Littlehodges7152

As a result three FDA approved drugs (Remdesivir, Saquinavir and Darunavir) and two natural compounds (. flavone and coumarine derivatives) were identified as promising hits. Further, MD simulation and binding free energy calculations were performed to evaluate the dynamic behavior, stability of protein-ligand contact, and binding affinity of the hit compounds. Our results indicate that the identified compounds can inhibit the function of Chymotrypsin-like protease (3CLpro) of Coronavirus. Considering the severity of the spread of coronavirus, the current study is in-line with the concept of finding the new inhibitors against the vital pathway of the corona virus to expedite the process of drug discovery.Communicated by Ramaswamy H. Sarma.Elucidating the mechanisms for circadian expression of drug-metabolizing enzymes is essential for a better understanding of dosing time-dependent drug metabolism and pharmacokinetics. CYP2B6 (Cyp2b10 in mice) is an important enzyme responsible for metabolism and detoxification of approximately 10% of drugs. Here, we aimed to investigate a potential role of nuclear receptor co-repressor RIP140 in circadian regulation of Cyp2b10 in mice.We first uncovered diurnal rhythmicity in hepatic RIP140 mRNA and protein with peak values at ZT10 (ZT, zeitgeber time). RIP140 ablation up-regulated Cyp2b10 expression and blunted its rhythm in mice and in AML-12 cells. Consistent with a negative regulatory effect, overexpression of RIP140 inhibited Cyp2b10 promoter activity and reduced cellular Cyp2b10 expression.Furthermore, RIP140 suppressed Car- and Pxr-mediated transactivation of Cyp2b10, and the suppressive effects were attenuated when the RIP140 gene was silenced. Chromatin immunoprecipitation assays revealed that recruitment of RIP140 protein to the Cyp2b10 promoter was circadian time-dependent in wild-type mice. More extensive recruitment was observed at ZT10 than at ZT2 consistent with the rhythmic pattern of RIP140 protein. However, the time-dependency of RIP140 recruitment was lost in RIP140-/- mice.Additionally, we identified a D-box and a RORE cis-element in RIP140 promoter. WNK-IN-11 order D-box- and RORE-acting clock components such as Dbp, E4bp4, Rev-erbα/β and Rorα transcriptionally regulated RIP140, potentially accounting for its rhythmic expression.In conclusion, RIP140 regulates diurnal expression of Cyp2b10 in mouse liver through periodical repression of Car- and Pxr-mediated transactivation. This co-regulator-driven mechanism represents a novel source of diurnal rhythmicity in drug-metabolizing enzymes.DNA topology changes continuously as replication proceeds. Unwinding of the DNA duplex by helicases is favored by negative supercoiling but it causes the progressive accumulation of positive supercoiling ahead of the fork. This torsional stress must be removed for the fork to keep advancing. Elimination of this positive torsional stress may be accomplished by topoisomerases acting solely ahead of the fork or simultaneously in the un-replicated and replicated regions after diffusion of some positive torsional strain from the un-replicated to the replicated regions by swivelling of the replication forks. In any case, once replication is completed fully replicated molecules are known to be heavily catenated and this catenation derives from pre-catenanes formed during replication. Although there is still controversy as to whether fork swiveling redistributes this positive torsional stress continuously or only as termination approaches, the forces that cause fork rotation and the generation of pre-catenanes are still poorly characterized. Here we used a numerical simulation, based on the worm-like chain model and the Metropolis Monte Carlo method, to study the interchange of supercoiling and pre-catenation in a naked circular DNA molecule of 4,440 bp partially replicated in vivo and in vitro. We propose that a dynamic gradient of torsional stress between the un-replicated and replicated regions drives fork swiveling allowing the interchange of supercoiling and pre-catenation.Communicated by Ramaswamy H. Sarma.Purpose To evaluate the efficacy and safety of magnetic field (MF) therapy by a randomized, double-blinded, controlled clinical trial.Materials and methods From February 2016 to August 2019, patients with advanced lung cancer who conformed to inclusion criteria were enrolled in this study. Patients were assigned into MF therapy group (MF group, receiving both MF therapy and chemotherapy) and control group (CON group, receiving sham MF therapy and chemotherapy) randomly. The treatment course was 21 days and 2 hours per day. Changes of life quality assessment scales, objective response rate (ORR) and disease control rate (DCR) were analyzed as primary end points. The secondary end points were progression-free survival (PFS), change of blood cytokine concentrations and safety. This study has been registered on Clinicaltrials.gov (ID NCT02701231).Results 77 patients were enrolled and 60 finished the study. Comparing to CON group, more patients in MF group (66.7% vs 25.9%) were experiencing life quality improvement on day 21. Besides, MF group patients had higher concentrations of IP-10 and GM-CSF, and lower concentration of sTREM-1 in plasma. However, the two groups were having similar ORR, DCR and PFS after treatment. Moreover, MF treatment did not increase adverse events in MF group.Conclusions MF therapy could improve life quality and modulate blood cytokine concentration in advanced lung cancer patients. Hence, it might be applied as an adjuvant therapy along with chemotherapy.Liposoluble liquid smoke (LS) preparations are versatile food additives used worldwide. The objective of the present work was to characterise the chemical composition of four types of industrial liposoluble LS currently used as the basis for the production of commercial smoke flavourings. The LS was obtained by vacuum fractional distillation from a raw pyrolysis oil (raw LS) obtained primarily from eucalyptus wood tar. The raw LS and the four LS flavourings obtained therefrom were analysed by gas chromatography/mass spectrometry (GC/MS) to characterise the main groups of components. Additional analyses were carried out to evaluate the occurrence of PAHs (polycyclic aromatic hydrocarbons) in the samples, as the producer claimed that these samples are free of PAHs. The main chemical components characterised in the LS were organic acids, aldehydes, esters, furans, pyrans and phenols, with phenolic compounds being the major chemical group. For the four LS tested samples, no PAHs could be detected with the method employed, which could indicate that the industrial processing was able to effectively remove this harmful class of compounds, or at least decrease its concentrations to levels below the limits of detection of the method of analysis.