3,3'-Diindolylmethane inhibits the proliferation of esophageal squamous cell carcinoma cells via downregulation of STIM1.

3,3'-Diindolylmethane (DIM) is a natural phytochemical derived from cruciferous plants that has inhibitory effects on a wide range of tumor cells; however, its relevant effects on esophageal cancer cells have been poorly studied. Therefore, in the present study, a pharmacology network approach was used to predict the possible core targets of DIM acting on esophageal cancer. Subsequently, using in vitro experiments, TE-1 human esophageal cancer cells were treated with different concentrations of DIM (0, 40, 60 and 80 µM) for 24 h. Changes in cell activity were detected by Cell Counting Kit-8 assay, and changes in the expression levels of stromal interaction molecule 1 (STIM1) and apoptosis-related proteins, B-cell lymphoma-2 (Bcl-2) and Bax, were assessed by western blotting, followed by the upregulation of STIM1 by thapsigargin (Tg). Network pharmacology analysis showed that there were 39 potential core targets of DIM in esophageal cancer. The results of the in vitro experiments showed that DIM could inhibit the viability of esophageal cancer cells, downregulate the expression of STIM1 and Bcl-2 proteins and upregulate the expression of Bax protein, all in a concentration-dependent manner. The results also demonstrated that toxic carotenoids were agonist against STIM1 protein and upregulated STIM1 and Bax protein expression. After agonizing STIM1 protein expression using Tg, DIM was able to counteract the expression trend of STIM1, Bcl-2 and Bax protein in TE-1 cells. In summary, DIM induced apoptosis and inhibited the viability of esophageal cancer cells by downregulating the expression of STIM1 protein; therefore, the natural phytochemical, DIM, may be a potential substance for the early prevention and treatment of esophageal cancer cells.

Spatio-temporal change of winter wheat yield and its quantitative responses to compound frost-dry events - An example of the Huang-Huai-Hai Plain of China from 2001 to 2020.

Extreme climate events such as frost and drought have great influence on wheat growth and yield. Understanding the effects of frost, drought and compound frost-dry events on wheat growth and yield is of great significance for ensuring national food security. In this study, wheat yield prediction model (SCYMvp) was developed by combining crop growth model (CGM), satellite images and meteorological variables. Wheat yield maps in the Huang-Huai-Hai Plain (HHHP) during 2001-2020 were generated using SCYMvp model. Meanwhile, accumulative frost days (AFD), accumulative dry days (ADD) and accumulative frost-dry days (AFDD) in different growth periods of wheat were calculated, and the effects of frost and drought on wheat yield were quantified by the first difference method and linear mixed model. The results showed that wheat yield increased significantly, while the rising trend was obvious at more than half of the regions. Extreme climate events (ECEs) showed a relatively stable change trend, although the change trend was significant only in a few areas. Compared with frost and drought in the early growth period, ECEs in the middle growth period (spring ECEs) had more negative effects on wheat growth and yield. Wheat yield was negatively correlated with spring ECEs, and yield loss was between 4.6 and 49.8 kg/ha for each 1 d increase of spring ECEs. The effects of spring ECEs on wheat yield were ranked as AFDD > AFD > ADD. The negative effect of ADD on wheat yield in the late growth period was higher than that in the other periods. The negative effects of spring ECEs on yield in southern regions were higher than those in northern regions. Overall, due to the adverse effects of frost and drought on wheat yield in the middle and late growth periods, the mean annual yield loss was 6.4 %, among which spring AFD caused the greatest loss to wheat yield (3.1 %). The results have important guiding significance for formulating climate adaptation management strategies.

Targeting KRASG12D mutation in non-small cell lung cancer: molecular mechanisms and therapeutic potential.

