A Novel TetR Family Transcriptional Regulator, CalR3, Negatively Controls Calcimycin Biosynthesis in Streptomyces chartreusis NRRL 3882

Calcimycin is a unique ionophoric antibiotic that is widely used in biochemical and pharmaceutical applications, but the genetic basis underlying the regulatory mechanisms of calcimycin biosynthesis are unclear. Here, we identified the calR3 gene, which encodes a novel TetR family transcriptional regulator and exerts a negative effect on calcimycin biosynthesis. Disruption of calR3 in Streptomyces chartreusis NRRL 3882 led to significantly increased calcimycin and its intermediate cezomycin. Gene expression analysis showed that the transcription of calR3 and its adjacent calT gene were dramatically enhanced (30- and 171-fold, respectively) in GLX26 (ΔcalR3) mutants compared with the wild-type strains. Two CalR3-binding sites within the bidirectional calR3-calT promoter region were identified using a DNase I footprinting assay, indicating that CalR3 directly repressed the transcription of its own gene and the calT gene. In vitro electrophoretic mobility shift assays suggested that both calcimycin and cezomycin can act as CalR3 ligands to induce CalR3 to dissociate from its binding sites. These findings indicate negative feedback for the regulation of CalR3 in calcimycin biosynthesis and suggest that calcimycin production can be improved by manipulating its biosynthetic machinery

Rhein induces apoptosis of human gastric cancer SGC-7901 cells via an intrinsic mitochondrial pathway

Rhein is a primary anthraquinone found in the roots of a traditional Chinese herb, rhubarb, and has been shown to have some anticancer effects. The aim of the present study was to investigate the effect of rhein on the apoptosis of the human gastric cancer line SGC-7901 and to identify the mechanism involved. SGC-7901 cells were cultured and treated with rhein (0, 50, 100, 150, and 200 µM) for 24, 48, or 72 h. Relative cell viability assessed by the MTT assay after treatment was 100, 99, 85, 79, 63% for 24 h; 100, 98, 80, 51, 37% for 48 h, and 100, 97, 60, 36, 15% for 72 h, respectively. Cell apoptosis was detected with TUNEL staining and quantified with flow cytometry using annexin FITC-PI staining at 48 h after 100, 200 and 300 µm rhein. The percentage of apoptotic cells was 7.3, 21.9, 43.5%, respectively. We also measured the mRNA levels of caspase-3 and -9 using real-time PCR. Treatment with 100 µM rhein for 48 h significantly increased mRNA expression of caspase-3 and -9. The levels of apoptosis-related proteins including Bcl-2, Bax, Bcl-xL, and pro-caspase-3 were evaluated in rhein-treated cells. Rhein increased the Bax:Bcl-2 ratio but decreased the protein levels of Bcl-xL and pro-caspase-3. Moreover, rhein significantly increased the expression of cytochrome c and apoptotic protease activating factor 1, two critical components involved in mitochondrial pathway-mediated apoptosis. We conclude that rhein inhibits SGC-7901 proliferation by inducing apoptosis and this antitumor effect of rhein is mediated in part by an intrinsic mitochondrial pathway

A three-dimensional porous Co@C/carbon foam hybrid monolith for exceptional oil–water separation

Frequent oil spill accidents and ever-increasing oily wastewater have become serious global environmental problems. To enhance the oil-sorption capacity and simplify the oil-recovery process, the construction of various advanced oil sorbents and oil-collecting devices is of great technological importance. Herein, a three-dimensional (3D) porous carbon-based hybrid monolith has been successfully fabricated, in which cobalt based metal-organic framework (Co-MOF) nanosheets are firstly immobilized on a carbon foam (CF) skeleton (denoted as Co-MOFs/CF) via a facile vapor-phase hydrothermal (VPH) technique followed by carbonation treatment under a N2 atmosphere into Co@C/CF. The resulting Co@C/CF hybrid monolith exhibits an exceptional oil/water separation ability, including high sorption capacity (from 85 to 200 times its own weight toward various solvents and oils), easy collection and remarkable recyclability, as reflected by no obvious reduction in uptake capacity even after 20 cycles of repeated operation. More significantly, the oil-collecting device based on the proposed carbon-based hybrid monolith can rapidly, efficiently, and continuously collect oil from water surfaces, making it a promising candidate for oil-spill remediation

