Highly Enantioselective Chiral Diol-Catalyzed Conjugate Addition of Boronic Acids to α,ß-Unsaturated Trifluoromethyl Ketones.

The (R)-3,3'-(3,5-(CF3)2-C6H3)2-BINOL-catalyzed enantioselective conjugate addition of organic boronic acids to α,ß-unsaturated 1,1,1-trifluoromethyl ketones affords corresponding addition products bearing a stereogenic center at the ß-position in moderate to high yields and excellent enantioselectivities (up to 99% ee), without any 1,2-addition product formation. Moreover, this catalytic protocol features mild reaction conditions, a broad substrate scope, suitability for alkenylboronic acids and (hetero)arylboronic acids, and easy scale-up.

Chiral-Boron-Complex Catalyzed Asymmetric Inverse-Electron-Demand Aza-Diels-Alder Reaction of ß-Trifluoromethyl α,ß-Unsaturated Ketones with Cyclic N-Sulfonyl Ketimines.

A highly efficient asymmetric inverse-electron-demand aza-Diels-Alder reaction of ß-trifluoromethyl α,ß-unsaturated ketone with cyclic N-sulfonyl ketimines catalyzed by (R)-3,3'-I2-BINOL-boron-complex was developed. A broad range of fused piperidine derivatives bearing stereogenic carbon containing CF3 motifs were prepared in high yields with excellent diastereo- and enantioselectivities (up to >20:1 dr, and >99% ee). This protocol had the characteristics of mild reaction conditions, high efficiency, and high stereoselectivity.

Enantioselective Synthesis of Chiral Organosilicon Compounds by Organocatalytic Asymmetric Conjugate Addition of Boronic Acids to ß-Silyl-α,ß-Unsaturated Ketones.

Herein, we report (R)-3,3'-(3,5-(CF3)2-C6H3)2-BINOL-catalyzed enantioselective conjugate addition of organic boronic acids to ß-silyl-α,ß-unsaturated ketones, furnishing moderate to excellent yields of the corresponding ß-silyl carbonyl compounds with stereogenic centers in excellent enantioselectivities (up to 98% ee). Moreover, the catalytic system features mild reaction conditions, high efficiency, broad substrate scope, and easy scale-up.

MRGPRX2 is critical for clozapine induced pseudo-allergic reactions.

BACKGROUND: Clozapine is one of the most widely used second-generation antipsychotics in clinic. However, allergy-like symptoms such as rash and angioedema have been reported frequently, and the mechanism is still not clear. Mas-related G protein-coupled receptor X2 (MRGPRX2) expressed on mast cells is a crucial receptor for drug induced pseudo-allergic reactions. Therefore, we explored whether the symptoms induced by clozapine were associated with allergic reaction through MRGPRX2. METHODS: The effects of clozapine on pseudo-allergic reactions were evaluated by mast cells degranulation and calcium mobilization assay in vitro, and mice hindpaw swelling, serum histamine detection, avidin and H&E staining assay in vivo. The overexpressed MRGPRX2 cells membrane chromatography (MRGPRX2-HEK293/CMC), MRGPRX2-HEK293 cells calcium mobilization assay and molecular docking were applied to research the correlation between clozapine and MRGPRX2. RESULTS: The study showed that clozapine induced the release of ß-hexosaminidase, histamine and monocyte chemoattractant protein-1 (MCP-1), and trigged calcium mobilization in mast cells. In vivo, clozapine induced paw swelling, degranulation and vasodilation. Furthermore, clozapine could activate the calcium mobilization obviously in MRGPRX2-HEK293 cells, not in NC-HEK293 cells. Clozapine also had a good retention characteristic on MRGPRX2-HEK293/CMC column and the K D value is (2.33 ± 0.21)×10-01M. CONCLUSIONS: Our findings demonstrated that clozapine could induce pseudo-allergic reactions and MRGPRX2 might be the critical receptor for it.

A combination of depression and liver Qi stagnation and spleen deficiency syndrome using a rat model.

A syndrome (Zheng in Chinese) plays a critical role in disease identification, diagnosis, and treatment in traditional Chinese medicine (TCM). Clinically, the liver Qi stagnation and spleen deficiency syndrome (LQSSDS) is one of the most common syndrome patterns. Over the past few decades, several animal models have been developed to understand the potential mechanisms of LQSSDS, but until now, simulation of the syndrome is still unclear. Recently, several studies have confirmed that an animal model combining a disease and a syndrome is appropriate for simulating TCM syndromes. Overlapping previous studies have reported that depression is highly associated with LQSSDS; hence, we attempted to develop a rat model combining depression and LQSSDS. We exposed the rats to different durations of chronic unpredictable mild stress (CUMS). Subsequently, the evaluation indicators at macrolevel consisted of behavioral tests including open field test, sucrose preference test, and forced swim test, food intake, body weight, white adipose tissue, fecal water content, visceral hypersensitivity, and small bowel transit, and the evaluation indicators at microlevel included changes of hypothalamic-pituitary-adrenal axis. Serum D-xylose absorption was used to comprehensively confirm and assess whether the model was successful during the CUMS-induced process. The results showed that rats exposed to 6-week CUMS procedure exhibited significantly similar traits to the phenotypes of LQSSDS and depression. This study provided a new rat model for the LQSSDS and could potentially lead to a better understanding of the pathophysiology of LQSSDS and the development of new drugs for this syndrome.

