Ligand-Promoted Iron-Catalyzed Nitrene Transfer for the Synthesis of Hydrazines and Triazanes through N-Amidation of Arylamines.

Herein, we report that bulky alkylphosphines such as PtBu3 can switch the roles from actor to spectator ligands to promote the FeCl2 -catalyzed N-amidation reaction of arylamines with dioxazolones, giving hydrazides in high efficiency and chemoselectivity. Mechanistic studies indicated that the phosphine ligands could facilitate the decarboxylation of dioxazolones on the Fe center, and the hydrogen bonding interactions between the arylamines and the ligands on Fe nitrenoid intermediates might play a role in modulating the delicate interplay between the phosphine ligand, arylamine, and acyl nitrene N, favoring N-N coupling over N-P coupling. The new ligand-promoted N-amidation protocols offer a convenient way to access various challenging triazane compounds via double or sequential N-amidation of primary arylamines.

Prevalence and risk factors of cognitive frailty in community-dwelling older adults with diabetes: A systematic review and meta-analysis.

AIMS: Cognitive frailty can increase the risk of adverse health outcomes in older adults. Estimates of the prevalence of cognitive frailty among older adults with diabetes varied widely in literature. This study aimed to conduct a systematic review and meta-analysis to assess the pooled prevalence of cognitive frailty and risk factors in community-dwelling older adults with diabetes, providing evidence for healthcare professionals to better understand the status of cognitive frailty and help develop effective interventions. METHODS: Databases of PubMed, Web of Science, Cochrane Library, Embase, Cumulative Index of Nursing and Allied Health, Proquest, China National Knowledge Infrastructure and China Biology Medicine were searched from inception to February 10th, 2022. The reviewers independently selected studies, extracted data and assessed the quality of studies. Pooled prevalence of cognitive frailty and risk factors were estimated. Subgroup analysis, meta-regression analysis, sensitivity analysis and publication bias were also conducted. RESULTS: A total of 15 studies with 6391 participants were included in this review. The pooled prevalence of cognitive frailty was 11% (95%CI = 7.9-14%) in community-dwelling older adults with diabetes. Pooled estimates showed that increasing age, higher level of HbA1c, shorter night sleep duration and depression were risk factors, and regular exercise was the protective factor of cognitive frailty in community-dwelling older adults with diabetes. CONCLUSION: Cognitive frailty was common in community-dwelling older adults with diabetes. Routine screening of cognitive frailty and effective interventions should be implemented for this population in community settings. REGISTRATION: PROSPERO ID CRD42021276973.

Evaluation of an Ussing Chamber System Equipped with Rat Intestinal Tissues to Predict Intestinal Absorption and Metabolism in Humans.

BACKGROUND AND OBJECTIVE: Oral bioavailability (F) is one of the key factors that need to be determined in drug discovery. This factor is determined by the permeability and solubility of new molecule entities (NMEs) according to the biopharmaceutics classification system (BCS). METHODS: In the present study, we evaluated the permeability of 22 drugs in rat intestinal tissues using an Ussing chamber system and correlated the permeability with data on human intestinal absorption (Fa) and intestinal availability (Fa × Fg) reported in the literature. RESULTS: The rat intestinal permeability data were better correlated with the combined effect of the absorbed fraction (Fa) and the fraction escaping intestinal metabolism (Fg) than Fa itself. Clear regional dependent absorption was observed for most of the test drugs, and ileal Papp was generally higher than that in other segments. Finally, the function of the efflux transporter P-glycoprotein (P-gp) with regard to oral absorption of substrates was evaluated with an Ussing chamber. We also demonstrated that the rat intestinal stability of the three cytochrome P450 (CYP) substrates was consistent with the human data. CONCLUSION: An Ussing chamber system incorporating rat intestinal tissue would be a valuable tool to predict human intestinal absorption and metabolism for molecules with various physicochemical properties.

Improved Mass-Transfer Enhances Photo-Driven Dye Degradation and H2 Evolution over a Few-Layer WS2/ZnO Heterostructure.

In this study, we observed the enhanced photocatalytic activity of a few-layer WS2/ZnO (WZ) heterostructure toward dye degradation and H2 production. The few-layer WS2 acted as a co-catalyst that separated photogenerated electron/hole pairs and provided active sites for reactions, leading to the rate of photocatalytic H2 production of WZ being 35% greater than that over the bare ZnO nanoparticles. Moreover, vortex-stirring accelerated the mass-transfer of the reactants, leading to the efficiency of dye photodegradation being 3 times higher than that obtained without high-speed stirring. We observed a similar effect for H2 production, with greater photocatalytic performance arising from the increased mass-transfer of H2 from the catalyst surface to the atmosphere.

Effects of membrane transport activity and cell metabolism on the unbound drug concentrations in the skeletal muscle and liver of drugs: A microdialysis study in rats.

