Synthesis and evaluation on triglyceride inhibitory activities of novel indole alkaloids / 药学学报

Three tricyclic [6,5,7] and six tetracyclic [6,5,5,5] novel indole alkaloids were synthesized and evaluated on triglyceride inhibitory activities for the first time. Among them, compound 4c showed the most potent activity with IC50 value of 6.35 μmol·L-1. Meanwhile, compound 4c also exhibited a good safety profile at the cellular level. Preliminary mechanism study indicated that 4c might increase intracellular lipid metabolism by activating AMPK. These results provide a novel family of lead compounds for the discovery of anti-NAFLD candidates.

Anti-MRSA activities of cycloberberine derivatives with a novel chemical scaffold / 药学学报

Using CBBR as the parent core constructed in our lab, we designed and synthesized 15 novel compounds with diverse structures for evaluation of anti-bacterial activities. Structure activity relationship studies revealed that ① ring C was essential for the activity; ② 7,8- or 8,13-disubstituted CBBR derivatives showed ideal activities, weaker or similar to those corresponding to 7-, 8-, or 13-monosubstituted CBBR derivatives. Among those, compound 9a showed the most potential activity against MRSA/VISA isolates with MIC values of 1-2 μg·mL-1, much better than Lev. 9a also displayed higher stability in the plasma and liver microsomes. Molecular docking indicated that 9a might target bacterial DNA Topo IV ParE subunit, indicating a mode of action distinct from current antibacterial drugs on market. The results provided key scientific evidence for developing such compounds into a new family of anti-MRSA drugs.

A pilot clinical study of adjunctive therapy with selective intracoronary hypothermia in patients with ST-segment elevation myocardial infarction.

OBJECTIVES: We aimed to assess the effect of selective intracoronary hypothermia on outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). BACKGROUND: Intracoronary hypothermia, the feasibility and safety of which has been validated in humans, induced by selective trans-coronary infusion of saline at different temperatures can reduce infarct size (IS) prior to reperfusion in animal models of STEMI. METHODS: Sixty STEMI patients presenting with thrombolysis in myocardial infarction (TIMI) flow grade 0/1 were randomized after coronary artery angiography. Intracoronary hypothermia was induced by selective trans-coronary infusion of saline at 4°C to the endangered myocardium in the 30 patients. The primary endpoint, absolute IS expressed as IS/myocardium at risk (MaR), was assessed by cardiac magnetic resonance imaging at day 7 post-PPCI in 50 patients. Clinical follow-up was undertaken at day 30 after procedure. RESULTS: Intracoronary hypothermia was successfully performed in hypothermia group, without increase in arrhythmia or hemodynamic instability. The mean temperature reduction of 5.8 ± 1.1°C in distal coronary artery was achieved before reperfusion. Mean IS/MaR was predominantly reduced in the hypothermia group (44.85 ± 5.89% vs. 50.69 ± 10.75%, P = 0.022), especially in the anterior STEMI subgroup (46.12 ± 7.54% vs. 55.27 ± 11.175%, P = 0.023). The clinical events appeared no statistical difference between the two groups at the 30-day follow-up. CONCLUSION: The statistical difference in IS/MaR by intracoronary hypothermia as adjunctive therapy to PPCI is an important observation and warrants a larger pivotal trial fully powered for efficacy.

Design, synthesis and anti-MRSA activities of cycloberberine derivatives with a novel chemical scaffold / 药学学报

9-Acetoxycycloberberine (1) with a unique skeleton was first identified to display a potent antimicrobial profile against methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 1-16 μg·mL-1. Taking the compound as a lead, 14 target cycloberberine analogues with diverse structures, such as berberine and chelerythrine derivatives, were synthesized and evaluated for their anti-bacterial activities. Analysis of the structure-activity relationship revealed that:① ring E was essential for the activity; ② the removing of ring B decreased the activity against MRSA. However, the antimicrobial activity against vancomycin-resistant Enterococcus faecium (VRE) was improved; ③ the introduction of a suitable rigid substituent at the 9-position was beneficial for the activity. Among them, compound 9a showed the most potential activity against methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA isolates with MIC values of 0.5-1 μg·mL-1, suggesting a different mechanism from clinical drugs. It displayed higher stability in blood. Therefore, we consider 9a worthy of further investigation. The results provide key scientific evidence for development of such compounds into a new type of anti-MRSA candidates.

