Design, synthesis, and evaluation of 1, 4-benzodioxan-substituted chalcones as selective and reversible inhibitors of human monoamine oxidase B

The inhibition of monoamine oxidase B (MAO-B) could be an effective approach for the treatment of various neurological disorders. In this study, a series of 1, 4-benzodioxan-substituted chalcone derivatives were designed, synthesised and evaluated for their inhibitory activity against human MAO-B (hMAO-B). The majority of these compounds showed inhibitory activity and high selectivity. The most potent compound, (E)-1-(3-bromo-4-fluorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)prop-2-en-1-one (22), exhibited an IC50 of 0.026 µM with a selectivity index greater than 1538. Kinetics and reversibility studies confirmed that the representative active compounds acted as competitive and reversible inhibitors of hMAO-B. The enzyme-inhibitor interactions were investigated by molecular docking studies and the rationale was provided. As these potent hMAO-B inhibitors exhibited low neurotoxicity and possessed promising drug-like properties, we believe that these active compounds could be further investigated as potential drug candidates for future in vivo studies

A Reversible Colorimetric and Fluorescence “Turn-Off” Chemosensor for Detection of Cu2+ and Its Application in Living Cell Imaging

Dual-function chemosensors that combine the capability of colorimetric and fluorimetric detection of Cu2+ are still relatively rare. Herein, we report that a 3-hydroxyflavone derivative (E)-2-(4-(dimethylamino)styryl)-3-hydroxy-4H-chromen-4-one (4), which is a red-emitting fluorophore, could serve as a reversible colorimetric and fluorescence “turn-off” chemosensor for the detection of Cu2+. Upon addition of Cu2+ to 4 in neutral aqueous solution, a dramatic color change from yellow to purple-red was clearly observed, and its fluorescence was markedly quenched, which was attributed to the complexation between the chemosensor and Cu2+. Conditions of the sensing process had been optimized, and the sensing studies were performed in a solution of ethanol/phosphate buffer saline (v/v = 3:7, pH = 7.0). The sensing system exhibited high selectivity towards Cu2+. The limit of naked eye detection of Cu2+ was determined at 8 × 10−6 mol/L, whereas the fluorescence titration experiment showed a detection limit at 5.7 × 10−7 mol/L. The complexation between 4 and Cu2+ was reversible, and the binding constant was found to be 3.2 × 104 M−1. Moreover, bioimaging experiments showed that 4 could penetrate the cell membrane and respond to the intracellular changes of Cu2+ within living cells, which indicated its potential for biological applications

Preparation of a Solvent-Resistant Nanofiltration Membrane of Liquefied Walnut Shell Modified by Ethylenediamine

N,N-dimethylformamide (DMF) has excellent chemical stability and is widely used as an aprotic polar solvent. In order to reduce production costs and reduce pollution to the surrounding environment, it is necessary to recycle and reuse DMF. Previous research has found that the thin film composite nanofiltration membrane prepared from liquefied walnut shells exhibited a high rejection rate in DMF, but relatively low permeance and mechanical strength. In order to increase permeance without compromising the separation performance, ethylenediamine (EDA) is used as a modifier to graft onto the structure of liquefied walnut shell through the Mannich reaction. Then, modified liquefied walnut shell as an aqueous monomer reacts with trimesoyl chloride (TMC) via the interfacial polymerization method on the EDA-crosslinked polyetherimide (PEI) membrane. The results show that the permeance of the prepared membrane is significantly improved by an order of magnitude, demonstrating a rejection rate of 98% for crystal violet (CV), and a permeance of 3.53 L m−2 h−1 bar−1 in DMF. In conclusion, this study reveals the potential of utilizing liquefied walnut shells as raw materials for preparing high-performance separation membranes and demonstrates that surface modification is a feasible approach to enhance permeance of membranes without sacrificing the rejection rate

Causal relationship between gut microbiota and gastrointestinal diseases: a mendelian randomization study

