A mitochondria-targeting dihydroartemisinin derivative as a reactive oxygen species -based immunogenic cell death inducer.

Immunogenic cell death (ICD) can activate the anticancer immune response and its occurrence requires high reliance on oxidative stress. Inducing mitochondrial reactive oxygen species (ROS) is a desirable capability for ICD inducers. However, in the category of ICD-associated drugs, numerous reported ICD inducers are a series of anthracyclines and weak in ICD induction. Herein, a mitochondria-targeting dihydroartemisinin derivative (T-D) was synthesized by conjugating triphenylphosphonium (TPP) to dihydroartemisinin (DHA). T-D can selectively accumulate in mitochondria to trigger ROS generation, leading to the loss of mitochondrial membrane potential (ΔΨm) and ER stress. Notably, T-D exhibits far more potent ICD-inducing properties than its parent compound. In vivo, T-D-treated breast cancer cell vaccine inhibits metastasis to the lungs and tumor growth. These results indicate that T-D is an excellent ROS-based ICD inducer with the specific function of trigging vigorous ROS in mitochondria and sets an example for incorporating artemisinin-based drugs into the ICD field.

Rh(III)-Catalyzed Reaction of 4-Diazoisochroman-3-imines with (2-Formylaryl)boronic Acids To Access a Straightforward Construction of 5H-Isochromeno[3,4-c]isoquinolines.

An Rh(III)-catalyzed one-pot synthesis of 5H-isochromeno[3,4-c]isoquinolines from readily available 4-diazoisochroman-3-imines and (2-formylphenyl)boronic acids is reported. The cascade annulation involves a Rh(III)-catalyzed cross-coupling and an intramolecular nucleophilic addition-elimination process. A series of biologically important 5H-isochromeno[3,4-c]isoquinolines were obtained in good to excellent yields. The method can be extended to synthesize 7H-isochromeno[3,4-b]thieno[3,2-d]pyridines and 7H-isochromeno[3,4-b]thieno[2,3-d]pyridines from the corresponding heteroaryl boronic acids.

Investigation of adsorption-diffusion behaviors of elementary O2, CO2, and N2 in coal particles: influence from temperature.

Adsorption-diffusion behaviors of gases (i.e., O2, CO2, and N2) in coal are directly related to the coal spontaneous combustion (CSC), in which the temperature is the key factor affecting the gas migration process in coal. In this work, isothermal adsorption experiments of O2, CO2, and N2 under different temperatures were carried out on bituminous coal and anthracite coal samples at 0.5 MPa, respectively. Based on the free gas density gradient diffusion (FDGD) model, the microchannel diffusion coefficients of different gases at different temperatures were calculated, and the effects from temperature were quantitatively evaluated. The results acquired from the experiment and simulation show that (i) the adsorption capacity of these three gases decreases as the temperature increases, and the adsorption capacity at the same temperature satisfies CO2 > O2 > N2; (ii) the FDGD model is verified to be still applicable at different temperatures, indicating that the adsorption-diffusion behavior of O2, CO2, and N2 in coal particles at different temperatures is still consistent with the FDGD diffusion; (iii) the microchannel diffusion coefficient Km of the three gases gradually increases when the temperature goes up. The present work contributes to the understanding of the gases migration process in the development of CSC.

Effect of agricultural soil wind erosion on urban PM2.5 concentrations simulated by WRF-Chem and WEPS: A case study in Kaifeng, China.

Dust emission induced by agricultural soil wind erosion is one of the main sources of atmospheric particulate matter (PM) in dryland areas. However, most current air quality models do not consider this emission source, resulting in large uncertainties in PM simulations. Here we estimated the agricultural PM2.5 (particulate matter with an aerodynamic diameter <2.5 µm) emission around Kaifeng, a prefecture-level city in central China, using the Wind Erosion Prediction System (WEPS), with the MEIC (Multi-resolution Emission Inventory for China) as an anthropogenic emission source. We then plugged these estimates into the Weather Research and Forecasting model coupled with chemistry (WRF-Chem) to simulate an air pollution episode in Kaifeng, China. Results showed that the addition of agricultural soil PM2.5 emissions significantly improved the ability of WRF-Chem to accurately simulate PM2.5 concentrations. The PM2.5 concentration mean bias and correlation coefficient of not considered and considered agricultural dust emission were -72.35 µg m-|3 and 3.31 µg m-|3 and 0.3 and 0.58, respectively. The PM2.5 emitted by the agricultural soil wind erosion contributed around 37.79% of the PM2.5 in the Kaifeng municipal district during this pollution episode. This study confirmed that the dust emission caused by agricultural soil wind erosion can significantly impact urban PM2.5 concentrations which surrounded by large areas of farmland, and also indicated that coupling dust emissions from farmland with anthropogenic air pollutant emissions can improve the accuracy of air quality models.

