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.

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.

Objective:Evidence on potential cardiovascular benefits of personal-level intervention among the elderly exposed to high levels of particulate matter(PM)remains limited.We aimed to assess improvements in surrogate markers of cardiovascular injury in vulnerable populations at risks by using indoor air filtration units.Methods:We conducted a randomized crossover trial for 2 separate 2-week air filtration interventions in 20 households of patients with stable chronic obstructive pulmonary disease and their partners in the winter of 2013,with concurrent measurements of indoor PM.The changes in biomarkers indicative of cardiac injury,atherosclerosis progression and systemic inflammation following intervention were evaluated using linear mixed-effect models.Results:In the analysis,average levels of indoor PM with aerodynamic diameters＜2.5 μm(PM2.5)decreased significantly by 59.2％(from 59.6 to 24.3 μg/m3,P＜0.001)during the active air filtration.The reduction was accompanied by improvements in levels of high-sensitivity cardiac troponin I by-84.6％(95％confidence interval[CI]:-90.7 to-78.6),growth differentiation factor-15 by-48.1％(95％CI:-31.2 to-25.6),osteoprotegerin by-65.4％(95％CI:-56.5 to-18.7),interleukin-4 by-46.6％(95％CI:-62.3 to-31.0)and myeloperoxidase by-60.3％(95％CI:-83.7 to-3.0),respectively.Conclusion:Indoor air filtration intervention may provide potential cardiovascular benefits in vulnerable popu-lations at risks.

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.

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.

Taking 12-N-p-chlorobenzyl sophoridinol 2 as a lead, a series of novel sophoridinic derivatives with various 3'-substituents at the 11-side chain were synthesized and evaluated for their anticancer activity from sophoridine (1), a natural antitumor medicine. Among them, the sophoridinic ketones 5a-b, alkenes 7a-b and sophoridinic amines 14a-b displayed reasonable antiproliferative activity with IC50 values ranging from 3.8 to 5.4 μmol/L. Especially, compounds 5a and 7b exhibited an equipotency in both adriamycin (AMD)-susceptible and resistant MCF-7 breast carcinoma cells, indicating a different mechanism from AMD. The primary mechanism of action of 5a was to arrest the cell cycle at the G0/G1 phase, consistent with that of parent compound 1. Thus, we consider 12-chlorobenzyl sophoridinic derivatives with a tricyclic scaffold to be a new class of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.

Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.
Antibodies, Monoclonal ; immunology ; therapeutic use ; Antibodies, Monoclonal, Humanized ; immunology ; therapeutic use ; B7-H1 Antigen ; antagonists & inhibitors ; immunology ; Humans ; Neoplasms ; drug therapy ; immunology ; pathology ; Programmed Cell Death 1 Receptor ; antagonists & inhibitors ; immunology ; Signal Transduction ; drug effects ; immunology ; T-Lymphocytes ; immunology

Aim To investigate the ameliorative effects pseudoberberine(Y53), a berberine(BBR) analogue, on diabetic nephropathy( DN) in streptozotocin( STZ)-induced diabetic mice. Methods Diabetes mellitus ( DM) of the C57BL/6J mice was induced by intraper-itoneal injection of STZ at 120 mg·kg-1 . The diabetic animals were divided into 4 groups, which were orally treated with saline, 50 mg · kg-1 of BBR, 50 mg · kg-1 of Y53 or 5 mg · kg-1 of rosiglitazone ( ROSI ) , respectively. During and after the experiment, the u-rine, blood, serum and kidney of the animals were harvested for determination of relevant parameters by kits. Kidney tissues of the mice were subjected to pathological examination by hematoxylin & eosin( HE) staining;mRNA and protein expression levels of target genes in the kidney were determined by quantitative re-al-time reverse transcriptase-polymerase chain reaction ( qRT-PCR) and Western blot, respectively. Results Y53 greatly reduced the fasting blood glucose ( FBG ) and glycosylated hemoglobin( GHb) , improved diabet-ic symptoms such as polyphagia and polyuria in the di-abetic mice( P<0. 01 vs DM control group) . Y53 po-tently reduced the blood urea nitrogen ( BUN ) , serum creatinine( Scr) , 24 h urinary protein, kidney index, serum and kidney advanced glycation end-products ( AGEs) and nitric oxide( NO) , as well as kidney cho-lesterol( CHO ) and triglyceride ( TG ) contents ( P <0. 05 or P<0. 01 vs DM control group) . In the patho-logical examination, Y53 greatly restored kidney mor-phology and suppressed glomerular sclerosis( P<0. 001 vs DM control group). In addition, Y53 significantly reduced the renal expression of fibrosis-related genes, such as the transforming growth factor-β1 ( TGF-β1 ) and smad2(P<0. 01 vs DM control group). The reno-protective efficacies of Y53 were superior to those of BBR and ROSI in our study ( P<0. 05 or P<0. 01 ) . Conclusions The BBR analogue Y53 has potent ac-tivities in ameliorating renal injury and restoring renal function in STZ-induced diabetic mice. Y53 may be developed as a novel kind of agent for the treatment of DN in the future.

Objective To investigate the effects of maxillary protraction combined with repetitive rapid palatal expansions and constrictions(RPE/C) vs.rapid palatal expansion(RPE) alone using cone-beam computed tomography(CBCT).Methods Twenty four subjects with maxillary retrusion were recruited and block randomized into either the control group(n=12) or the RPE/C(n=12) group.Control group:facemask protraction after RPE.RPE/C group:facemask protraction after RPE/C.3D reconstruction,landmarks identifying,superimposition and cephalometric analysis were performed to compare the pre-treatment and post-treatment CBCT images.Results One subject in the RPE/C group was lost to follow up during the treatment.Maxilla moved forward[(2.5 ± 1.0) mm] after maxillary protraction with RPE/C,which was significantly greater than that in the control group[(1.6±0.8) mm](P＜0.05).The distance of basion to subspinale (Ba-A) increased[(3.1 ± 1.0) mm] in the RPE/C group,which was significantly greater than that in the control group[(2.2 ± 0.9) mm] (P＜0.05).The amount of forward movement of upper first molars was significantly greater in the RPE/C group(P＜0.05).Conclusions Maxillary protraction with RPE/C might positively affect the forward movement of maxilla compared with the RPE alone protocol with the early treatment of maxillary retrusion patients.

Chronic hepatitis C virus (HCV) infection has become a major public health burden worldwide. Twenty-two sophocarpinic acid or matrine derivatives were synthesized and their anti-HCV activities were evaluated in vitro. The structure-activity analysis revealed that (i) sophocarpinic acids with a D-seco 3-ring structure scaffold were more favorable than matrines with a 4-ring scaffold; (ii) the introduction of an electron-withdrawing group on the phenyl ring in 12-N-benzenesulfonyl Δ (βγ) sophocarpinic acids was beneficial for the antiviral activity against HCV. Among them, compounds 9h and 9j exhibited the most potent inhibitory activities on HCV replication with selectivity indies of 70.3 and 30.9, respectively. Therefore, both were selected as antiviral candidates for further investigation.