Toll-like Receptors as a Target of Food-derived Anti-inflammatory Compounds

Toll-like receptors (TLRs) play a key role in linking pathogen recognition with the induction of innate immunity. They have been implicated in the pathogenesis of chronic inflammatory diseases, representing potential targets for prevention/treatment. Vegetable-rich diets are associated with the reduced risk of several inflammatory disorders. In the present study, based on an extensive screening of vegetable extracts for TLR-inhibiting activity in HEK293 cells co-expressing TLR with the NF-κB reporter gene, we found cabbage and onion extracts to be the richest sources of a TLR signaling inhibitor. To identify the active substances, we performed activity-guiding separation of the principal inhibitors and identified 3-methylsulfinylpropyl isothiocyanate (iberin) from the cabbage and quercetin and quercetin 4′-O-β-glucoside from the onion, among which iberin showed the most potent inhibitory effect. It was revealed that iberin specifically acted on the dimerization step of TLRs in the TLR signaling pathway. To gain insight into the inhibitory mechanism of TLR dimerization, we developed a novel probe combining an isothiocyanate-reactive group and an alkyne functionality for click chemistry and detected the probe bound to the TLRs in living cells, suggesting that iberin disrupts dimerization of the TLRs via covalent binding. Furthermore, we designed a variety of iberin analogues and found that the inhibition potency was influenced by the oxidation state of the sulfur. Modeling studies of the iberin analogues showed that the oxidation state of sulfur might influence the global shape of the isothiocyanates. These findings establish the TLR dimerization step as a target of food-derived anti-inflammatory compounds.     

杭白菊花水提物的UHPLC-ESI-Orbitrap质谱联用分析

为阐明杭白菊花水提物的药效物质基础,采用超高压液相-高分辨质谱联用技术对杭白菊(Chrysanthemum morifolium)花水提物的化学成分进行分析和鉴定。结果表明,从杭白菊花水提物中鉴定出376种化学成分,其中相对含量大于0.1%的成分有152种,相对含量较高的有绞股蓝皂苷XXⅦ、含羞草碱-O-β-葡萄糖苷、甲基-β-葡萄糖苷、D-1-O-甲基粘质肌醇、L(+)-甲基肌醇、过氧化苯甲酰、甲基-β-半乳糖苷、甲基-α-果糖苷、芒柄醇、松醇、(E)-2-己烯-α-阿拉伯糖-(1→2)-β-葡萄糖苷、米瑟毒苷等。杭白菊花水提物主要以黄酮类和生物碱类成分为主,分别有40和53种,相对含量分别为22.68%和26.57%,是杭白菊花发挥功效的主要物质基础。     

Lumi-mestranol and epi-lumi-mestranol.

Treatment of lumi-estrone 3-methyl ether (I) with acetylene gave the C-17-epimeric compounds lumi-mestranol (3-methoxy-17 alpha-ethynyl-13 alpha-estra-1,3,5(10)-trien-17 beta-ol, III ) and epi-lumi-mestranol (3-methoxy-17 beta-ethynyl-13 alpha-estra-1,3,5(10)-trien-17 alpha-ol, IV). The structures of the two isomers were assigned on the basis of their molecular rotations and shift-reagent experiments in the NMR. The irradiation of estrone 3-methyl ether (II) to provide compound I was investigated in two solvent systems. Minor products of these reactions were the seco-steroids VII, VIII and X.     

Effects of chemical and botanical insecticides used for locust control on Metarhizium anisopliae var. acridum conidia after short- to medium-term storage at 30°C

The short- to medium-term viability and growth of Metarhizium anisopliae var. acridum conidia were investigated when combined with six insecticides, at three different concentrations. All of the insecticides used in this study were suitable for immediate spraying with M. anisopliae var. acridum conidia except for fenitrothion. Fipronil, teflubenzuron, and fenitrothion formulations significantly reduced conidial viability over time. The 10% teflubenzuron treatment caused loss of viability relatively quickly with 9.9% germination after 28 days. Mycelial growth was affected by all the treatments except fenitrothion.     

