Highly Chemoselective Synthesis of Purino[3,2-c]oxazoles via the Asymmetric Dearomative [3+2] Cycloaddition of Purines with Donor-Acceptor Oxiranes.

A Ni(II)/bisoxazoline-catalyzed asymmetric dearomative [3+2] cycloaddition of substituted purines with donor-acceptor oxiranes was developed. This reaction, which proceeds via highly chemoselective C-C bond cleavage of the oxiranes, accesses chiral purino[3,2-c]oxazole compounds (≤99% ee after enrichment via crystallization). The electronic effects of the purine ring determine the reactivity of the substrate. The general applicability of this method was illustrated by gram-scale synthesis, the diverse transformations of the product, and the promising biological activities of selected derivatives.

Safety and efficacy of metformin in systemic lupus erythematosus: a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Immunometabolism is involved in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to repurpose metformin, an anti-diabetic drug that regulates systemic and cellular metabolism, and assess its effects in Chinese patients with SLE without diabetes. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled trial in three hospitals in Shanghai, China. We enrolled adult patients with SLE, without diabetes, who had Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores no higher than 6; with no A score or no more than one B score on the British Isles Lupus Assessment Group (BILAG) scale at screening; who had had at least one lupus flare; and were treated with prednisone (≥20 mg per day) within the preceding 12 months. Patients were randomly assigned (1:1) in blocks of four by a computer algorithm to add metformin tablets (250 mg per tablet with a target dose of 0·5 g three times per day; metformin group) or placebo tablets (placebo group) to their standard therapy, for a maximum of 12 months. Patients, assessment staff, and statisticians were masked to group assignment. The primary endpoint was a composite index of major or mild-to-moderate disease flares (SELENA-SLEDAI Flare Index) at 12 months. The full analyses were done in all patients who received at least one dose of the study drug using the χ2 test. Adverse events were recorded during the 12-month follow-up. This study is registered with ClinicalTrials.gov, NCT02741960. FINDINGS: Between May 24, 2016, and Dec 13, 2017, 180 patients were screened, of whom 140 (78%) of them were enrolled. 31 (17%) did not meet the inclusion criteria and nine (5%) withdrew informed consent without treatment after randomisation. 67 patients were assigned to the metformin group and 73 to the placebo group. By 12 months of follow-up, there was no significant difference in the incidence of lupus flares, which occurred in 14 (21%) patients in the metformin group versus 25 (34%) in the placebo group (relative risk 0·68, 0·42-1·04, p=0·078). Patients receiving metformin experienced more gastrointestinal adverse events (three [4%] discontinued for this reason vs one [1%] for placebo; overall 26 [39%] vs 11 [15%], p=0·0015), but the incidence of non-flare serious adverse events was similar between groups (one [1%] vs three [4%], p=0·35). The frequency of infection events was significantly lower in patients in the metformin group than in the placebo group (17 [25%] vs 32 [44%], p=0·022). No patients died as a result of treatment. INTERPRETATION: This trial was underpowered to draw a sound conclusion on the efficacy of metformin to reduce disease flares as an add-on treatment to standard care in patients with SLE. Nonetheless, metformin had a favourable safety profile and our data present a basis for larger trials to investigate its potential effect on reducing the frequency of flares for patients with SLE with low-grade disease activity who are at risk of relapse. FUNDING: Shanghai Shenkang Promoting Project and the National Key Research and Development Program of China.

A new method to quantify the health risks from sources of perfluoroalkyl substances, combined with positive matrix factorization and risk assessment models.

A hybrid model based on the positive matrix factorization (PMF) model and the health risk assessment model for assessing risks associated with sources of perfluoroalkyl substances (PFASs) in water was established and applied at Dianchi Lake to test its applicability. The new method contains 2 stages: 1) the sources of PFASs were apportioned by the PMF model and 2) the contribution of health risks from each source was calculated by the new hybrid model. Two factors were extracted by PMF, with factor 1 identified as aqueous fire-fighting foams source and factor 2 as fluoropolymer manufacturing and processing and perfluorooctanoic acid production source. The health risk of PFASs in the water assessed by the health risk assessment model was 9.54 × 10-7 a-1 on average, showing no obvious adverse effects to human health. The 2 sources' risks estimated by the new hybrid model ranged from 2.95 × 10-10 to 6.60 × 10-6 a-1 and from 1.64 × 10-7 to 1.62 × 10-6 a-1 , respectively. The new hybrid model can provide useful information on the health risks of PFAS sources, which is helpful for pollution control and environmental management. Environ Toxicol Chem 2018;37:107-115. © 2017 SETAC.