Lung malignant tumors are a type of cancer with high incidence and mortality rates worldwide. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung malignant tumors, and most patients are diagnosed at advanced stages, leading to poor prognosis. Over the past decades, various oncogenic driver alterations associated with lung cancer have been identified, each of which can potentially serve as a therapeutic target. Rat sarcoma (RAS) genes are the most commonly mutated oncogenes in human cancers, with Kirsten rat sarcoma (KRAS) being the most common subtype. The role of KRAS oncogene in NSCLC is still not fully understood, and its impact on prognosis remains controversial. Despite the significant advancements in targeted therapy and immune checkpoint inhibitors (ICI) that have transformed the treatment landscape of advanced NSCLC in recent years, targeting KRAS (both directly and indirectly) remains challenging and is still under intensive research. In recent years, significant progress has been made in the development of targeted drugs targeting the NSCLC KRASG12C mutant subtype. However, research progress on target drugs for the more common KRASG12D subtype has been slow, and currently, no specific drugs have been approved for clinical use, and many questions remain to be answered, such as the mechanisms of resistance in this subtype of NSCLC, how to better utilize combination strategies with multiple treatment modalities, and whether KRASG12D inhibitors offer substantial efficacy in the treatment of advanced NSCLC patients.

Research Note: SOCS2 contributes to reduction of the third digit during development of the chicken forelimb.

The development of the avian wing pattern has been the subject of heated debate due to its special shape. The Suppressor of cytokine signaling 2 (SOCS2) gene encodes a negative regulator of growth hormone (GH) signaling and bone growth and is known to be strongly expressed in the third digit of chicken forelimbs. These observations suggest that SOCS2 might regulate the morphology of the avian wing, however, the function of SOCS2 in avian limb development remains unknown. Here, we reexamined SOCS2 expression in successive developmental stages of chicken limb development by in situ hybridization (ISH) and describe extended expression from the posterior of the stypolod to the third digit of the forelimbs. We used the RCAS avian retrovirus to overexpress SOCS2 in the developing chicken limb buds, which resulted in reduced or malformed chicken wings while hindlimbs developed normally. Transcriptome sequencing (mRNA-Seq) revealed changes in expression of genes known to be associated with growth and development in forelimbs with overexpressed SOCS2. This study highlights a pivotal role for SOCS2 during the development of the wing in the chicken and provides new insight into molecular mechanisms regulating avian limb development.

Design, synthesis and anti-necroptosis activity of fused heterocyclic MLKL inhibitors.

Necroptosis is an important form of programmed cell death (PCD), which is mediated by a death receptor and independent of the caspase proteolytic enzyme. Mixed lineage kinase domain-like (MLKL) is the final effector of necroptosis, playing an irreplaceable role in the execution of necroptosis. However, the studies on MLKL inhibitors are in their infancy. Necrosulfonamide (NSA) is an early-discovered covalent MLKL inhibitor, possessing medium anti-necroptosis activity and a structure-activity relationship (SAR) not widely disclosed. In this study, with the covalent motif maintained, we aim to improve the activity by introducing the terminal fused heterocycles and meanwhile revealing the SAR on the part. As a result, compounds 9 and 14 showed the best activity (EC50 = 148.4 and 595.9 nM) against necroptosis among the analogues by covalently binding to MLKL. The SAR was also concluded to guide further structural optimization in this field.

Embryonic and skeletal development of the albino African clawed frog (Xenopus laevis).

The normal stages of embryonic development for wild-type Xenopus laevis were established by Nieuwkoop and Faber in 1956, a milestone in the history of understanding embryonic development. However, this work lacked photographic images and staining for skeleton structures from the corresponding stages. Here, we provide high-quality images of embryonic morphology and skeleton development to facilitate studies on amphibian development. On the basis of the classical work, we selected the albino mutant of X. laevis as the observation material to restudy embryonic development in this species. The lower level of pigmentation makes it easier to interpret histochemical experiments. At 23°C, albino embryos develop at the same rate as wild-type embryos, which can be divided into 66 stages as they develop into adults in about 58 days. We described the complete embryonic development system for X. laevis, supplemented with pictures of limb and skeleton development that are missing from previous studies, and summarized the characteristics and laws of limb and skeleton development. Our study should aid research into the development of X. laevis and the evolution of amphibians.

PbO2 modified BDD electrode by dicationic ionic liquids assisted electrodeposition for efficient electrocatalytic degradation of pesticide wastewater.