New Models for Estimating the Sorption of Sulfonamide and Tetracycline Antibiotics in Soils.

Sulfonamides (SAs) and tetracyclines (TCs) are two classes of widely used antibiotics. There is a lack of easy models for estimating the parameters of antibiotic sorption in soils. In this work, a dataset of affinity coefficients (Kf and Kd) of seven SA/TC antibiotics (i.e., sulfachlorpyridazine, sulfamethazine, sulfadiazine, sulfamethoxazole, oxytetracycline, tetracycline, and chlortetracycline) and associated soil properties was generated. Correlation analysis of these data showed that the affinity coefficients of the SAs were predominantly affected by soil organic matter and cation exchange capacity, while those of the TCs were largely affected by soil organic matter and pH. Pedotransfer functions for estimating Kf and Kd were built by multiple linear regression analysis and were satisfactorily validated. Their performances would be better for soils having higher organic matter content and lower pH. These pedotransfer functions can be used to aid environmental risk assessment, prioritization of antibiotics and identification of vulnerable soils.

Transdermal Delivery of Metformin Utilizing Ionic Liquid Technology: Insight Into the Relationship Between Counterion Structures and Properties.

PURPOSE: The purpose of the present study was to explore the feasibility of transdermal delivery of metformin, a commonly used oral antidiabetic drug, by ionic liquid (IL) technology. METHODS: Metformin hydrochloride (MetHCl) was first transformed into three kinds of ILs with different counterions. The physicochemical properties of the obtained ILs were characterized in depth. The simulation of stable configuration and calculation of interaction energies were conducted based on density functional theory (DFT). Skin-PAMPA was used to evaluate the intrinsic transdermal permeation properties. The cytotoxicity assay of these ILs was conducted using HaCaT cells to evaluate the toxicity to skin. These metformin ILs were then formulated into transdermal patch, and the transdermal potential was further evaluated using in vitro dissolution test and skin permeation assay. Finally, the pharmacokinetic profiles of these metformin IL-containing patches were determined. RESULTS: Among all the three Met ILs, metformin dihexyl sulfosuccinate (MetDH) with proper overall physiochemical and biological properties demonstrated the highest relative bioavailability. Metformin docusate (MetD) with the highest lipophilicity and intrinsic transdermal permeability exhibited the most significant sustained release profile in vivo. Both MetDH and MetD were the promising candidates for further clinical investigations. CONCLUSIONS: Overall, the properties of ILs were closely related to the structures of counterion. IL technology provided the opportunities to finely tune the solid-state and biological properties of Metformin and facilitated the successful delivery by transdermal route.

Cu(II)-Catalyzed Synthesis of 4-(1,4,5,6-Tetrahydropyridin-3-yl)-1,4-dihydroisoquinolin-3-ones from 4-Diazoisoquinolin-3-ones.

We report a simple, efficient, and highly selective C-H bond insertion of copper carbenes generated in situ from 4-diazo-1,4-dihydroisoquinolin-3-ones into ß-C(sp2)-H bonds of N-sulfonyl enamides, which gave a series of 4-(1,4,5,6-tetrahydropyridin-3-yl)-1,4-dihydroisoquinolin-3(2H)-ones in good to excellent yields. Operationally simple and mild reaction conditions, a cheap catalyst, readily accessible starting materials, and a broad substrate scope are the merits of this reaction.

Rh(III)-Catalyzed C-H bond activation/annulation reactions of arylacyl ammonium salts with 4-diazoisochroman-3-imines and 4-diazoisoquinolin-3-ones.

