive fluorescent probe could be conveniently introduced on the peptide, which displays green fluorescence in cells while showing blue fluorescence in medium. The photophysical investigations reveal that the red shift of the emission fluorescence is attested to reduction of carbonyl group to the corresponding hydroxyl moiety. Interestingly, the fluorescence change of tagged peptide could be reverted in cells by treatment of H2O2, arising from the reoxidation of hydroxyl group back to ketone by the elevated level of reactive oxygen species (ROS).

Citrinin and α-pyrone derivatives with pancreatic lipase inhibitory activities from Penicillium sp. SCSIO 41302.

One new citrinin monomer derivative (1), and two new natural products α-pyrone analogues (2a and 2b), were isolated from the sponge derived fungus Penicillium sp. SCSIO 41302. Their structures were determined by extensive spectroscopic analysis, chiral-phase HPLC analysis, modified Mosher's method, ECD calculations, and X-ray single-crystal diffraction. Bioactivity screening showed that compounds 2b and 8 exhibited obvious inhibitory activities against pancreatic lipase and acetyl cholinesterase with IC50 values of 48.5 and 4.8 µM, respectively, which indicated that different chiral center between enantiomers (2a and 2b) might result in different biological activities (IC50 value against PL for 2a >100 µg/ml).

Diketopiperazine and enterotoxin analogues from the mangrove derived-soil Streptomyces sp. SCSIO 41400 and their biological evaluation.

A new diketopiperazine, cyclo-(d-8-acetoxyl-Pro-l-Leu) (1), together with eight known compounds (2-9) including three enterotoxins (2-4), four diketopiperazines (5-8) and maltol (9), were isolated from the mangrove derived-soil Streptomyces sp. SCSIO 41400. The planar structures of all compounds were determined from analysis of NMR spectra, MS, optical rotation and comparing with literature data. The absolute configuration of compound 1 was assigned by electronic circular dichroism (ECD). The isolated compounds (1-9) were tested for their acetyl cholinesterase (AChE) and pancreatic lipase (PL) enzyme inhibitory activities. Among them, the new diketopiperazine (1) displayed preferable PL enzyme inhibitory activity with IC50 value of 27.3 µg/mL, while compounds 2, 5 and 6 showed weak PL enzyme inhibitory activity. Further molecular docking simulation exhibited that compound 1 could be well bind with the catalytic pocket of the PL. Besides, compound 9 showed moderate antibacterial activity against Methicillin-resistant Staphylococcus aureus with MIC value of 12.5 µg/mL, which was comparable to that of the positive control ampicillin with MIC value of 3.125 µg/mL.

Au25 Nanoclusters Incorporating Three-Dimensionally Ordered Macroporous In2O3 for Highly Sensitive and Selective Formaldehyde Sensing.

Detection of formaldehyde (FA) in the atmosphere is of significant importance because exposure to FA may cause serious health problems such as sick-house syndrome, leukemia, and cancer. Modifying metal oxide semiconductors (MOSs) with noble metal nanoparticles (NPs) is an efficient method to enhance FA-sensing properties. Herein, a series of Au25 nanocluster (NC)-decorated three-dimensionally ordered macroporous In2O3 materials (Au25/3DOM In2O3) is created, and the loading amount of Au25 NCs was optimized based on FA responses. To reveal the effect of gold size on FA responses, we constructed Au144 NC-loaded 3DOM In2O3 and Au NP (2.9 nm)-modified 3DOM In2O3 and compared their gas-sensing properties with the optimal Au25/3DOM In2O3. The results show that in comparison with its counterparts, the optimal Au25/3DOM In2O3 presents higher sensitivity, shorter response/recovery times, better selectivity, and excellent reproducibility. More attractively, the responses to FA are dependent on the size of Au particles loaded on In2O3. We suggest that the enhanced FA responses for the optimal material are mainly attributed to the electronic and chemical-sensitization effects of Au25 NCs, and the size-dependent effect of FA responses is ascribed to the size of Au NPs affecting the formation of oxygen-adsorbing species. This work provides an efficient way for fabricating noble metal NP-loaded MOSs with tunable gas-sensing properties.

