Palladium-Catalyzed Asymmetric Decarboxylation of 5-Vinyloxazolidine-2,4-Diones Triggering the Dearomatization of Electron-Deficient Indoles for the Synthesis of Chiral Highly Functionalized Pyrroloindolines.

A catalyst system consisting of a chiral phosphoramidite ligand and Pd2(dba)3·CHCl3 causes the decarboxylation of 5-vinyloxazolidine-2,4-diones to generate amide-containing aza-π-allylpalladium 1,3-dipole intermediates, which are capable of triggering the dearomatization of 3-nitroindoles for diastereo- and enantioselective [3+2] cycloaddition, leading to the formation of a series of highly functionalized pyrroloindolines containing three contiguous stereogenic centers with excellent results (up to 99% yield, 88:12 dr, and 96% ee).

Diastereoselective Formal 1,3-Dipolar Cycloaddition of Trifluoroethyl Amine-Derived Ketimines Enables the Desymmetrization of Cyclopentenediones.

In this research, a metal-free diastereoselective formal 1,3-dipolar cycloaddition of N-2,2,2-trifluoroethylisatin ketimines and cyclopentene-1,3-diones which can efficiently lead to the desymmetrization of cyclopentene-1,3-diones is developed. With the developed protocol, a series of tetracyclic spirooxindoles containing pyrrolidine and cyclopentane subunits can be smoothly obtained with good results (up to 99% yield and 91:9 dr). Furthermore, the methodology can be extended to trifluoromethyl-substituted iminomalonate, and the corresponding formal [3+2] cycloaddition reaction affords bicyclic heterocycles containing fused pyrrolidine and cyclopentane moieties in moderate yields with >20:1 dr. The synthetic potential of the methodology is demonstrated by the scale-up experiment and by versatile transformations of the products.

Catalytic enantioselective hydrophosphinylation of in situ-generated indole-derived vinylogous imines to access 3-(1-diphenylphosphoryl-arylmethyl)indoles.

An efficient organocatalyzed enantioselective hydrophosphinylation of indole-derived vinylogous imines generated in situ from sulfonyl indoles has been developed. Using quinine-derived bifunctional thiourea as the catalyst, a wide range of structurally diverse chiral 3-(1-diphenylphosphoryl-arylmethyl)indoles were obtained with good to excellent results (up to 99% yield and 99% ee). This method represents the first example of the catalytic asymmetric Michael addition of phosphine oxides to vinylogous imine intermediates.

Interactions of chlorogenic acid and isochlorogenic acid A with model lipid bilayer membranes: Insights from molecular dynamics simulations.

Because of the negative side-effects of synthetic preservatives, the naturally-occurring polyphenols aroused intense interest of researchers. It has been suggested that chlorogenic acid (CA) and isochlorogenic acid A (iso-CAA) were good candidates to replace the synthetic preservatives. Moreover, the bactericidal activity of iso-CAA was stronger than CA, and the anti-bacterial activities of iso-CAA and CA were highly membrane-dependent. However, the mechanisms were still unclear. Therefore, in the present study, we investigated the mechanisms of the interactions between the two polyphenols and lipid bilayers through molecular dynamics simulations. The results revealed that iso-CAA could be inserted much deeper into POPG lipid bilayer than CA. We also found that hydrophobic interactions and hydrogen bonds both contributed to the insertion of iso-CAA into the POPG lipid bilayer, and the quinic acid moiety was the key structure in iso-CAA to form hydrogen bonds with POPG lipid bilayer. We believed that these findings would provide more useful information to explain the stronger bactericidal activity of iso-CAA than CA at the atomic level.

Influence of the gallate moiety on the interactions between green tea polyphenols and lipid membranes elucidated by molecular dynamics simulations.