Xiaoyaosan Produces Antidepressant Effects in Rats via the JNK Signaling Pathway.

BACKGROUND: Xiaoyaosan (XYS) has achieved definite curative effects in clinic. However, the mechanism is not clear. Previous studies of our team indicated XYS improved anxiety-like behaviors through inhibiting c-Jun N-terminal kinase (JNK) signaling pathway of hippocampus. OBJECTIVES: In the study, we explored whether the JNK signaling pathway is involved in the mechanism of XYS treating depression. METHOD: Forty-eight rats were divided randomly into 4 groups (n = 12): the control group (deionized water, p.o.), the model group (deionized water, p.o.), the fluoxetine group (2.08 mg/kg/day, p.o.), and the XYS group (3.9 g/kg/day, p.o.). All rats except for the control group were given continuous 21 days of chronic immobilization stress (CIS; 3 h/day). On day 29, the body weights and the behavioral tests, including the novelty suppressed feeding test, the open field test, and the elevated plus maze test, were measured. On day 30, all the rats were sacrificed, and three indices of the JNK signaling pathway were tested by Western blot. RESULTS: The body weight and behavioral tests of all groups indicated that 21 days of CIS induced depression-like behaviors. After 21 days of treatment with fluoxetine and XYS, changes were seen in body weight, behaviors, and JNK, phosphorylated JNK (P-JNK), and phosphorylated c-Jun (P-c-Jun) levels in the hippocampus. CONCLUSIONS: XYS ameliorated the depression-like behaviors, potentially through affecting the JNK signaling pathway in the hippocampus.

Synthesis and biological evaluation of novel biphenyl-furocoumarin derivatives as vasodilator agents.

A series of novel biphenyl-furocoumarin derivatives were synthesized based on the nuclear structure of imperatorin and identified by IR, 1H NMR, 13C NMR and MS, and evaluated for their ability to relax vessel on isolated rat mesenteric artery, basilar artery and renal artery, respectively. The majority of compounds demonstrated potent vasodilatation, and compound 8e expressed the highest activity (EC50 = 0.56 µM) in MA. Compounds with fluorine at 2-position of 5-phenyl get better activity than others with chlorine or bromine, and the compounds containing a bulky structure had relatively low activity, such as 8c (EC50 = 22.39 µM) in MA. As a follow-up, 8e, 10e, and 8c were docked into L-calcium channel (PDB code: 3G43) to explain the difference in the activity of the compounds.

Design, synthesis, and evaluation of new series of Imperatorin analogs with potential vasodilatory activity.

Two series of imperatorin analogs were synthesized based on our previous research and evaluated for their vasodilatation activities on in vitro rat mesenteric artery, basilar artery, and renal artery ring models. Target compounds were characterized by infrared, 1H NMR, and mass spectra. Most derivatives possessed significant vasodilatory activity on the mesenteric artery, and compound 3a exhibited favorable and broad vasodilatation activities on three kinds of rat artery ring models. The pharmacological results indicated that introducing nitrogen-contained ring in side chain or large steric hindrance at the distal end could increase the vasodilatory activity. Further, replacement of oxygen atom (-O-) in the skeleton of furocoumarin derivatives with nitrogen (-NH-) could cause the decrease of vasodilatory activity. The molecular docking also indicated that compound 3a showed a best affinity with α-1C receptor (PDB ID: 3G43). All these results suggested compound 3a would be a potential vasodilatory agent for hypertension.

Relationship between Insulin Levels and Nonpsychotic Dementia: A Systematic Review and Meta-Analysis.

Objectives: To explore the relationship between insulin levels and nonpsychotic dementia. Methods: Six electronic databases (PubMed, Cochrane, SCI, CNKI, VIP, and Wanfang) were searched from January 1, 2007, to March 1, 2017. Experimental or observational studies that enrolled people with nonpsychotic dementia or abnormal insulin levels in which insulin levels or MMSE scores (events in nonpsychotic dementia) were the outcome measures. Random-effects models were chosen for this meta-analysis. Sample size, mean, s.d., and events were primarily used to generate effect sizes (with the PRIMA registration number CRD42017069860). Results: 50 articles met the final inclusion criteria. Insulin levels in cerebrospinal fluid were lower (Hedges' g = 1.196, 95% CI = 0.238 to 2.514, and P = 0.014), while the levels in peripheral blood were higher in nonpsychotic dementia patients (Hedges' g = 0.853 and 95% CI = 0.579 to 1.127), and MMSE scores were significantly lower in the high insulin group than in the healthy control group (Hedges' g = 0.334, 95% CI = 0.249 to 0.419, and P = 0.000). Conclusions: Our comprehensive results indicate that blood insulin levels may increase in patients with nonpsychotic dementia.