Herein, we report a C-H bond functionalization strategy for the construction of oxo- and aza-spirocyclic compounds from diazo compounds as coupling partners. Our method comprises ortho sp2 C-H bond activation of arylacyl ammonium salts, followed by coupling with two types of cyclic diazo compounds i.e. 4-diazoisochroman-3-imines and 4-diazoisoquinolin-3-ones, respectively. The mechanism involves the formation of dual metal carbene intermediates in situ with the breakage of oxidizing C-N bonds in arylacyl ammonium salts. The cascade C-H activation/annulation process gave a variety of novel spiro[indene-1,4'-isochromane]-3,3'(2H)-diones and spiro[indene-1,4'-isoquinoline]-3,3'(2H)-diones in good to excellent yields. Readily available starting materials, broad substrate scope, and operationally simple and mild reaction conditions are the prominent features of this method.

Inhibition of the Inflammasome Activity of NLRP3 Attenuates HDM-Induced Allergic Asthma.

Inhaled allergens promote inflammatory response, tissue damage, and airway hyperresponsiveness in the lungs, leading to allergic asthma. NLRP3, as an immune sensor of infections and cellular stress, is associated with the development and exacerbation of asthma. However, the mechanism by which NLRP3 affects asthma requires further investigation. Here, we showed that inhaled house dust mite (HDM) promotes NLRP3 inflammasome activation in the lungs and specifically induces the maturation of caspase-1 and IL-1ß in alveolar macrophages (AMs). Using Nlrp3-mutant mice, we found that NLRP3 promotes the inflammatory response and pathogenesis in HDM-induced allergic asthma in an inflammasome-dependent manner. Treatment with RRx-001, an NLRP3 inhibitor, significantly reduced inflammatory cell infiltration and mucus secretion in the airway. Our results showed that NLRP3 in myeloid cells promoted the development and progression of allergic asthma in an inflammasome-dependent manner. Small molecules targeting the NLRP3 inflammasome may provide new treatment options for this disease.

Development of gliclazide ionic liquid and the transdermal patches: An effective and noninvasive sustained release formulation to achieve hypoglycemic effects.

Ionic liquids (IL) technology provides a useful platform to achieve the topical delivery of therapeutic agents, because of its capability to improve skin permeability. While the majority of the researches aimed to achieve local action by topical IL delivery, systemic action of therapeutic agents by local topical application has rarely been reported. In the present work, Gliclazide (GLI), a second-generation sulfonylurea drug was transformed into an IL with tributyl(tetradecyl)phosphonium for the first time. The physicochemical properties of this IL were systematically characterized by DSC, TGA, FT-IR, NMR, and HPLC. The transdermal patch based on this IL was further prepared using DURO-TAK®87-4098. The fabricated gliclazide based ionic liquid [P6,6,6,14][GLI] transdermal patch displayed satisfactory in vitro and in vivo performance. The [P6,6,6,14][GLI] patch released 88.17% of the loaded drug within a 3-day period in the in vitro dissolution test, confirming its sustained release property. Meanwhile, GLI effectively permeated through the artificial skin from [P6,6,6,14][GLI] transdermal patch in the in vitro skin permeation test, with the permeation rate and lag time of 16.571 ± 0.328 µg/cm2/h and 3.027 ± 0.154 h respectively. The [P6,6,6,14][GLI] transdermal patch showed favorable PK profile in rat as compared with GLI oral suspension. The relative bioavailability of GLI reached 92.06% of GLI oral suspension, while the Cmax was significantly reduced. Most importantly, [P6,6,6,14][GLI] transdermal patch demonstrated superior hypoglycemic effect to the oral suspension both in the fasted and fed condition, confirming the feasibility of systemic action by local topical delivery of IL. In addition, the [P6,6,6,14][GLI] transdermal patch caused no skin irritation based on histopathological analysis.

Research on the prediction of dangerous goods accidents during highway transportation based on the ARMA model.

