Length and rigidity of the spacer impact on aldose reductase inhibition of the 5F-like ARIs in a dual-occupied mode.

The primary objective of this study was to investigate the structure-activity relationship of a new series of 5F-like Aldose Reductase Inhibitors (ARIs) using in silico docking method. In this perspective, 6 novel ARIs have been designed and synthesized. Evaluation of the inhibition of these compounds to ALR2 was carried on with epalrestat and 5F as the references. It was found that the spacer of 5F-like ARIs has a great influence on their inhibitory activity. Rigid spacer with length equal to 3 âˆ¼ 4 carbon alkyl chain brings about better inhibitory activity. Among them, compound 4b was verified as the most active ARIs, where its IC50 value was 16.8 ± 1.3 nM. Furthermore, in silico docking studies using AutoDock 4.2 as well as molecular simulation using GROMACS 2022.1 showed that 5F-like ARIs adopt a dual-occupation mode. The interaction energy (-25 to -74 kcal/mol), as well as MM-GBSA binding free energy (-37 to -65 kcal/mol) was positively correlated with their ALR2 inhibition constant (2000 to 16.8 nM). Docking interaction explained well the structure-activity relationship. A pharmacophore model has been set up for 5F-like ARIs thereafter. This model indicates that as an effective ARI, the entity should have four characteristics: an aromatic center, two hydrogen bond donors, and one hydrogen bond acceptor. By the way, all the 5F-like ARIs reported here are good to mild antioxidant with EC50 value between 13.6 ± 1.2 and 71.1 ± 3.2 µM. All our data direct the further development of more optimal ARIs for the treatment of diabetic complication in the future.

Status and associations of nursing practice environments in intensive care units: A cross-sectional study in China.

OBJECTIVE: The objective of this study is to investigate the status and associations of nursing practice environments in intensive care units of tertiary hospitals and provide suggestions for improvement. BACKGROUND: Nursing shortage is an urgent global problem and a concern in China. Intensive care unit nurses have been reported to have one of the highest rates of burnout; however, their comprehensive perceptions of nursing practice environments have not yet been examined. METHODS: The Nursing Practice Environment Scale was used to conduct a questionnaire-based survey of 1,523 intensive care unit nurses from 22 tertiary hospitals in China. The data collection was conducted in 2020. RESULTS: The overall score for the nursing practice environment was 77.042 ± 19.682 (where 100 was the highest possible score). The three highest scoring dimensions were quality management, clinical nursing professionalism and professional improvement, whereas the three lowest-scoring dimensions were hospital management participation, remuneration package and social status. Educational background, position, gender and hospital type were significantly associated with nurses' satisfaction with the working environment. CONCLUSION: Chinese nurses in the intensive care units of tertiary hospitals reported relatively satisfactory nursing practice environments, but the scale scores in dimensions such as hospital management participation, remuneration package and social status remained low. IMPLICATIONS FOR NURSING MANAGEMENT: Understanding the status and associations of the nursing practice environment in intensive care units provides evidence that new policies are needed. Furthermore, managers are responsible for supervising and ensuring that nursing practice environments meet the criteria necessary to improve job satisfaction.

Synergistic integration of dihydro-artemisinin with γ-aminobutyric acid results in a more potential anti-depressant.

Three hybrids of dihydro-artemisinin (DHA) with ß-aminopropionic acid, γ-aminobutyric acid, and histamine have been designed and synthesized. The conjugate of DHA with GABA labelled as 5b was confirmed the most active candidate against both Cort- and SNP-induced PC12 cell impairments with EC50 value of 8.04 ± 0.35, and 9.38 ± 0.56 µM, respectively. 5b was clearly highlighted as a good modulator on protein expression of Akt, Bcl-2, and Bax, indicating its functions against programmed cell apoptosis. 5b significantly reversed the Cort-induced excessive calcium influx and release from internal organelles. It was demonstrated the ability to express increased levels of ß-tubulin III and to up-regulate phosphorylation level of cAMP response element-binding protein (CREB), leading to cell differentiation. It can penetrate blood - brain barrier (BBB) with propriate stability. Altogether, these data strongly support that 5b is a potential anti-depressant.

1,3,5,8-Tetrahydroxy-9H-xanthen-9-one exerts its antiageing effect through the regulation of stress-response genes and the MAPK signaling pathway.

