LC-MS/MS based untargeted lipidomics uncovers lipid signatures of late-onset preeclampsia.

The mechanisms underlying late-onset preeclampsia (LOPE) remain unknown. Metabolic disturbances have been implicated as a primary factor in LOPE development. Lipids have been shown to have great clinical value in recent years. This study aimed to use lipidomics to provide evidence for the etiology and potential therapeutic approaches for LOPE. Twenty patients with LOPE and 20 healthy controls were enrolled in this study. Placental lipidomic data were acquired using liquid chromatographymass spectrometry (LC-MS/MS), and the data were analyzed by weighted gene correlation network analysis (WGCNA) and statistical methods. Of 1508 identified lipids, 226 were differentially expressed between the LOPE and control groups. In the LOPE group, the abundance of most unsaturated triglycerides (TG) increased, whereas that of other lipids, including phosphatidylcholine (PC), sphingomyelin, and phosphatidylserine (PS) increased. The WGCNA implied that the correlation network module of lipids was highly related to clinical traits. Pathway analysis revealed that these dysregulated lipids are closely related to glycerophospholipid metabolism. Lipidomics may help identify the pathogenesis underlying placental dysfunction in LOPE patients and provide potential therapeutic targets in the future.

Chemical constituents of Ferula seravschanica.

Phytochemical investigation of Ferula seravschanica afforded seven new compounds, including three new bicyclic-type sesquiterpene coumarins (1-3), two new monocyclic-type sesquiterpene coumarins (16-17), two new phenylpropanoids (23-24) as well as twenty-two known compounds (4-15, 18-22, and 25-29). The structures of new compounds were determined by HRESIMS, NMR, ECD calculations, and X-ray single-crystal diffraction analysis. Furthermore, crude EtOAc extract and separated fractions (F1-F12) possessed cytotoxic activity against four human tumor cell lines (HT-29, DU145, HeLa, and Jurkat). Subsequently, we examined Jurkat inhibitory activity of isolated compounds. Compound 12 significantly inhibited the proliferation of the leukemia cells with IC50 value of 2.50 µM.

Hand-foot-skin reaction of grade ≥ 2 within sixty days as the optimal clinical marker best help predict survival in sorafenib therapy for HCC.

Background & Aims Sorafenib-related adverse events have been reported as clinical surrogates for treatment response in hepatocellular carcinoma (HCC); however, no consensus has been reached regarding the definition of responders. We evaluated the predictive abilities of different definitions for sorafenib response based on treatment-emergent adverse events, aiming to identify the most discriminatory one as a clinical marker. Methods From January 2010 to December 2014, 435 consecutive HCC patients treated with sorafenib were enrolled. Considering the type, severity and timing of adverse events, twelve different categories of sorafenib response were defined. By comparing their discriminatory abilities for survival, an indicative criterion was defined, the prognostic value of which was evaluated by time-dependent multivariate analysis, validated in various subsets and confirmed by landmark analysis. Results Using concordance (C)-index analysis and time-dependent receiver operating characteristic curves, the development of a hand-foot-skin reaction ≥ grade 2 within 60 days of sorafenib initiation (2HFSR60) showed the highest discriminating value. Based on this criterion, 161 (37.0%) sorafenib responders achieved decreased risk of death by 47% (adjusted HR 0.53, 95%CI 0.43-0.67, P < 0.001) and likelihood of progression by 26% (adjusted HR 0.74, 95%CI 0.58-0.96, P = 0.020) compared with non-responders. Notably, 2HFSR60 remained an effective discriminator among most subgroups and had superior predictive ability to previous definitions, even according to the landmark analysis. Conclusions Our study demonstrated that 2HFSR60, with the best discriminatory ability compared to currently available definitions of sorafenib-related adverse events, could be the optimal clinical marker to identify sorafenib responders with decreased risk of death by half.

Discovery of a New Pterocarpan-Type Antineuroinflammatory Compound from Sophora tonkinensis through Suppression of the TLR4/NFκB/MAPK Signaling Pathway with PU.1 as a Potential Target.

