Structure-aided optimization of 3-O-ß-chacotriosyl epiursolic acid derivatives as novel H5N1 virus entry inhibitors.

It is urgent to develop new antiviral agents due to the continuous emergence of drug-resistant strains of influenza virus. Our earlier studies have identified that certain pentacyclic triterpene saponins with 3-O-ß-chacotriosyl residue are novel H5N1 virus entry inhibitors. In the present study, a series of C-28 modified 3-O-ß-chacotriosyl epiursolic acid derivatives via conjugation with different kinds of sides were synthesized, of which anti-H5N1 activities in A549 cells were evaluated in vitro. Among them, 10 exhibited strongest anti-H5N1 potency at the low-micromole level without cytotoxicity, surpassing the potency of ribavirin. Further mechanism studies of the lead compound 10 based on HI, SPR and molecular modeling revealed that these new 3-epiursolic acid saponins could bind tightly to the viral envelope HA protein, thus blocking the invasion of H5N1 viruses into host cells.

Ultrahigh-power supercapacitors based on highly conductive graphene nanosheet/nanometer-sized carbide-derived carbon frameworks.

In order to develop energy storage devices with high power performance, electrodes should hold well-defined pathways for efficient ionic and electronic transport. Herein, we demonstrate a highly conductive graphene nanosheet/nanometer-sized carbide-derived carbon framework (hcGNS/nCDC). In this architecture, nCDC possesses short transport paths for electrolyte ions, thus ensuring the rapid ions transportation. The excellent electrical conductivity of hcGNS can reduce the electrode internal resistance for the supercapacitor and thus endows the hcGNS/nCDC composite electrodes with excellent electronic transportation performance. Electrochemical measurements show that the cyclic voltammogram of hcGNS/nCDC can maintain a rectangular-like shape with the increase of the scan rate from 5 mV s-1 to 20 V s-1, and the specific capacitance retention is up to 51% even at a high scan rate of 20 V s-1, suggesting ultrahigh power performance, which, to the best of our knowledge, is among the best power performances reported so far for the carbon materials. Furthermore, the hcGNS/nCDC composite also shows an excellent cycling stability (no drop in its capacitance occurs even after 10000 cycles). This work demonstrates the advantage in the ultrahigh power performance for the framework having both short transport pathways for electrolyte ions and high electrical conductivity.

A novel and facile synthesis approach for a porous carbon/graphene composite for high-performance supercapacitors.

We propose a novel and facile synthesis approach to a porous carbon/graphene composite. Graphene is obtained from room-temperature expanded graphite (RTEG), not involving the use of graphite oxide (GO). Porous carbon is acquired by carbonization and KOH-activation of polyvinylpyrrolidone (PVP), which is used to exfoliate RTEG into graphene and inhibit the restacking of the resultant graphene in the present work. The prepared porous carbon/graphene composite has a high specific surface area (SSA) (3008 m2 g-1) and a hierarchical micro- and meso- pore structure (dominant pores in the range of 1-5 nm). Electrochemical measurement demonstrates that the as-prepared porous carbon/graphene composite can deliver an outstanding specific capacitance of up to 340 F g-1 at 5 mV s-1 in 6 M KOH electrolyte. This specific capacitance is among the highest reported so far for porous carbon/graphene materials. Moreover, the prepared composite as an electrode material also exhibits excellent cycling stability (94.4% capacitance retention over 10 000 cycles). The as-fabricated symmetrical supercapacitor exhibits a high energy density of 10.9 W h kg-1 (based on total mass of electrode materials) and an outstanding energy density retention, even at high power density. Compared with conventional preparation routes for porous carbon/graphene composites, the present approach is significantly simple, convenient and cost-effective, which will make it more competent in the development of electrode materials for high-performance supercapacitors.

Effect of Histamine H2 Receptor Antagonists on All-Cause Mortality in Critically Ill Patients With Essential Hypertension: A Retrospective Cohort Study.