Combined Effects of Family History of Cardiovascular Disease and Serum C-reactive Protein Level on the Risk of Stroke: A 9.2-year Prospective Study among Mongolians in China.

OBJECTIVE: We aimed to evaluate the combined effect of a family history of cardiovascular disease (CVD) and high serum C-reactive protein (CRP) on the stroke incidence in an Inner Mongolian population in China. METHODS: A prospective cohort study was conducted from June 2002 to July 2012, with 2,544 participants aged 20 years and over from Inner Mongolia, China. We categorized participants into four groups based on the family history of CVD and CRP levels. RESULTS: We adjusted for age; sex; smoking; drinking; hypertension; body mass index; waist circumference; and blood glucose, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels. Compared with the group with no family history of CVD/low CRP levels, the group with family history of CVD/high CRP levels had a hazard ratio (HR) of 1.78 [95% confidence interval (CI), 1.03-3.07; P = 0.039] of stroke, and an HR of 2.14 (95% CI, 1.09-4.20; P = 0.027) of ischemic stroke. The HRs of hemorrhagic stroke for the other three groups were not statistically significant (all P > 0.05). CONCLUSION: Participants with both a family history of CVD and high CRP levels had the highest stroke incidence, suggesting that high CRP levels may increase stroke risk, especially of ischemic stroke, among individuals with a family history of CVD.

C-reactive Protein Level, Apolipoprotein B-to-apolipoprotein A-1 Ratio, and Risks of Ischemic Stroke and Coronary Heart Disease among Inner Mongolians in China.

OBJECTIVE: We aimed to investigate the cumulative effect of high CRP level and apolipoprotein B-to-apolipoprotein A-1 (ApoB/ApoA-1) ratio on the incidence of ischemic stroke (IS) or coronary heart disease (CHD) in a Mongolian population in China. METHODS: From June 2003 to July 2012, 2589 Mongolian participants were followed up for IS and CHD events based on baseline investigation. All the participants were divided into four subgroups according to C-reactive protein (CRP) level and ApoB/ApoA-1 ratio. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the IS and CHD events in all the subgroups. RESULTS: The HRs (95% CI) for IS and CHD were 1.33 (0.84-2.12), 1.14 (0.69-1.88), and 1.91 (1.17-3.11) in the 'low CRP level with high ApoB/ApoA-1', 'high CRP level with low ApoB/ApoA-1', and 'high CRP level with high ApoB/ApoA-1' subgroups, respectively, in comparison with the 'low CRP level with low ApoB/ApoA-1' subgroup. The risks of IS and CHD events was highest in the 'high CRP level with high ApoB/ApoA-1' subgroup, with statistical significance. CONCLUSION: High CRP level with high ApoB/ApoA-1 ratio was associated with the highest risks of IS and CHD in the Mongolian population. This study suggests that the combination of high CRP and ApoB/ApoA-1 ratio may improve the assessment of future risk of developing IS and CHD in the general population.

Study on chemical constituents of Inula cappa / 中国中药杂志

Column chromatographies over silica gel, Sephadex LH-20, reverse phase C18, and MCI, and semi-preparative HPLC were used for separation and purification of constituents from Inula cappa. The 22 compounds were obtained and their strutures were determined by NMR and MS spectra data as nine flavonoids: luteolin (1), apigenin (2), chrysoeriol (3), artemetin (4), 2', 5-di- hydroxy-3, 6, 7, 4', 5'-pentamethoxyflavone (5), chrysosplenol C (6), apigenin-5-0-β-D-glucopyranoside (7), luteolin-3-methyl, luteolin-3-methylether-4'-0-β-D-glucopyranoside (8), luteolin-4'-0-β-D-glucopyranoside (9); four triterpenes: darma-20, 24-dien- 3β-0-acetate (10), darma-20, 24-dien-3β-ol (11), epirfiedelanol (12), friedelin (13); three coumarins: scopoletin (14) , isosco- poletin (15) , scopolin(16) , and other types of compounds stigmasta-5, 22-dien-3β-0-7-one (17), stigmasterol (18), palmitic acid (19), linoleic acid (20), linoleic acid methyl ester (21), (E) -9, 12, 13-trihydroxyoetadee-10-enoie acid (22). Compound 5 is a new natural product. Compounds 3-9, 15, 17, 21, and 22 were isolated from this genus for the first time.