Neuroinflammation underlies many neuro-degenerative diseases. In this paper, we report the identification of a new pterocarpan-type anti-inflammatory compound named sophotokin isolated from Sophora tonkinensis. S. tonkinensis has been used traditionally for treatment of conditions related to inflammation. Our initial screening showed that sophotokin dose-dependently inhibits lipopolysaccharide (LPS)-stimulated production of NO, TNF-α, PGE2, and IL-1ß in microglial cells. This antineuroinflammatory effect was associated with sophotokin's blockade of LPS-induced production of the inflammatory mediators iNOS and COX-2. Western blot and qPCR analysis demonstrated that sophotokin inhibits both the p38-MAPK and NF-κB signal pathways. Further studies revealed that sophotokin also suppresses the expression of cluster differentiation 14 (CD14) in the toll-like receptor 4 (TLR4) signaling pathway. Following down-regulation of MyD88 and TRAF6, sophotokin inhibits the activation of the NF-κB and MAPK signal pathways in LPS-induced BV-2 cells. In silico studies suggested that sophotokin could interact with PU.1-DNA complex through hydrogen binding at sites 1 and 2 of the complex, blocking the DNA binding. This suggests that PU.1 may be a potential target of sophotokin. Taken together, these results suggest that sophotokin may have therapeutic potential for diseases related to neuroinflammation. The mechanism of antineuroinflammatory effects involves inhibition of the TLR4 signal pathway at the sites of NF-κB and MAPK with PU.1 as a likely upstream target.

Cembrane-type diterpenoids from Macaranga pustulata.

Three new cembrane-type diterpenoids, deheiculatins M-O (1-3), together with five known analogues (4-8), were isolated from the twigs of Macaranga pustulata King ex Hook. The structures of new compounds 1-3 were elucidated by extensive spectroscopic analyses, modified Mosher's method, and the experimental and calculated electronic circular dichroism (ECD) experiments. All the isolates were evaluated for their cytotoxicity on three human cancer cell lines (CNE1, CNE2, and HCT 116), and all of them showed weak cytotoxicity (IC50 > 20 µM).

Berberine containing quadruple therapy for initial Helicobacter pylori eradication: An open-label randomized phase IV trial.

BACKGROUND: Due to increasing antimicrobial resistance, a bismuth-based quadruple regimen has been recommended as an alternative first-line therapy for Helicobacter pylori (H pylori) eradication. However, different results are varied greatly and the availability of bismuth was limited in some countries. We assessed the efficacy and safety of 14-day berberine-containing quadruple therapy as an alternative regimen for H pylori eradication. METHODS: In a randomized, open-label, non-inferiority, phase IV trial between November 25, 2014, and October 15, 2015, 612 treatment-naive patients were randomly assigned to 14-day berberine-containing (n = 308) or 14-day bismuth-containing (n = 304) quadruple therapy. The primary outcomes were eradication rates determined by the C urea breath test (C-UBT) 28 days after the end of treatment. The secondary outcomes were adverse events and compliance. RESULTS: The baseline demographic data including age, gender, body mass index (BMI), general condition and severity score were not statistically different in both groups. The eradication rates in bismuth and berberine groups were 86.4% (266/308) and 90.1% (274/304) in intention-to-treat (ITT) analysis (P = .149), and 89.6% (266/297) and 91.3% (273/299) in per-protocol (PP) analysis (P = .470), respectively. No statistically significant difference was found in the overall incidence of adverse events between both groups (35.7% vs 28.6%, P = .060). CONCLUSIONS: Both regimens achieved the recommended efficacy for H pylori eradication. The berberine-containing quadruple regimen was not inferior to bismuth-containing quadruple regimen and can be recommended as an alternative regimen for H pylori eradication in the local region.

Pterosin Sesquiterpenoids from Pteris cretica as Hypolipidemic Agents via Activating Liver X Receptors.

Four new pterosin sesquiterpenoids (1-4), a new ent-kaurane diterpenoid (17), and 18 known compounds were isolated from the aerial parts of Pteris cretica L. The structures of the isolates were elucidated based on spectroscopic data analysis, and their absolute configurations were determined by comparison of experimental and calculated electronic circular dichroism spectra. The compounds were evaluated for lipid-lowering effects in 3T3-L1 adipocytes. Compounds 4, 8, 17, and 22 were more potent than the positive control, berberine, in decreasing triglycerides activity, with compound 4 exerting the most potent activity. Compound 4 activated LXRα/ß in a HEK 293T cell-based reporter gene assay. Molecular dynamic simulations revealed that compound 4 activates liver X receptors (LXRs) through hydrogen bonding with the residues of LXRα/ß, suggesting that compound 4 reduces total triglycerides through the regulation of LXRα/ß.