Pesticide wastewater is difficult to treat, and it is necessary to develop a new anode material electrochemical oxidation to efficiently degrade pesticide wastewater. DIL-PbO2-Ti/BDD electrodes with better electrocatalytic oxidation performance were obtained by using dicationic ionic liquid (DIL) for assisted electrodeposition of PbO2 modified boron-doped diamond (BDD) electrodes. At a current density of 100 mA cm-2 and a temperature of 25 °C, the DIL-PbO2-Ti/BDD electrode was used as anode and titanium plate as cathode. The electrochemical window and oxygen evolution potential (OEP) of the DIL-PbO2-Ti/BDD electrode obtained by CV testing at a scan rate of 50 mV s-1 in 1 M H2SO4 were 4.12 and 3.29 V, respectively. Under the conditions of current density of 100 mA cm-2, 25 °C, pH 12, salt content of 8%, chemical oxygen demand (COD) of 24,280.98 mg L-1, and total nitrogen (TN) content of 5268 mg L-1, after electrification for 12 h, the removal efficiency of COD and TN reached 64.88 and 67.77%, respectively, indicating that the DIL-PbO2-Ti/BDD electrode has excellent electrocatalytic performance. In order to further understand the mechanism of electrochemical degradation of pesticide wastewater, HPLC-MS was used to detect the intermediates in the degradation process, and the possible degradation pathways were proposed in turn.

Efficient electrochemical degradation of X-GN dye wastewater using porous boron-doped diamond electrode.

Surface porous Ti substrates were obtained by electrodeposition-hot melt-alkali etching. Porous-Ti/BDD and flat-Ti/BDD electrodes were prepared for comparative study. The results of SEM, Raman, and XRD analyses show that the BDD films of these two electrodes had good uniformity and stable quality. The electrochemical window (EW) and electrochemical-active surface area (EASA) of the porous-Ti/BDD electrode is as high as 4.21 V and 22.78 cm2 (11.39 cm2/cm2), respectively. Furthermore, the electrochemical catalytic performance and degradation mechanism of porous-Ti/BDD electrode as the anode were studied by the electrolysis of Active Orange dye X-GN (X-GN), and the optimal electrochemical degradation operating parameters were obtained. The results show that when the degradation time was 50 min, the X-GN was completely decolorized. The TOC removal rate reached 69.24%, and the energy consumption was 5.62 kWh m-3. The contribution rate of •OH and SO4•- was calculated to be 91.40% and 1.26% by radical quenching experiments, respectively, indicating that the active substances in the degradation system were mainly •OH and SO4•-. The high specific surface characteristics of porous-Ti/BDD electrode enhanced its electrochemical oxidation advantages, and it showed a high degradation efficiency and low energy consumption for the treatment of X-GN simulated wastewater.

The adsorption mechanism of CF4 on the surface of activated carbon made from peat and modified by Cu.

In order to find a way to deal with CF4 with good removal effect and easy to promote. In this study, peat was used as raw material, and copper-loaded activated carbon (Cu/AC) was successfully prepared through nitric acid oxidation and copper chloride impregnation. Compared with commercial activated carbon and widely used metal organic frameworks (MOFs), it shows a fast adsorption rate and larger adsorption capacity for CF4. The static experiment was used to study the influence of Cu/AC on the adsorption of CF4 in the adsorbent dosage, reaction time, temperature, and initial concentration. SEM, FTIR, XPS, XRF, and BET were used to study the changes of physical and chemical properties before and after the adsorption. It was found that the oxygen-containing group was consumed during this process. Unsaturated sites on Cu can accelerate the adsorption of CF4, and the adsorption process is reversible. For the first time, the kinetic model, adsorption isotherm, and thermodynamic model are used to analyze the adsorption mechanism of CF4 on the Cu/AC surface from different angles. The results show that the adsorption of CF4 on the Cu/AC surface is a process of exothermic entropy reduction. The static adsorption process conforms to the pseudo-first-order, the pseudo-second-order, and the Freundlish adsorption model. Through 5 adsorption and desorption processes, it is found that Cu/AC has excellent recycling and recyclability performance.