UiO-66 derived Ru/ZrO2@C as a highly stable catalyst for hydrogenation of levulinic acid to gamma-valerolactone

The hydrogenation of levulinic acid (LA) to gamma-valerolactone (GVL) is a crucial reaction included in many biorefinery schemes for the production of renewable chemicals and fuels. The development of highly stable supported Ru-based catalysts in the polar protic liquid phase under hydrothermal conditions is still a major challenge. Here, we prepared a 0.85 wt% Ru/ZrO2@C catalyst using a new stabilization strategy based on the UiO-66 (Zr-MOF) material. The catalytic performance of this Ru/ZrO2@C in LA-to-GVL was tested and compared with commercial 5 wt% Ru/C at 10 bar H-2, 413 K in water and also in high protic aqueous solution (pH = 1). The full conversion of LA and quantitative yield of GVL were achieved with both catalysts. However, the 5 wt% Ru/C showed poor resistance to deactivation already after the first run. ICP, XPS, HRTEM, AC-STEM, TPR and physisorption data showed that quick deactivation of Ru/C was mainly caused by the leaching of ruthenium in addition to the loss of surface area via carbonaceous deposition in micro-pores. In contrast, the self-prepared Ru/ZrO2@C catalyst showed no apparent drop in catalytic performance either in water or in high protic aqueous solution upon multiple recycling, and no leaching of ruthenium was found even under harsh conditions (pH = 1). Remarkably, in the Ru/ZrO2@C catalyst, Ru (probable single-atom) was highly dispersed on nanotetragonal ZrO2 (3.3 nm), embedded in the amorphous carbon, and no apparent Ru nanoclusters were observed even after reactions. TPR results indicated that this excellent stability might be attributed to strong metal-support interaction between Ru and nanotetragonal ZrO2

Different types of screen time, physical activity, and incident dementia, Parkinson’s disease, depression and multimorbidity status

Abstract Background Several previous studies have shown that excessive screen time is associated with an increased prevalence of dementia, Parkinson’s disease (PD), and depression. However, the results have been inconsistent. This study aimed to prospectively investigate the association between different types of screen time and brain structure, as well as the incidence of dementia, Parkinson’s disease, depression, and their multimorbidity status. Methods We included 473,184 participants initially free of dementia, PD, and depression from UK Biobank, as well as 39,652 participants who had magnetic resonance imaging (MRI) data. Screen time exposure variables including TV viewing and computer using were self-reported by participants. Cox proportional hazards regression models were used to estimate the association between different types of screen time and the incidence of dementia, Parkinson’s disease, depression, and their multimorbidity status. Multiple linear regression models were used to assess the linear relationship between different types of screen time and MRI biomarkers in a subgroup of participants. Results During the follow up, 6,096, 3,061, and 23,700 participants first incident cases of dementia, PD, and depression respectively. For moderate versus the lowest computer uses, the adjusted HRs (95% CIs) were 0.68 (0.64, 0.72) for dementia, 0.86 (0.79, 0.93) for PD, 0.85 (0.83, 0.88) for depression, 0.64 (0.55, 0.74) for dementia and depression multimorbidity, and 0.59 (0.47, 0.74) for PD and depression multimorbidity. The multivariable HRs (95% CIs) for the highest versus the lowest group of TV viewing time were 1.28 (1.17, 1.39) for dementia, 1.16 (1.03, 1.29) for PD, 1.35 (1.29, 1.40) for depression, 1.49 (1.21, 1.84) for dementia and depression multimorbidity, and 1.44 (1.05, 1.97) for PD and depression multimorbidity. Moderate computer using time was negatively associated with white matter hyperintensity volume (β = -0.042; 95% CI -0.067, -0.017), and positively associated with hippocampal volume (β = 0.059; 95% CI 0.034, 0.084). Participants with the highest TV viewing time were negatively associated with hippocampal volume (β = -0.067; 95% CI -0.094, -0.041). In isotemporal substitution analyses, substitution of TV viewing or computer using by equal time of different types of PA was associated with a lower risk of all three diseases, with strenuous sports showing the strongest benefit. Conclusion We found that moderate computer use was associated with a reduced risk of dementia, PD, depression and their multimorbidity status, while increased TV watching was associated with a higher risk of these disease. Notably, different screen time may affect the risk of developing diseases by influencing brain structures. Replacing different types of screen time with daily-life PA or structured exercise is associated with lower dementia, PD, and depression risk