The COVID-19 epidemic has caused a lack of data on highway transportation accidents involving dangerous goods in China in the first quarter of 2020, and this lack of data has seriously affected research on highway transportation accidents involving dangerous goods. This study strives to compensate for this lack to a certain extent and reduce the impact of missing data on research of dangerous goods transportation accidents. Data pertaining to 2340 dangerous goods accidents in the process of highway transportation in China from 2013 to 2019 are obtained with webpage crawling software. In this paper, the number of monthly highway transportation accidents involving dangerous goods from 2013 to 2019 is determined, and the time series of transportation accidents and an autoregressive moving average (ARMA) prediction model are established. The prediction accuracy of the model is evaluated based on the actual number of dangerous goods highway transportation accidents in China from 2017 to 2019. The results indicate that the mean absolute percentage error (MAPE) between the actual and predicted values of dangerous goods highway transportation accidents from 2017 to 2019 is 0.147, 0.315 and 0.29. Therefore, the model meets the prediction accuracy requirements. Then, the prediction model is applied to predict the number of dangerous goods transportation accidents in the first quarter of 2020 in China. Twenty-two accidents are predicted in January, 23 accidents in February and 27 accidents in March. The results provide a reference for the study of dangerous goods transportation accidents and the formulation of accident prevention and emergency measures.

Development of a gliclazide ionic liquid and its mesoporous silica particles: an effective formulation strategy to improve oral absorption properties.

Ionic liquid (IL) technology provides a useful platform to enhance the oral absorption of therapeutic agents. In the present work, gliclazide (GLI), a second-generation sulfonylurea drug was transformed into an IL with tetrabutylphosphonium. The physicochemical properties of this IL were systematically characterized by DSC, TGA, FT-IR, NMR, and HPLC. For the further preparation development, a solution stability test was conducted. GLI-based IL could improve the solution stability in a neutral environment. To assess oral potential, the solubility characteristics including equilibrium solubility, 24 h kinetic saturation solubilities and supersaturation profiles were first explored. Significant enhancement of solubilities, supersaturation ratio and duration of supersaturation was found for the synthesized IL. Computational methodology was utilized to better understand the improved solubility results. From the simulated results, [TBP][GLI] showed a longer time period when the distance between cation and anion was far above the baseline and a higher deviation degree, indicating less stable ion pairs of [TBP][GLI] in an aqueous environment and it being easy for the cation and anion to tear apart and form interactions with water molecules. The prepared [TBP][GLI] exhibited intestinal transportation ability and safety as evidenced by the in vitro gastrointestinal tract artificial membrane permeability assays (GIT-PAMPA) and cytotoxicity experiments with Caco-2 cells. A mesoporous carrier, AEROPERL® 300 Pharma, was chosen to load the IL and then encapsuled into enteric capsules. The prepared oral capsules containing GLI-based IL loaded mesoporous silica particles released fast and could realize 100% release within 60 min.

Preparation and Properties of Cellulose-Based Films Regenerated from Waste Corrugated Cardboards Using [Amim]Cl/CaCl2.

1-Ally-3-methylimidazolium chloride ([Amim]Cl), dimethyl sulfoxide (DMSO), and CaCl2 were selected to construct dissolution systems to produce value-added products from pretreatment of waste corrugated cardboards (P-WCCs). The dissolution behaviors of P-WCCs before and after ball milling were studied in different dissolution systems. The regenerated cellulose films were quickly and efficiently prepared via dissolving, regenerating, and pressurized drying. When 4 wt % waste corrugated cardboard was dissolved in [Amim]Cl for 4 h at 90 °C, the regenerated cellulose films featured tensile strengths as high as 59.00 MPa. Adding 40% DMSO and 2 wt % CaCl2 increased the tensile strength of the film to a maximum value of 85.86 MPa. This demonstrates that DMSO improves the ability of WCC to dissolve in ionic liquids; Ca2+ improves the tensile strength and thermal stability of the regenerated cellulose film but reduces its transparency. This work provides a new, simple, and highly efficient way to use WCCs for packaging and wrapping.

Preparation and characterization of ß-cyclodextrin-oregano essential oil microcapsule and its effect on storage behavior of purple yam.