The antioxidative effects of 30 xanthone derivatives (XDs) (XD-n, n = 1-30) in HepG2 cells were evaluated by the cellular antioxidant activity assay. Results showed that all XDs were antioxidants and 1,3,5,8-tetrahydroxy-9H-xanthen-9-one (XD-2) was the most active antioxidant. The all-oxygenated substituted xanthones extended the lifespan of wild-type N2 nematodes under normal culture conditions and XD-2 was the best one. XD-2 eliminated excessive intracellular reactive oxygen species and enhanced the expression levels and activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. XD-2 inhibited the H2 O2 -increased phosphorylation levels of c-JUN N-terminal kinase, extracellular signal-regulated kinase, and p38 in HepG2 cells. In vivo, XD-2 also extended the lifespan of wild-type N2 nematodes under oxidative stress induced by paraquat, but failed in extending the lifespan of CF1038 (daf-16 deletion) and AY102 (pmk-1 deletion) mutant nematodes. It was revealed by real-time polymerase chain reaction that the genes daf-16, sir-2.1, akt-1, and age-1 were all inhibited by paraquat stimuli, while XD-2 reversed these inhibitions; in contrast, paraquat stimuli upregulated both the skn-1 and pmk-1 genes. However, treatment by XD-2 further increased the levels of both genes. These pieces of evidence implied that XD-2 promotes longevity through endogenous signaling pathways rather than through the antioxidative activity alone. Taken all together, it may be concluded that XD-2 is a promising antiageing agent.

Synthesis and antiageing properties of antioxidant pseudopeptides designed based on the bioisostere principle.

Nineteen antioxidant pseudopeptides were designed and synthesized. They were confirmed as mild antioxidants, in which L1-11 was the most active antioxidant with a cellular antioxidant activity (CAA) value of 5.65 ± 0.64 µmol QE/g, and L1-12 was the second most active one (5.58 ± 0.66 µmol QE/g). The existence of nonnatural amino acids in L1-12 increased its stability. Pretreatment with L1-12 dose-dependently extended the lifespan of Caenorhabditis elegans. L1-12 improved resistance against UVB irradiation, oxidative stress induced by paraquat, and thermal shock. It decreased the reactive oxygen species level and upregulated the superoxide dismutase activity inside C. elegans. This pseudopeptide sensitively enhanced the expressions of the Cat-1 and Nhr-8 genes to reduce oxidative damage, leading to an extension of the lifespan. All the evidence support that L1-12 may probably be a potential antiageing agent.

A novel method for evaluating load restraint assemblies to ensure the safety of railway freight transportation.

The violent goods vibration during curve negotiation is a huge threat to the vehicle running safety. Qualified load restraint assemblies that can significantly suppress the cargo vibration are necessary. This study proposes a novel method for evaluating the essential restraint strength, focusing on the relative motion between cargo and wagon. In the beginning, as a comparison, current methods are used to calculate the necessary stiffness of lashings, which are adopted to restrain the cargo vibration on the wagon. Based on the data of the field test, the accuracy of the established wagon-cargo coupled dynamics model is validated. The loaded wagon model negotiates the curve under different running and loading conditions. The simulation results and analysis demonstrate effective strategies for suppressing the vibration of the cargo and reveal the necessary lashing stiffness. The comparison among the results of different evaluation methods shows that the stability of the cargo can be improved by optimizing the lashing stiffness with the method of dynamics simulations. We hope this study will make a positive contribution to the safety of railway freight transportation.

Regioselective sulfation of Artemisia sphaerocephala polysaccharide: Solution conformation and antioxidant activities in vitro.

Regioselective modification is an effective approach to synthesize polysaccharides with different structure features and improved properties. In this study, regioselective sulfation of Artemisia sphaerocephala polysaccharide (SRSASP) was prepared by using triphenylchloromethane (TrCl) as protecting precursor. The decrease in fractal dimension (df) values (1.56-2.04) of SRSASP was observed in size-exclusion chromatography combined with multi angle laser light scattering (SEC-MALLS) analysis. Compared to sample substituted at C-6, SRSASP showed a more expanded conformation of random coil, which was attributed to the breakup of hydrogen bonds and elastic contributions. Circular dichroism (CD), methylene blue (MB) and congo red (CR) spectrophotometric method and atomic force microscopy (AFM) results confirmed the conformational transition and stiffness of the chains after sulfation. SRSASP exhibited enhanced antioxidant activities in the DPPH, superoxide and hydroxyl radical scavenging assay. Sulfation at C-2 or C-3 was favorable for the chelation which might prevent the generation of hydroxyl radicals. It concluded that the degree of substitution and substitution position were the factors influencing biological activities of sulfated polysaccharides.