Source profiles and contributions of biofuel combustion for PM2.5, PM10 and their compositions, in a city influenced by biofuel stoves.

Source and ambient samples were collected in a city in China that uses considerable biofuel, to assess influence of biofuel combustion and other sources on particulate matter (PM). Profiles and size distribution of biofuel combustion were investigated. Higher levels in source profiles, a significant increase in heavy-biomass ambient and stronger correlations of K+, Cl-, OC and EC suggest that they can be tracers of biofuel combustion. And char-EC/soot-EC (8.5 for PM2.5 and 15.8 for PM10 of source samples) can also be used to distinguish it. In source samples, water-soluble organic carbon (WSOC) were approximately 28.0%-68.8% (PM2.5) and 27.2%-43.8% (PM10) of OC. For size distribution, biofuel combustion mainly produces smaller particles. OC1, OC2, EC1 and EC2 abundances showed two peaks with one below 1 µm and one above 2 µm. An advanced three-way factory analysis model was applied to quantify source contributions to ambient PM2.5 and PM10. Higher contributions of coal combustion, vehicular emission, nitrate and biofuel combustion occurred during the heavy-biomass period, and higher contributions of sulfate and crustal dust were observed during the light-biomass period. Mass and percentage contributions of biofuel combustion were significantly higher in heavy-biomass period. The biofuel combustion attributed above 45% of K+ and Cl-, above 30% of EC and about 20% of OC. In addition, through analysis of source profiles and contributions, they were consistently evident that biofuel combustion and crustal dust contributed more to cation than to anion, while sulfate & SOC and nitrate showed stronger influence on anion than on cation.

Source regional contributions to PM2.5 in a megacity in China using an advanced source regional apportionment method.

To quantify contributions of individual source categories from diverse regions to PM2.5, PM2.5 samples were collected in a megacity in China and analyzed through a newly developed source regional apportionment (SRA) method. Levels, compositions and seasonal variations of speciated PM2.5 dataset were investigated. Sources were determined by Multilinear Engine 2 (ME2) model, and results showed that the PM2.5 in Tianjin was mainly influenced by secondary sulphate & secondary organic carbon SOC (percent contribution of 26.2%), coal combustion (24.6%), crustal dust & cement dust (20.3%), secondary nitrate (14.9%) and traffic emissions (14.0%). The SRA method showed that northwest region R2 was the highest regional contributor to secondary sources, with percent contributions to PM2.5 being 9.7% for secondary sulphate & SOC and 6.0% for secondary nitrates; the highest coal combustion was from local region R1 (6.2%) and northwest R2 (8.0%); the maximum contributing region to crustal & cement dust was southeast region R4 (5.0%); and contributions of traffic emissions were relatively spatial homogeneous. The seasonal variation of regional source contributions was observed: in spring, the crustal and cement dust contributed a higher percentage and the R4 was an important contributor; the secondary process attributed an increase fraction in summer; the mixed coal combustion from southwest R5 enhanced in autumn.

Centrally administered apelin-13 induces depression-like behavior in mice.

Apelin, a novel bioactive peptide highly concentrated in the brain, is identified as the endogenous ligand for angiotensin-like 1 receptor (APJ). The present study was designed to investigate the effect of apelin-13 on emotion-related behavior using the forced swimming test (FST) and tail suspension test (TST). Intracerebroventricular (i.c.v.) administration of apelin-13 (0.3, 1 and 3µg/mouse) dose-dependently increased the immobility time in the FST and TST, compared with control group. However, the APJ receptor antagonist apelin-13(F13A) (0.3-10µg/mouse, i.c.v.) had no influence on immobility time in the FST. The increase of immobility time induced by apelin-13 was significantly blocked by apelin-13(F13A), non-selective opioid receptor antagonist naloxone and κ-opioid receptor antagonist nor-binaltorphimine dihydrochloride (nor-BNI), respectively, but not the non-selective corticotrophin-releasing factor (CRF) receptor antagonist α-helical CRF(9-41) in the FST. In order to eliminate the possibility of a false-positive result in the FST or TST, spontaneous activity and motor function were checked. The results demonstrate that apelin-13 alone or antagonists co-administered with apelin-13 did influence spontaneous activity counts. And apelin-13 had no effect on the motor behavior in the rotarod test and wire hanging test. These results indicate that centrally administered apelin-13 elicited depression-like behavior in mice, which was mediated via APJ receptor and κ-opioid receptor, but not CRF receptor.