A novel graphene oxide-dicationic ionic liquid composite for Cr(VI) adsorption from aqueous solutions.

A novel graphene oxide-dicationic ionic liquid composite (GO-DIL) was prepared by modifying graphene oxide (GO) with a dicationic ionic liquid (DIL), 3,3'-(butane-1,4-diyl) bis (1-methyl-1H-imidazol-3-ium) chloride ([C4(MIM)2]Cl2). GO and GO-DIL were characterized by SEM, BET, FTIR, and XPS, and the materials were used for Cr(VI) adsorption. Batch adsorption studies showed that adsorption reached equilibrium within 40 min, and the optimal pH was 3, where the electrostatic attraction between GO-DIL and Cr(VI) was maximized. The maximum theoretical Cr(VI) adsorption capacity (qm) was 271.08 mg g-1, and qm remained above 228.00 mg g-1 after five cycles. The adsorption data were fitted well by both the pseudo-first-order kinetic model and the Langmuir model. Furthermore, thermodynamics calculations revealed that adsorption was a spontaneous endothermic process. Importantly, electrostatic attraction between Cr(VI) and the protonated imidazole N+ of GO-DIL played a critical role in Cr(VI) adsorption, and Cr(VI) was reduced to Cr(III). Thus, GO-DIL is predicted to be an effective adsorbent for Cr(VI) and other heavy metal ions in wastewater.

Hypoxia-induced hsa_circ_0000826 is linked to liver metastasis of colorectal cancer.

BACKGROUND: hsa_circ_0000826 has been previously linked to CRC through the competing endogenous RNA network; however, the upstream driver of hsa_circ_0000826 elevation remains unknown. In this study, we aim to elucidate the effect of hypoxia-induced hsa_circ_0000826 on CRC tumorigenesis and metastasis. METHODS: RNA scope assay was used to evaluate the expression of hsa_circ_0000826 in CRC cells under hypoxia condition. The effects of hsa_circ_0000826 on phenotypes of CRC cells were evaluated through cell migration and invasion assay. The nude, AOM-DSS model mice and APCMin /+ mice were used to investigate the relationship between circ_0000826, hypoxia, and CRC in mice. A total of 100 CRC tissue samples, as well as the paired adjacent tissues, were collected, and qRT-PCR assay was used to detect the expression of hsa_circ_0000826 in these samples. RESULTS: Hypoxia-induced hsa_circ_0000826 overexpression can increase the malignant phenotypes, tumor formation, and metastasis capability of CRC cells in vitro. mmu_circ_0000826 levels were significantly increased in the CRC tissues from AOM-DSS and APC mice model under hypoxia conditions. Further, the hypoxia-induced upregulation of mmu_circ_0000826 can also promote CRC tumorigenesis and liver metastasis in vivo. The expression of hsa_circ_0000826 in serum was significantly increased in CRC tissues in 100-pair of CRC and according to the adjacent normal tissues by qRT-PCR assays. Moreover, the expression levels of hsa_circ_0000826 in serum of patient with liver metastasis were significantly increased than those without metastasis. CONCLUSION: Our results suggested that hsa_circ_0000826 was induced by the hypoxia in CRC, which can be a potential biomarker of CRC liver metastasis.

Electrochemical oxidative degradation of X-6G dye by boron-doped diamond anodes: Effect of operating parameters.

Boron-doped diamond (BDD) is an excellent electrode material. As the anode in an electrochemical degradation tank, BDD has been receiving widespread attention for the treatment of azo dye wastewater. In this study, electrochemical oxidation (EO) was applied to electrolyze reactive brilliant yellow X-6G (X-6G) using BDD as the anode and Pt as the cathode. To balance the degradative effects and power consumption in the electrolysis process, the effects of a series of operating parameters, including current density, supporting electrolyte, initial pH, reaction temperature and initial dye concentration, were systematically studied. The oxidative process was analyzed by color removal rate, and the degree of mineralization was evaluated by TOC. The optimal experimental parameters were finally determined: 100 mA cm-2, 0.05 M Na2SO4 electrolyte, pH 3.03, 60 °C, and an initial X-6G concentration of 100 mg L-1. As a result, color completely disappeared after 0.75 h of electrolysis, and TOC was removed by 72.8% after 2 h of electrolysis. In conclusion, the EO of a BDD electrode as an anode can be a potent treatment method for X-6G synthetic wastewater.