Previous studies suggested that naturally occurring EGCG primarily acted on the bacterial cell membrane then damaged the membrane and the gallate moiety in EGCG was very important to its anti-bacterial activity. However, the detailed mechanisms were still poorly understood. In this paper, EGCG and EGC were selected to study the great contribution of gallate moiety on the anti-bacterial activities of polyphenols. The results indicated that EGCG could penetrate deeper into the POPG lipid bilayer and possess more potent structure-perturbing potency on the POPG lipid bilayer than EGC. We also found that EGCG had the ability to form hydrogen bonds with the deeper inside oxygen atoms in the POPG lipid bilayer and the gallate moiety was the key functional group for EGCG forming hydrogen bonds with the POPG lipid bilayer. Moreover, results from the binding free energy analysis demonstrated that the gallate moiety made great contribution to the high affinity between EGCG and the POPG lipid bilayer. We believed that these findings could yield useful insights into the influence mechanisms of gallate moiety on the anti-bacterial activities of polyphenols.

Asymmetric dearomatization of 2-nitrobenzofurans by organocatalyzed one-step Michael addition to access 3,3'-disubstituted oxindoles.

An efficient enantioselective dearomatization of 2-nitrobenzofurans was realized via an organocatalyzed one-step Michael addition process. This method provides a facile strategy to access a range of structurally diverse 3,3'-disubstituted oxindoles, which feature an intriguing combination of two privileged motifs including 3-pyrrolyl-substituted-oxindoles and 2,3-dihydrobenzofurans substructures, in excellent results.

Downregulation of serum exosomal miR-150-5p is associated with poor prognosis in patients with colorectal cancer.

Growing evidence have revealed the serum exosomal miRNAs emerged as biomarkers for various cancer types, including colorectal cancer (CRC). Here, we sought to explore the potential clinical significance of serum exosomal miR-150-5p in CRC. A total of 133 CRC patients and 60 healthy volunteers as control group were recruited in this study. Exosomes were isolated from the serum of all the participants. The total RNA was isolated from the exosomes and the serum exosomal miR-150-5p levels were measured by quantitative reverse transcription-polymerase chain reaction. The findings showed that the serum exosomal miR-150-5p levels were significantly reduced in CRC cases compared with those in the control group. Serum exosomal miR-150-5p levels in post-operative blood samples were greatly upregulated one month after surgical treatment. In addition, decreased serum exosomal miR-150-5p expression was closely correlated with poorly differentiation, positive lymph node metastasis and advanced TNM stage. Moreover, receiver operating characteristic (ROC) curve analysis showed serum exosomal miR-150-5p level had good performance to identify CRC cases from healthy volunteers, and a combination of serum exosomal miR-150-5p and carcinoembryonic antigen (CEA) could improve the diagnostic accuracy with an increased the area under the ROC curve (AUC) value. Furthermore, the survival time of patients with higher serum exosomal miR-150-5p expression was significantly longer than those with lower expression. Serum exosomal miR-150-5p was confirmed as an independent prognostic indicator in CRC. Mechanistically, ZEB1 was identified as a direct downstream target of miR-150-5p. Collectively, serum exosomal miR-150-5p might be a novel noninvasive biomarker for CRC diagnosis and prognosis.

Interactions between highly galloylated persimmon tannins and pectins.

The interactions between pectins of different degrees of esterification (DE) and highly galloylated persimmon tannins with average degrees of polymerisation (DP26 and DP5) were investigated by UV-Vis spectrophotometry, dynamic light scattering, transmission electron microscopy, isothermal titration calorimetry and pyrene fluorescence methods Pectins displayed strong effects on the self-aggregation of persimmon tannins and improved the homogeneity of condensed tannin aggregates. The interaction between tannins and pectins may result from hydrogen bonding and hydrophobic interactions; by contrast, electrostatic interactions, which involve charged molecules in general, played no dominant role. In addition, the presence of gallate moieties in the high-polymerisation proanthocyanidin could enhance affinity with highly methylated pectins. Stronger association was observed with the high-polymerisation tannins (DP26) with high-methoxyl pectin (DE74) (Ka=(8.50±3.0)×103M-1) than with low-methylated pectin (DE30) (Ka=(3.62±1.92)×103M-1). The present results are expected to promote the application of the formed complexes as functional ingredients in food.