Previous studies found that histamine H2 receptor antagonists (H2RAs) had blood pressure lowering and cardioprotective effects, but the impact of H2RAs on the survival outcomes of critically ill patients with essential hypertension is still unclear. The aim of this study was to investigate the association of H2RAs exposure with all-cause mortality in patients with essential hypertension based on Medical Information Mart for Intensive Care III database. A total of 17,739 patients were included, involving 8482 H2RAs users and 9257 non-H2RAs users. Propensity score matching (PSM) was performed to improve balance between 2 groups that were exposed to H2RAs or not. Kaplan-Meier survival curves were used to compare the cumulative survival rates and multivariable Cox regression models were performed to evaluate the association between H2RAs exposure and all-cause mortality. After 1:1 PSM, 4416 pairs of patients were enrolled. The results revealed potentially significant association between H2RAs exposure and decreased 30-day, 90-day, and 1-year mortalities in multivariate analyses (HR = 0.783, 95% CI: 0.696-0.882 for 30-day; HR = 0.860, 95% CI: 0.778-0.950 for 90-day; and HR = 0.883, 95% CI: 0.811-0.961 for 1-year mortality, respectively). Covariate effect analyses showed that the use of H2RAs was more beneficial in essential hypertension patients with age ≥ 60, BMI ≥ 25 kg/m2, coronary arteriosclerosis, stroke, and acute kidney failure, respectively. In conclusion, H2RAs exposure was related to lower mortalities in critically ill patients with essential hypertension, which provided novel potential strategy for the use of H2RAs in essential hypertension patients.

Histamine H2 receptor antagonist exhibited comparable all-cause mortality-decreasing effect as ß-blockers in critically ill patients with heart failure: a cohort study.

Background: Our previous study reported that histamine H2 receptor antagonists (H2RAs) exposure was associated with decreased mortality in critically ill patients with heart failure (HF) through the same pharmacological mechanism as ß-blockers. However, population-based clinical study directly comparing the efficacy of H2RAs and ß-blockers on mortality of HF patients are still lacking. This study aims to compare the association difference of H2RAs and ß-blockers on mortality in critically ill patients with HF using the Medical Information Mart for Intensive Care III database (MIMIC-III). Methods: Study population was divided into 4 groups: ß-blockers + H2RAs group, ß-blockers group, H2RAs group, and Non-ß-blockers + Non-H2RAs group. Kaplan-Meier curves and multivariable Cox regression models were employed to evaluate the differences of all-cause mortalities among the 4 groups. Propensity score matching (PSM) was used to increase comparability of four groups. Results: A total of 5593 patients were included. After PSM, multivariate analyses showed that patients in H2RAs group had close all-cause mortality with patients in ß-blockers group. Furthermore, 30-day, 1-year, 5-year and 10-year all-mortality of patients in ß-blockers + H2RAs group were significantly lower than those of patients in ß-blockers group, respectively (HR: 0.64, 95%CI: 0.50-0.82 for 30-day; HR: 0.80, 95%CI: 0.69-0.93 for 1-year mortality; HR: 0.83, 95%CI: 0.74-0.93 for 5-year mortality; and HR: 0.85, 95%CI: 0.76-0.94 for 10-year mortality, respectively). Conclusion: H2RAs exposure exhibited comparable all-cause mortality-decreasing effect as ß-blockers; and, furthermore, H2RAs and ß-blockers had additive or synergistic interactions to improve survival in critically ill patients with HF.

Discovery and structural optimization of 3-O-ß-chacotriosyl oleanane-type triterpenoids as potent entry inhibitors of SARS-CoV-2 virus infections.

Currently, SARS-CoV-2 virus is an emerging pathogen that has posed a serious threat to public health worldwide. However, no agents have been approved to treat SARS-CoV-2 infections to date, underscoring the great need for effective and practical therapies for SARS-CoV-2 outbreaks. We reported that a focused screen of OA saponins identified 3-O-ß-chacotriosyl OA benzyl ester 2 as a novel small molecule inhibitor of SARS-CoV-2 virus entry, via binding to SARS-CoV-2 glycoprotein (S). We performed structure-activity relationship profiling of 2 and discovered C-17-COOH of OA was an important modification site that improved both inhibitor potency toward SARS-CoV-2 and selectivity index. Then optimization from hit to lead resulted in a potent fusion inhibitor 12f displaying strong inhibition against infectious SARS-CoV-2 with an IC50 value of 0.97 µM in vitro. Mechanism studies confirmed that inhibition of SARS-CoV-2 viral entry of 12f was mediated by the direct interaction with SARS-CoV-2 S2 subunit to block membrane fusion. These 3-O-ß-chacotriosyl OA amide saponins are suitable for further optimization as SARS-CoV-2 entry inhibitors with the potential to be developed as therapeutic agents for the treatment of SARS-CoV-2 virus infections.