Identification of the hot spot residues for pyridine derivative inhibitor CCT251455 and ATP substrate binding on monopolar spindle 1 (MPS1) kinase by molecular dynamic simulation

<p>Protein kinase monopolar spindle 1 plays an important role in spindle assembly checkpoint at the onset of mitosis. Over expression of MPS1 correlated with a wide range of human tumors makes it an attractive target for finding an effective and specific inhibitor. In this work, we performed molecular dynamics simulations of protein MPS1 itself as well as protein bound systems with the inhibitor and natural substrate based on crystal structures. The reported orally bioavailable 1 h-pyrrolo [3,2-c] pyridine inhibitors of MPS1 maintained stable binding in the catalytic site, while natural substrate ATP could not stay. Comparative study of stability and flexibility of three systems reveals position shifting of β-sheet region within the catalytic site, which indicates inhibition mechanism was through stabilizing the β-sheet region. Binding free energies calculated with MM-GB/PBSA method shows different binding affinity for inhibitor and ATP. Finally, interactions between protein and inhibitor during molecular dynamic simulations were measured and counted. Residue Gly605 and Leu654 were suggested as important hot spots for stable binding of inhibitor by molecular dynamic simulation. Our results reveal an important position shifting within catalytic site for non-inhibited proteins. Together with hot spots found by molecular dynamic simulation, the results provide important information of inhibition mechanism and will be referenced for designing novel inhibitors.</p

Microencapsulation of Ionic Liquid by Interfacial Self-Assembly of Metal-Phenolic Network for Efficient Gastric Absorption of Oral Drug Delivery

Improving bioavailability of orally delivered drugs is still challenging, as conventional drug delivery systems suffer from non-specific drug delivery in the gastrointestinal (GI) tract and limited drug absorption efficiency. Gastric drug delivery is even more difficult due to the harsh microenvironment, short retention time, and physiologic barriers in the stomach. Here, an oral drug delivery microcapsule system was developed for gastric drug delivery, which consists of ionic liquid (IL) as the inner carrier and metal-phenolic network (MPN) as the microcapsule shell. The IL@MPN microcapsules are prepared by interfacial self-assembly of FeIII and quercetin at the interface of hydrophobic IL ([EMIM][NTf2]) and water. The formation of MPN shell could improve the stability of IL droplets in water and endow the system with pH-response drug release properties, while the encapsulated IL core could efficiently load the drug and enhance the drug tissue permeability. The IL@MPN microcapsules showed enhanced drug absorption in the stomach after oral administration in a rat model, where the microcapsules are disassembled in gastric acid, and the released IL could reduce the viscosity of mucus gel and increase the drug transport rate across endothelial cells. This work presents a simple yet efficient strategy for oral drug delivery to the stomach. Given the diversity and versatility of both MPN and IL, the proposed self-assembled microcapsules could expand the toolbox of drug delivery systems with enhanced oral drug bioavailability