Comparison of disaggregative effect of A-type EGCG dimer and EGCG monomer on the preformed bovine insulin amyloid fibrils.

In the present study, the disruptive effects of epigallocatechin-3-gallate (EGCG) and A-type dimeric epigallocatechin-3-gallate (A-type EGCG dimer) on the preformed bovine insulin amyloid fibrils were studied by several biophysical methods including thioflavin-T (ThT) fluorescence assay, 1-anilinonaphthalene-8-sulfonic (ANS) fluorescence assay, Congo red (CR) binding assay, dynamic light scattering (DLS), transmission electron microscopy (TEM), Gel electrophoresis (SDS-PAGE) and Bradford assay. Our results demonstrated that A-type EGCG dimer showed significantly more potential disaggregative effects on the bovine insulin amyloid fibrils than EGCG. A-type EGCG dimer could not only dramatically promote the disaggregation of the preformed bovine insulin amyloid fibrils, but also restructure the amyloid fibrils into amorphous aggregates. While, EGCG could only shorten and thin the fibrils, but induce no small amorphous aggregates. Our present results provided additional evidence for the more potent disaggregation effects of dimeric polyphenols than monomeric polyphenols and suggested that A-type EGCG dimer seems to have potential application as an excellent anti-amyloidogenic agent.

Hepatotoxicity in Rats Induced by Aqueous Extract of Polygoni Multiflori Radix, Root of Polygonum multiflorum Related to the Activity Inhibition of CYP1A2 or CYP2E1.

The objective of this study is to investigate the relationship between the hepatotoxicity induced by Polygoni Multiflori Radix (PMR, root of Polygonum multiflorum Thunb., He Shou Wu) and the activity of CYP1A2 or CYP2E1 in the rat liver. Levels of rat serum transaminases ALT and AST were not altered but the activity of CYP1A2 or CYP2E1 in the rat liver was significantly inhibited after oral administration of aqueous extract of PMR under the experimental dosage. However, levels of ALT and AST were significantly increased and the activity of CYP1A2 or CYP2E1 was significantly decreased after injection of specific inhibitor for CYP1A2 or CYP2E1 combined with oral administration of aqueous extract of PMR, especially under the repeated treatment over interval times. Liver histopathological observation showed that a moderate liver injury occurred in rats receiving PMR treatment with the activity of CYP1A2 or CYP2E1 inhibited, but there was no significant liver damage in rats receiving PMR treatment or CYP inhibitor alone. These suggested that low level activity of CYP1A2 or CYP2E1 from genetic polymorphism among people might be one of the important reasons for the hepatotoxicity induced by PMR in clinical practice.

Comparison of sensory and compositions of five selected persimmon cultivars (Diospyros kaki L.) and correlations between chemical components and processing characteristics.

Persimmon is one of the most popular and valuable fruits in markets because of its distinguished flavor as well as its significant benefits to health. The present study systematically compared the sensory characteristics and chemical compositions of five commercial persimmon fruits, and the correlations between chemical components and processing characteristics were also included. Our results showed that obvious differences in aroma and taste were found among the cultivars. Likewise, the contents of chemical components including sugar, total phenol, ß-carotene and ascorbic acid, varied significantly (p < 0.05) across different persimmon cultivars. The processing characteristics of persimmon fruit closely correlated with the chemical compositions. Pectin (r = 0.76, p < 0.01) and total phenol (r = 0.576, p < 0.05) were found to enhance the viscosity of persimmon pulp, and the colour of persimmon powder was greatly influenced by ß-carotene, ascorbic acid and sugar contents (r = 0.823, -0.729 and -0.685, p < 0.01, respectively). Powder recovery of persimmon was positively correlated with pectin content (r = 0.503, p < 0.05) and negatively related to total sugar content (r = -0.668, p < 0.01). Pectin content exerted positive effect (r = 0.719, p < 0.01) on hygroscopicity of persimmon powder, and the powder solubility showed a positive correlation to sugar and a negative relationship to pectin contents (r = 0.662 and -0.716, p < 0.01, respectively). In addition, a positive correlation (r = 0.642, p < 0.01) of the content of ascorbic acid to phenolic retention was also observed.