The Electrochemical Oxidation of Hydroquinone and Catechol through a Novel Poly-geminal Dicationic Ionic Liquid (PGDIL)-TiO2 Composite Film Electrode.

A novel poly-geminal dicationic ionic liquid (PGDIL)-TiO2/Au composite film electrode was successfully prepared by electrochemical polymerization of 1,4-bis(3-(m-aminobenzyl)imidazol-1-yl)butane bis(hexafluorinephosphate) containing polymerizable anilino groups in the electrolyte containing nano-TiO2. The basic properties of PGDIL-TiO2/Au composite films were studied by SEM, cyclic voltammetry, electrochemical impedance spectroscopy, and differential pulse voltammetry. The SEM results revealed that the PGDIL-TiO2 powder has a more uniform and smaller particle size than the PGDIL. The cyclic voltammetry results showed that the catalytic effect on electrochemical oxidation of hydroquinone and catechol of the PGDIL-TiO2 electrode is the best, yet the Rct of PGDIL-TiO2 electrode is higher than that of PGDIL and TiO2 electrode, which is caused by the synergistic effect between TiO2 and PGDIL. The PGDIL-TiO2/Au composite electrode presents a good enhancement effect on the reversible electrochemical oxidation of hydroquinone and catechol, and differential pulse voltammetry tests of the hydroquinone and catechol in a certain concentration range revealed that the PGDIL-TiO2/Au electrode enables a high sensitivity to the differentiation and detection of hydroquinone and catechol. Furthermore, the electrochemical catalytic mechanism of the PGDIL-TiO2/Au electrode was studied. It was found that the recombination of TiO2 improved the reversibility and activity of the PGDIL-TiO2/Au electrode for the electrocatalytic reaction of HQ and CC. The PGDIL-TiO2/Au electrode is also expected to be used for catalytic oxidation and detection of other organic pollutants containing -OH groups.

Adsorption of Ni2+ and Pb2+ from water using diethylenetriamine-grafted Spirodela polyrhiza: behavior and mechanism studies.

Novel adsorbent, diethylenetriamine-grafted Spirodela polyrhiza (DSP), was synthesized via modifying natural S. polyrhiza (SP) with diethylenetriamine by cross-linking with epichlorohydrin and applied to adsorb Ni2+ and Pb2+ from water. The effecting parameters on adsorption of Ni2+ and Pb2+ such as adsorbent dosage, pH, contact time, temperature, and initial concentration were studied through equilibrium experiments. The adsorption of Ni2+ and Pb2+ followed the pseudo-second-order model and the Langmuir isotherm adsorption model. The study discusses thermodynamic parameters, including changes in Gibbs free energy, entropy, and enthalpy, for the adsorption of Ni2+ and Pb2+ on DSP, and revealed that the adsorption process was spontaneous and exothermic under natural conditions. The maximum Ni2+ and Pb2+ adsorption capacities of DSP were 33.02 and 36.50 mg/g, respectively. The newly prepared materials were characterized through scanning electron microscopy (SEM), mapping analysis, and zeta potential analysis. Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) analyses indicated that functional groups (-OH and N-H) were involved in Ni2+ and Pb2+ adsorption. Notably, DSP can be easily regenerated and reused for multiple cycles. Therefore, DSP is a promising adsorbent for effective Ni2+ and Pb2+ removal.

Characterization of modified Alternanthera philoxeroides by diethylenetriamine and its application in the adsorption of copper(II) ions in aqueous solution.