BACKGROUND: Natural plant essential oils have antimicrobial properties; however, essential oils are difficult to maintain in a system because of their volatile nature. First, we prepared microcapsules from ß-cyclodextrin and oregano essential oil and characterized their properties. Second, the effect of microcapsules on the preservation of freshly cut purple yam was studied using an edible coating technique. Purple yams immersed in distilled water were used as control, and their characteristics were compared with yams coated with citric acid, citric acid + sodium alginate, and citric acid + sodium alginate + ß-cyclodextrin-oregano essential oil microcapsules (CA-SA-MC) and stored at 4 °C for 5 days. RESULTS: Microcapsules of oregano essential oil and ß-cyclodextrin solution were successfully prepared via the inclusion method, with an optimal encapsulation efficiency of 55.14%. Scanning electron microscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis showed strong bonds between ß-cyclodextrin and oregano essential oil. All edible coatings, particularly CA-SA-MC, significantly (P ≤ 0.05) maintained firmness, total soluble solids, ascorbic acid content, and anthocyanin content compared with control treatment. This treatment also prevented browning and extended the shelf life of purple yam. CONCLUSION: Oregano essential oil can be successfully encapsulated into cyclodextrin microcapsules. It has a great impact on the shelf life extension of purple yam and could be successfully applied to other fresh produce. © 2020 Society of Chemical Industry.

Preparation and Properties of Cassava Residue Cellulose Nanofibril/Cassava Starch Composite Films.

Because of its non-toxic, pollution-free, and low-cost advantages, environmentally-friendly packaging is receiving widespread attention. However, using simple technology to prepare environmentally-friendly packaging with excellent comprehensive performance is a difficult problem faced by the world. This paper reports a very simple and environmentally-friendly method. The hydroxyl groups of cellulose nanofibrils (CNFs) were modified by introducing malic acid and the silane coupling agent KH-550, and the modified CNF were added to cassava starch as a reinforcing agent to prepare film with excellent mechanical, hydrophobic, and barrier properties. In addition, due to the addition of malic acid and a silane coupling agent, the dispersibility and thermal stability of the modified CNFs became significantly better. By adjusting the order of adding the modifiers, the hydrophobicity of the CNFs and thermal stability were increased by 53.5% and 36.9% ± 2.7%, respectively. At the same time, the addition of modified CNFs increased the tensile strength, hydrophobicity, and water vapor transmission coefficient of the starch-based composite films by 1034%, 129.4%, and 35.95%, respectively. This material can be widely used in the packaging of food, cosmetics, pharmaceuticals, and medical consumables.

Probing the degradation mechanism of forsythiaside A and simultaneous determination of three forsythiasides in Forsythia preparations by a single marker.

Forsythiaside A is the major component of Forsythia suspensa. This study investigated the degradation mechanism of forsythiaside A. Eight degraded components including forsythiaside I, forsythiaside H, forsythiaside E, caffeic acid, suspensaside A, ß-hydroxy forsythiaside I, ß-hydroxy forsythiaside H, and ß-hydroxy forsythiaside A were identified by using ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry. Then, the quantitative analysis of multi-components by a single-marker was performed with ultra-high performance liquid chromatography to simultaneously determine forsythiaside A, forsythiaside H, and forsythiaside I in Forsythia suspensa preparations. The result showed good linear relationships within 2.871-287.1, 0.231-23.1, and 0.983-98.3 µg/mL (r > 0.9998), with average recoveries of 97.7, 95.7, and 95.8% and relative standard deviations of 1.4, 2.4, and 1.8%, respectively. Using forsythiaside A as an internal reference, the relative retention values of forsythiaside H and forsythiaside I to forsythiaside A were calculated to be 0.89 and 0.61, respectively, and the relative correction factors were 0.816 and 0.799, respectively. The method for quantitative analysis of multi-components by a single-marker was applied to evaluate the overall quality of forsythia preparations. There was no significant difference in the measurement results of the method developed and the method of external standard.

The perturbed expression of m6A in parthenogenetic mouse embryos.

Parthenogenetically activated oocytes cannot develop to term in mammals owing to abnormal epigenetic modifications. Methylation of the N6 position of adenosine (m6A) is a post-transcriptional epigenetic modification of RNA. To investigate the role of m6A methylation in parthenogenetic (PA) embryonic development, we analyzed METTL3, METTL14, FTO, ALKBH5, YTHDF2, IGF2BP1, and IGF2BP2 expression by quantitative real-time PCR. These genes were found dynamically expressed during the 2-cell, 4-cell, 8-cell, and blastocyst stages of the embryo. Compared to normally fertilized embryos, the expression of these genes was perturbed in PA embryos, especially at the 8-cell stage. Furthermore, immunofluorescence was used to detect m6A expression. The results demonstrated that m6A expression decreased in the 2-cell stage, whereas it increased in the 8-cell stage of PA embryos. Taken together, these results suggest that the expression of RNA methylation-related genes was perturbed, leading to abnormal m6A modification during early development in PA embryos.