A-type dimeric epigallocatechin-3-gallate (EGCG) is a more potent inhibitor against the formation of insulin amyloid fibril than EGCG monomer.

Because fibrillary protein aggregates is regarded to be closely associated with many diseases such as Alzheimer's disease, diabetes, and Parkinson's disease, growing interest and researches have been focused on finding potential fibrillation inhibitors. In the present study, the inhibitory effects of epigallocatechin-3-gallate (EGCG) and A-type dimeric epigallocatechin-3-gallate (A-type EGCG dimer) on the formation of insulin fibrillation were compared by multi-dimensional approaches including thioflavin-T (ThT) fluorescence assay, 1-anilinonaphthalene-8-sulfonic (ANS) fluorescence assay, dynamic light scattering (DLS), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy and circular dichroism (CD) spectroscopy. Our results confirmed that A-type EGCG dimer is a more potent inhibitor against the formation of bovine insulin amyloid fibril than EGCG. In addition, A-type EGCG dimer could not only inhibit insulin amyloid fibril formation, but also change the aggregation pathway and induce bovine insulin into amorphous aggregates. The results of the present study may provide a new guide on finding novel anti-amyloidogenic agents.

Metabolites and Changes in Antioxidant Activity of A-Type and B-Type Proanthocyanidin Dimers after Incubation with Rat Intestinal Microbiota.

Metabolism of B-type EC dimer, A-type EC dimer, A-type ECG dimer, and A-type EGCG dimer was compared in vitro after incubation with rat intestinal microbiota for 0-24 h. A "dimeric" catabolite (m/z 815.6) was detected in four procyanthocyanidin dimers. Although the early cleavage of the C4-C8 interflavan bond and the reductive cleavage of the C-ring occurred in both B-type and A-type dimers, the degradation routes of these two types of dimers might somewhat differ. A dimeric catabolite C1 and more low molecular weight phenolic acids were detected in the metabolites of A-type EC dimer, but not in B-type EC dimer. The antioxidant capabilities of the A-type dimers were enhanced significantly after incubation for 6 h, whereas the antioxidant capacity of B-type EC dimer decreased. The results suggested that changes in antioxidant activity of procyanidin dimers after bioconversion by rat intestinal microbiota were not only structure dependent but also incubation condition dependent.

Screening of key antioxidant compounds of longan (Dimocarpus longan Lour.) seed extract by combining online fishing/knockout, activity evaluation, Fourier transform ion cyclotron resonance mass spectrometry, and high-performance liquid chromatography electrospray ionization mass spectrometry methods.

To figure out the key phenolic compounds accounting for the antioxidant effects of longan (Dimocarpus longan Lour.) seed extract, online fishing/knockout method, activity evaluation assays, Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS), and high-performance liquid chromatography electrospray ionization mass spectrometry (HPLC-ESI-MS) analysis were used jointly for the first time. p-Coumaric acid-glycoside, (S)-flavogallonic acid, ellagic acid derivative, and methyl-ellagic acid glucopyranoside were first identified in longan seeds. In addition, our study revealed that ellagic acid as well as its derivative and p-coumaric acid-glycoside had important contribution to the potent antioxidant activity of longan seed extract, while gallic acid, corilagin, (S)-flavogallonic acid, methyl-ellagic acid glucopyranoside, and ethyl gallate showed very little contribution to the total antioxidant activity of longan seed extract. The combining use of the online fishing/knockout method, activity evaluation assays, FT-ICR-MS, and HPLC-ESI-MS analysis is a useful and simple strategy for screening of key bioactive compounds from complex extracts.