Abstract Background Recent research increasingly highlights a strong correlation between gut microbiota and the risk of gastrointestinal diseases. However, whether this relationship is causal or merely coincidental remains uncertain. To address this, a Mendelian randomization (MR) analysis was undertaken to explore the connections between gut microbiota and prevalent gastrointestinal diseases. Methods Genome-wide association study (GWAS) summary statistics for gut microbiota, encompassing a diverse range of 211 taxa (131 genera, 35 families, 20 orders, 16 classes, and 9 phyla), were sourced from the comprehensive MiBioGen study. Genetic associations with 22 gastrointestinal diseases were gathered from the UK Biobank, FinnGen study, and various extensive GWAS studies. MR analysis was meticulously conducted to assess the causal relationship between genetically predicted gut microbiota and these gastrointestinal diseases. To validate the reliability of our findings, sensitivity analyses and tests for heterogeneity were systematically performed. Results The MR analysis yielded significant evidence for 251 causal relationships between genetically predicted gut microbiota and the risk of gastrointestinal diseases. This included 98 associations with upper gastrointestinal diseases, 81 with lower gastrointestinal diseases, 54 with hepatobiliary diseases, and 18 with pancreatic diseases. Notably, these associations were particularly evident in taxa belonging to the genera Ruminococcus and Eubacterium. Further sensitivity analyses reinforced the robustness of these results. Conclusions The findings of this study indicate a potential genetic predisposition linking gut microbiota to gastrointestinal diseases. These insights pave the way for designing future clinical trials focusing on microbiome-related interventions, including the use of microbiome-dependent metabolites, to potentially treat or manage gastrointestinal diseases and their associated risk factors

Data_Sheet_1_The relationship between processed meat, red meat, and risk of types of cancer: A Mendelian randomization study.ZIP

BackgroundObservational studies have suggested processed and red meat may increase the risk of cancer. However, the causal effects and direction between them were still unclear. We conducted two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of processed meat and red meat on the risk of nine common types of cancer, namely, lung, ovarian, endometrial, breast, kidney, gastric, prostate, skin, and oropharyngeal cancer.MethodsGenome-wide association studies (GWAS) for processed meat and red meat (pork, beef, and mutton) were obtained from the UK Biobank. GWAS of types of cancer in this study were extracted from the genetic consortia and the FinnGen consortium. The inverse variance weighted (IVW) was carried out as the main method for two-sample MR analysis. Sensitivity analyses were used to assess the robustness of the results.ResultsGenetically predicted processed meat intake was causally associated with increased risk of lung cancer (OR [odds ratio] = 1.923, 95% CI = 1.084–3.409, P = 0.025). There is no convincing evidence for the associations between genetically determined processed meat, red meat, and the risk of other cancers we studied.ConclusionOur results suggested that intake of processed meat may increase the risk of lung cancer. These findings provided no evidence to support that consumption of processed and red meat has a large effect on the risk of other cancers we studied. Further research is needed to clarify the results.</p

Stirring rate regulates the proliferation and metabolism of microencapsulated recombinant CHO cells

Stirred tank bioreactors are the most widely used method for the large-scale culture of mammalian cells. However, the scale of stirred tank bioreactors is limited by insufficient oxygen/nutrient mixing and the accumulation of waste products in high cell density cultures. The most effective method to solve these problems is to increase the stirring rate; this usually leads to increased cell proliferation, but can decrease the utilization of nutrients for recombinant protein synthesis. To investigate the effects of stirring rate on the proliferation, metabolism, and recombinant protein yield of microencapsulated recombinant Chinese hamster ovary (rCHO) cells, the cells were cultured under different stirring rates, and cell viability, metabolic activity, and protein yield were measured. Microencapsulation promoted Desmodus rotundus salivary plasminogen activator expression, and higher stirring rates promoted increases in microencapsulated cell density and metabolic activity. However, the maximum yield of recombinant protein was obtained at a moderate stirring rate, whereas protein yield was decreased at the highest tested stirring rate. The stirring rate had a significant impact on the growth and protein expression of microencapsulated rCHO cells, and a specific stirring rate was identified to maximize the yield of recombinant protein. (C) 2014 International Union of Biochemistry and Molecular Biology, Inc

Growth and production of microencapsulated recombinant CHO in a stirred tank bioreactor

Microencapsulation supplies cells with a three-dimensional microenvironment enhancing the metabolic activity, cell density and recombinant protein expression in a stirred tank bioreactor which is used widely to culture mammalian cells in many biochemical processes. In this paper, we address the growth and Desmodus rotundus salivary plasminogen activator (DSPA) production of recombinant CHO (rCHO) in a stirred tank bioreactor. Cells were cultured using two different methods-in an unmicroencapsulated versus microencapsulated culture-and compared differences between them in terms of cell reproduction and DSPA protein productivity. Compared to the unmicroencapsulated rCHO, microencapsulated cells got higher cell density and prolonged the plateau phase. Microencapsulated rCHO promoted DSPA production, with a maximum rate that was 4.8 times higher than in unmicroencapsulated cells, and the accumulated production of DSPA was 3.3 higher than in unmicroencapsulated cells. Negative relationship was found between specific growth rate and DSPA production capacity of unit cells. These findings will facilitate the methods for higher DSPA production in stirred tank bioreactors