Ascorbic acid improves parthenogenetic embryo development through TET proteins in mice.

The TET (Ten-Eleven Translocation) proteins catalyze the oxidation of 5mC (5-methylcytosine) to 5hmC (5-hydroxymethylcytosine) and play crucial roles in embryonic development. Ascorbic acid (Vc, Vitamin C) stimulates the expression of TET proteins, whereas DMOG (dimethyloxallyl glycine) inhibits TET expression. To investigate the role of TET1, TET2, and TET3 in PA (parthenogenetic) embryonic development, Vc and DMOG treatments were administered during early embryonic development. The results showed that Vc treatment increased the blastocyst rate (20.73 ± 0.46 compared with 26.57 ± 0.53%). By contrast, DMOG reduced the blastocyst rate (20.73 ± 0.46 compared with 11.18 ± 0.13%) in PA embryos. qRT-PCR (quantitative real-time PCR) and IF (immunofluorescence) staining results revealed that TET1, TET2, and TET3 expressions were significantly lower in PA embryos compared with normal fertilized (Con) embryos. Our results revealed that Vc stimulated the expression of TET proteins in PA embryos. However, treatment with DMOG significantly inhibited the expression of TET proteins. In addition, 5hmC was increased following treatment with Vc and suppressed by DMOG in PA embryos. Taken together, these results indicate that the expression of TET proteins plays crucial roles mediated by 5hmC in PA embryonic development.

Determination of the absolute CH4 adsorption using simplified local density theory and comparison with the modified Langmuir adsorption model.

Accurately determining the adsorbed amount of CH4 on shale is significant for understanding the mechanisms of shale gas storage and shale methane recovery from shale gas reservoirs. Excess CH4 adsorption is measured using the thermogravimetric method. Simplified local density (SLD) theory is applied to calculate the adsorbed CH4 density to obtain the absolute adsorption. Moreover, the modified Langmuir adsorption model is employed to fit the excess adsorption to describe the absolute adsorption. The adsorbed CH4 density from the SLD model is affected by the system pressure and temperature, while such density obtained from the modified Langmuir model is only a function of temperature. Compared to the modified Langmuir model, the SLD model can better capture the adsorbed CH4 density, which allows accurate determination of the absolute CH4 adsorption.

Discovery of potent 2,4-difluoro-linker poly(ADP-ribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy.

Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially in breast and ovarian cancers; tumor cells that are deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, we identified a series of 2,4-difluorophenyl-linker analogs (15-55) derived from olaparib as novel PARP1 inhibitors. Four potent analogs 17, 43, 47, and 50 (IC50=2.2-4.4 nmol/L) effectively inhibited the proliferation of Chinese hamster lung fibroblast V-C8 cells (IC50=3.2-37.6 nmol/L) in vitro, and showed specificity toward BRCA-deficient cells (SI=40-510). The corresponding hydrochloride salts 56 and 57 (based on 43 and 47) were highly water soluble in pH=1.0 buffered salt solutions (1628.2 µg/mL, 2652.5 µg/mL). In a BRCA1-mutated xenograft model, oral administration of compound 56 (30 mg·kg-1·d-1, for 21 d) exhibited more prominent tumor growth inhibition (96.6%) compared with the same dose of olaparib (56.3%); in a BRCA2-mutated xenograft model, oral administration of analog 43 (10 mg·kg-1·d-1, for 28 d) significantly inhibited tumor growth (69.0%) and had no negative effects on the body weights. Additionally, compound 56 exhibited good oral bioavailability (F=32.2%), similar to that of olaparib (F=45.4%). Furthermore, the free base 43 of the hydrochloride salt 56 exhibited minimal hERG inhibition activity (IC50=6.64 µmol/L). Collectively, these data demonstrate that compound 56 may be an excellent drug candidate for the treatment of cancer, particularly BRCA-deficient tumors.