Persimmon tannin accounts for hypolipidemic effects of persimmon through activating of AMPK and suppressing NF-κB activation and inflammatory responses in high-fat diet rats.

The present study was to investigate whether high molecular weight persimmon tannin (HMWPT) is the main component associated with the anti-hyperlipidemic effect of consuming persimmon and its underlying mechanism. Male wistar rats were given a basic diet (control), a high-fat diet, a high-fat diet plus 0.5% of HMWPT or 4.2% of lyophilized fresh persimmon fruit (with the same diet HMWPT content in the two groups) for 9 weeks. Administration of HMWPT or persimmon fruit significantly (p < 0.05) lowered serum triglycerides and free fatty acids, enhanced the excretion of triglycerides, cholesterol and bile acids, and improved hepatic steatosis in rats fed a high-fat diet. Dietary HMWPT or persimmon fruit significantly decreased the protein levels of fatty acid synthase (FAS), and stimulated AMP-activated protein kinase (AMPK) phosphorylation and down-regulated genes involved in lipogenesis, including transcriptional factor sterol regulatory element binding protein 1 (SREBP1) and acetyl CoA carboxylase (ACC). In addition, the expression of proteins involved in fatty acid oxidation, such as carnitine palmitoyltransferase-1 (CPT-1), was notably up-regulated. Furthermore, HMWPT and persimmon fruit suppressed inflammatory cytokines such as tumor necrosis factor α (TNFα) and C-reactive protein (CRP) and the protein level of nuclear factor-kappa B (NFκB) in the liver. Taken together, our findings demonstrated that HMWPT reproduced the anti-hyperlipidemic effects of persimmon fruit, and was a pivotal constituent of persimmon fruit accounting for prevention of liver steatosis and its progression to nonalcoholic steatohepatitis (NASH) by activation of the AMPK and regulation of its downstream targets, suppressing NF-κB activation and inflammatory responses, and inhibiting lipids and bile acid absorption.

Preparation of A-type proanthocyanidin dimers from peanut skins and persimmon pulp and comparison of the antioxidant activity of A-type and B-type dimers.

We have established a simple method for preparing large quantities of A-type dimers from peanut skin and persimmon for further structure-activity relationship study. Peanut skins were defatted with hexane and oligomeric proanthocyanidins were extracted from it with 20% of methanol, and the extract was fractionated with ethyl acetate. Persimmon tannin was extracted from persimmon with methanol acidified with 1% hydrochloric acid, after removing the sugar and small phenols, the high molecular weight persimmon tannin was partially cleaved with 6.25% hydrochloric acid in methanol. The ethyl acetate fraction from peanut skins and persimmon tannin cleaved products was chromatographed on AB-8 macroporous resin followed by Toyopearl HW-50F resin to yield about 378.3mg of A-type (epi)catechin (EC) dimer from 1 kg dry peanut skins and 34.3mg of A-type (epi)catechin-3-O-gallate (ECG) dimer and 37.7 mg of A-type (epi)gallocatechin-3-O-gallate (EGCG) dimer from 1 kg fresh persimmon fruit. The antioxidant properties of the A-type and B-type dimers were compared in five different assays, namely, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, 2,2-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical, hydroxyl radical, lipid peroxidation in mice liver homogenate and erythrocyte hemolysis in rat blood. Our results showed that both A-type and B-type dimers showed high antioxidant potency in a dose-dependent manner. In general, B-type dimers showed higher radical scavenging potency than A-type ones with the same subunits in aqueous systems. But in tissue or lipid systems, A-type dimers showed similar or even higher antioxidant potency than B-type ones.