By a simple and convenient method of using epichlorohydrin as linkages, a novel Alternanthera philoxeroides (AP) derivative modified with diethylenetriamine (DAP) was synthesized, which can remove copper(II) ions (Cu(II)) in the water environment efficiently. The adsorption capacity of DAP for Cu(II) under various factors was measured using ultraviolet spectrophotometer. The adsorption capacity and removal ratio were 19.33 mg/g and 95.57% at pH 5.5 and 298 K. The kinetic and equilibrium study shows that pseudo-second-order kinetic (R2 = 0.9964) and Langmuir isotherm models (R2 > 0.982) could properly describe DAP adsorption behaviors, and thermodynamic parameters indicate a spontaneous endothermic process (ΔG = - 3.6636 kJ/mol). The combined results of SEM, XRD, FTIR, and XPS analyses reveal that the dominant contribution for enhancement in Cu(II) adsorption is made by the formation of an amino group. And the adsorption mechanism is mainly the complexation reaction. The adsorption efficiency of DAP remained above 72.06% after 6 cycles of adsorption-desorption, which indicated that DAP has good regenerability and stability. All the results suggest that DAP could serve as promising adsorbents for Cu(II) pollution minimization.

Paraptosis-Inducing Nanomedicine Overcomes Cancer Drug Resistance for a Potent Cancer Therapy.

Most chemotherapeutic drugs and their nanomedicine formulations exert anticancer activity by inducing cancer cell apoptosis. However, cancer cells inherently have and acquire many antiapoptosis mechanisms, causing cancer drug resistance and poor prognoses in patients. Herein, a potent paraptosis-inducing nanomedicine is reported that causes quick nonapoptotic death of cancer cells, overcoming apoptosis-based resistance and effectively inhibiting drug-resistant tumor growth. The nanomedicine is composed of micelles made from an amphiphilic 8-hydroxyquinoline (HQ)-conjugate block copolymer with polyethylene glycol. Cu2+ can catalyze the hydrolysis of the HQ conjugation linker and liberate HQ, and these molecules can form the complex Cu(HQ)2 , a strong proteasome inhibitor effective at inducing cell paraptosis. In vivo, the Cu2+ -responsive HQ-releasing micelles respond to elevated tumor Cu2+ levels or externally administered Cu2+ and effectively inhibit the growth of human breast adenocarcinoma doxorubicin-resistant (MCF-7/ADR) tumors. Compared with other nanomedicines that overcome drug resistance via delivering several agents or even siRNA, this paraptosis-inducing nanomedicine provides a simple but potent approach to overcoming cancer drug resistance.

[Preparation of freeze-dried long-circulation oridonin liposomes and their pharmacokinetics in rats].

OBJECTIVE: To prepare freeze-dried long-circulation oridonin liposomes with optimized parameters. METHODS: Ethanol injection method followed by freeze-drying was used to prepare the liposomes. Sephadex column was used to purify liposomes. Effects of formulation factors on entrapment efficiency of long-circulation oridonin liposomes were studied. The particle size, distribution and in vitro release were determined. Pharmacokinetics of oridonin liposomes in rats was determined by HPLC and the pharmacokinetic parameters calculated by Kinetica(TM) software were compared with conventional oridonin liposomes and solution. RESULTS: The optimized lipid formulation for long-circulation liposomes was composed of soy lecithin, cholesterol and DSPE-PEG 2000 with a ratio of 1:0.5:1.8(w/w). The ratio of drug to lipid was 1:6. Freeze-drying protectant was a mixture of glucose and mannitol (3:1). The entrapment efficiency (EE) of long-circulation oridonin liposomes was about 65%. The particle size of liposomes after hydrolyzation was 164 nm with good DPI. The liposomes showed a sustained drug release in vitro. Intravenous injected oridonin fitted with two-compartment pharmacokinetic model. The MRT of long-circulation liposomes was 2 times and 6 times and AUC was about 2 times and 3 times of conventional liposomes and oridonin solution, respectively. CONCLUSION: Freeze-dried liposomes with high EE have been obtained by the proposed approach. This long-circulation liposomes extend oridonin half time and significantly increase AUC in rats.