Single-Atom Ru Implanted on Co3 O4 Nanosheets as Efficient Dual-Catalyst for Li-CO2 Batteries.

Li-CO2 battery has attracted extensive attention and research due to its super high theoretical energy density and its ability to fix greenhouse gas CO2 . However, the slow reaction kinetics during discharge/charge seriously limits its development. Hence, a simple cation exchange strategy is developed to introduce Ru atoms onto a Co3 O4 nanosheet array grown on carbon cloth (SA Ru-Co3 O4 /CC) to prepare a single atom site catalyst (SASC) and successfully used in Li-CO2 battery. Li-CO2 batteries based on SA Ru-Co3 O4 /CC cathode exhibit enhanced electrochemical performances including low overpotential, ultra high capacity, and long cycle life. Density functional theory calculations reveal that single atom Ru as the driving force center can significantly enhance the intrinsic affinity for key intermediates, thus enhancing the reaction kinetics of CO2 reduction reaction in Li-CO2 batteries, and ultimately optimizing the growth pathway of discharge products. In addition, the Bader charge analysis indicates that Ru atoms as electron-deficient centers can enhance the catalytic activity of SA Ru-Co3 O4 /CC cathode for the CO2 evolution reaction. It is believed that this work has important implications for the development of new SASCs and the design of efficient catalyst for Li-CO2 batteries.

Radical Anion Promoted Chemoselective Cleavage of Csp2-S Bond Enables Formal Cross-Coupling of Aryl Methyl Sulfones with Alcohols.

A novel formal cross-coupling of aryl methyl sulfones and alcohols affording alkyl aryl ethers via an SRN1 pathway is developed. Two marketed antitubercular drugs were efficiently prepared employing this approach as the key step. A dimsyl-anion initiated radical chain process was revealed as the major pathway. DFT calculations indicate that the formation of a radical anion via nucleophilic addition of alkoxide to the aryl radical is the key step in determining the observed chemoselectivity.

Autocatalytic photoredox Chan-Lam coupling of free diaryl sulfoximines with arylboronic acids.

N-Arylation of NH-sulfoximines represents an appealing approach to access N-aryl sulfoximines, but has not been successfully applied to NH-diaryl sulfoximines. Herein, a copper-catalyzed photoredox dehydrogenative Chan-Lam coupling of free diaryl sulfoximines and arylboronic acids is described. This neutral and ligand-free coupling is initiated by ambient light-induced copper-catalyzed single-electron reduction of NH-sulfoximines. This electron transfer route circumvents the sacrificial oxidant employed in traditional Chan-Lam coupling reactions, increasing the environmental friendliness of this process. Instead, dihydrogen gas forms as a byproduct of this reaction. Mechanistic investigations also reveal a unique autocatalysis process. The C-N coupling products, N-arylated sulfoximines, serve as ligands along with NH-sulfoximine to bind to the copper species, generating the photocatalyst. DFT calculations reveal that both the NH-sulfoximine substrate and the N-aryl product can ligate the copper accounting for the observed autocatalysis. Two energetically viable stepwise pathways were located wherein the copper facilitates hydrogen atom abstraction from the NH-sulfoximine and the ethanol solvent to produce dihydrogen. The protocol described herein represents an appealing alternative strategy to the classic oxidative Chan-Lam reaction, allowing greater substrate generality as well as the elimination of byproduct formation from oxidants.

Atom Transfer Radical Addition to Styrenes with Thiosulfonates Enabled by Synergetic Copper/Photoredox Catalysis.

A synergetic copper/photoredox catalyzed ATRA of styrenes and thiosulfonates is developed. Besides aryl ethylenes, the challenging α-substituted styrenes were employed to construct the benzylic quaternary carbon centers. Owing to the mild conditions as well as the high level of substrate compability, this ATRA could be applied to derivatize bioactive natural products in late stage, and to install fluorophores across alkenes. The mechanistic studies reveal sulfonyl radicals as the key intermediate in the transformation.