Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4-512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.

Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects

Using chemoproteomic techniques, we first identified EIF2AK2, eEF1A1, PRDX3 and VPS4B as direct targets of berberine (BBR) for its synergistically anti-inflammatory effects. Of them, BBR has the strongest affinity with EIF2AK2 via two ionic bonds, and regulates several key inflammatory pathways through EIF2AK2, indicating the dominant role of EIF2AK2. Also, BBR could subtly inhibit the dimerization of EIF2AK2, rather than its enzyme activity, to selectively modulate its downstream pathways including JNK, NF-κB, AKT and NLRP3, with an advantage of good safety profile. In EIF2AK2 gene knockdown mice, the inhibitory IL-1β, IL-6, IL-18 and TNF-α secretion of BBR was obviously attenuated, confirming an EIF2AK2-dependent anti-inflammatory efficacy. The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target, and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammation-related disorders.

Synthesis and biological evaluation of novel tricyclic matrinic derivatives as potential anti-filovirus agents

Twenty-six novel tricyclic sophoridinic and matrinic derivatives containing a common chlorinated benzene fragment were designed, synthesized and evaluated for their anti-ebolavirus (EBOV) activities. Structure-activity relationship analysis indicated: (i) 12-dichlorobenzyl motif was beneficial for the activity; (ii) the chiral configuration at C5 atom might not affect the activity much. Among the target compounds, compound exhibited the most potent potency against EBOV with an IC value of 5.29 μmol/L and an SI value of over 37.8. Further anti-EBOV assay of identified its high effectiveness, and anti-MARV assay of suggested its inspiring broad-spectrum anti-filovirus activity. The results provided powerful information on further strategic optimization and development of this kind of compounds against filoviruses.

Design of a Front-end Device of Heart Rate Variability Analysis System Based on Photoplethysmography / 生物医学工程学杂志

Heart rate variability (HRV) is the difference between the successive changes in the heartbeat cycle, and it is produced in the autonomic nervous system modulation of the sinus node of the heart. The HRV is a valuable indicator in predicting the sudden cardiac death and arrhythmic events. Traditional analysis of HRV is based on a multielectrocardiogram (ECG), but the ECG signal acquisition is complex, so we have designed an HRV analysis system based on photoplethysmography (PPG). PPG signal is collected by a microcontroller from human's finger, and it is sent to the terminal via USB-Serial module. The terminal software not only collects the data and plot waveforms, but also stores the data for future HRV analysis. The system is small in size, low in power consumption, and easy for operation. It is suitable for daily care no matter whether it is used at home or in a hospital.

Synthesis and structure-activity relationship of N-(2-arylethyl) isoquinoline derivatives as anti-cancer agents / 药学学报

A series of novel N-(2-arylethyl) isoquinoline derivatives were designed, synthesized and evaluated for their anti-cancer activities. Among these analogs, compound 9a exhibited the potential anti-cancer activities on HepG2 and HCT116 cells with IC50 values of 2.52 and 1.99 microg x mL(-1), respectively. Cell cycle was blocked at S phase of HepG2 cells treated with 9a by flow cytometry detection. Our results provided a basis for the development of a new series of anti-cancer candidates.