The unbound concentrations of 14 commercial drugs, including five non-efflux/uptake transporter substrates-Class I, five efflux transporter substrates-class II and four influx transporter substrates-Class III, were simultaneously measured in rat liver, muscle, and blood via microanalysis. Kpuu,liver and Kpuu,muscle were calculated to evaluate the membrane transport activity and cell metabolism on the unbound drug concentrations in the skeletal muscle and liver. For Class I compounds, represented by antipyrine, unbound concentrations among liver, muscle and blood are symmetrically distributed when compound hepatic clearance is low. And when compound hepatic clearance is high, unbound concentrations among liver, muscle and blood are asymmetrically distributed, such as Propranolol. For Class II and III compounds, overall, the unbound concentrations among liver, muscle, and blood are asymmetrically distributed due to a combination of hepatic metabolism and efflux and/or influx transporter activity.

Applicability of free drug hypothesis to drugs with good membrane permeability that are not efflux transporter substrates: A microdialysis study in rats.

In clinical pharmacology, the free drug hypothesis has been widely applied in the interpretation of the relationship between pharmacokinetics and pharmacodynamics (PK/PD). The free drug hypothesis assumes that the unbound drug concentration in blood is the same as that in the site of action at steady state. The objective of this study is to demonstrate whether the free drug hypothesis is universally applicable for all drugs. The unbound concentrations of the 18 compounds in blood and in brain interstitial fluids (ISF) at steady state following constant intravenous infusion were simultaneously monitored up to 6 hours via in vivo microdialysis technique. Based on the permeability and efflux ratio (ER), the test compounds can be divided into two classes. Class I includes the compounds with good membrane permeability that are not substrates of efflux transporters (eg, P-gp, BCRP, and MRPs), whereas Class II includes the compounds that are substrates of efflux transporters. The steady-state unbound drug concentrations in blood, brain, and CSF are quantitatively very similar for Class I compounds, whereas the steady-state unbound concentrations in the brain and CSF are significantly lower than those in blood for Class II compounds. These results strongly suggest that the free drug hypothesis is not universal for all drugs but is only applicable for drugs with good permeability that are not substrates of efflux transporters.

Identification of rosmarinic acid and sulfated flavonoids as inhibitors of microfouling on the surface of eelgrass Zostera marina.

A bioassay-guided approach was used to identify defense compounds that are present on the surface of Zostera marina and which inhibit settlement of microfoulers at natural concentrations. Moderately polar eelgrass surface extracts inhibited the settlement of seven marine bacteria and one yeast that originated from non-living substrata. In contrast, five other bacterial strains that had been directly isolated from eelgrass surfaces were all insensitive, which suggested a selective effect of surface metabolites on the microbial communities present on eelgrass. Bioassay-guided isolation of active compounds from the extracts in combination with UPLC-MS and 1H-NMR spectroscopy resulted in the identification of rosmarinic acid, luteolin-7-sulfate and diosmetin-7-sulfate or its isomer chrysoeriol-7-sulfate. All three compounds are nontoxic repellents, as they did not inhibit bacterial growth, but prevented bacterial settlement in a dose-dependent manner. Between 15.6 and 106.8 µg ml-1 of rosmarinic acid were present on the eelgrass surface, enough for half maximal settlement inhibition of bacteria.

Fine mapping of a linear epitope on EDIII of Japanese encephalitis virus using a novel neutralizing monoclonal antibody.

The domain III (EDIII) of the envelope protein of Japanese encephalitis virus (JEV) is proposed to play an essential role in JEV replication and infection; it is involved in binding to host receptors and contains specific epitopes that elicit neutralizing antibodies. However, most previous studies have not provided detailed molecular information about the functional epitopes on JEV EDIII protein. In this study, we described a monoclonal antibody (mAb 2B4) we produced and characterized by IFA, PRNT, ELISA and Western blot analyses. The results showed that mAb 2B4 was specific to JEV EDIII protein and possessed high neutralization activity against JEV in vitro. Furthermore, we found that the motif, (394)HHWH(397), was the minimal unit of the linear epitope recognized by mAb 2B4 through screening a phage-displayed random 12-mer peptide library. Using sequence alignment analysis it was found that this motif was highly conserved among JEV strains and was present in West Nile Virus (WNV). Indeed, ELISA data showed that this epitope could be recognized by both JEV-positive swine serum and WNV-positive swine serum. Notably, this linear epitope was highly hydrophilic and was located within the terminal end of a ß-pleated sheet of EDIII. An analysis of the spatial conformation supported the possibility of inducing specific antibodies to this epitope. Taken together, we identified (394)HHWH(397) as an EDIII-specific linear epitope recognized by mAb 2B4, which would be beneficial for studying the pathogenic mechanism of JEV; and mAb 2B4 was also a potential diagnostic and therapeutic reagent.