Chemical reactivity and uses of 1-phenyl-3-methyl-5-pyrazolone (PMP), also known as edaravone

1-Phenyl-3-methyl-5-pyrazolone is a reagent, known as PMP, used to derivatize monosaccharides for the study of polysaccharides composition and structure, and for the dosage of carbohydrates in complex media. The same molecule is also known as edaravone, a drug approved for the treatment of stroke and amyotrophic lateral sclerosis. It is also a reactive molecule susceptible to form stable adducts with aromatic aldehydes, such as formylpterin and vanillin. In addition, the molecule serves as a scaffold to design of edaravone analogs and drug conjugates, with various pharmacological properties (antioxidant, anticancer, antiviral). We have analyzed the multiple usages of PMP/edaravone to highlight the reactivity of the molecule and its wide range of applications. This phenyl-pyrazolone compound, considered by many as a biochemical reagent and by other as a clinically useful drug, has not yet revealed the full extent of its capacities and benefits.     

Molecular probes for the human adenosine receptors

Adenosine receptors, G protein–coupled receptors (GPCRs) that are activated by the endogenous ligand adenosine, have been considered potential therapeutic targets in several disorders. To date however, only very few adenosine receptor modulators have made it to the market. Increased understanding of these receptors is required to improve the success rate of adenosine receptor drug discovery. To improve our understanding of receptor structure and function, over the past decades, a diverse array of molecular probes has been developed and applied. These probes, including radioactive or fluorescent moieties, have proven invaluable in GPCR research in general. Specifically for adenosine receptors, the development and application of covalent or reversible probes, whether radiolabeled or fluorescent, have been instrumental in the discovery of new chemical entities, the characterization and interrogation of adenosine receptor subtypes, and the study of adenosine receptor behavior in physiological and pathophysiological conditions. This review summarizes these applications, and also serves as an invitation to walk another mile to further improve probe characteristics and develop additional tags that allow the investigation of adenosine receptors and other GPCRs in even finer detail.

     

A Laboratory study on the visual and chemical orientation of the gastropod Nerita Fulgurans Gmelin, 1791

Behavioural responses of the gastropod Nerita fulgurans Gmelin, 1791 to flat black rectangles and intraspecific mucus trails were measured in a circular arena. Snails were tested in water either in the presence or absence of chemicals generated from a predator gastropod, Chicoreus brevifrons (Lamarck, 1822). The test hypothesis was that this snail has different behavioural responses as result of visual and chemical cue integration. Nerita fulgurans has the capacity to orient to solid targets subtending angles larger than 10° and follow its own mucus trails. In water conditioned by the predator C . brevifrons, snails exhibited an avoidance response when 10°, 20° and 45° sectors were presented, demonstrating an integration of chemical and visual information. The simultaneous presentation of two orienting cues (black sectors and mucus trails) was tested to determine the nature of the interaction. When the two cues were oriented in the same direction there was no effect. When the two cues were presented from directions 180° apart a preference for visual cues over mucus trail cues was evident when the visual angle of the visual cue subtended angles greater than 90°. This result demonstrates a hierarchical usage of the orienting references.     

Determination of new biomarkers to monitor the dietary consumption of isothiocyanates

Isothiocyanates (ITCs) found in cruciferous vegetables have been associated with a reduced cancer risk in humans. We determined serum albumin adducts of allyl isothiocyanate (AITC), benzylisothiocyanate (BITC), phenylethylisothiocyanate (PEITC) and sulforaphane (SFN) in 85 healthy men from a dietary, randomized, controlled trial. After enzymatic digestion of albumin we determined the adducts of the ITCs with lysine (Lys) using liquid chromatography–tandem mass spectrometry. At the beginning of the study (and after 4 weeks) 4.7% (2.4%), 48.2% (35.3%), 5.9% (10.6%), and 24.7% (23.5%) of the samples were found positive for AITC-Lys, BITC-Lys, PEITC-Lys and SFN-Lys, respectively. This method enables the quantification of ITC adducts in albumin from large, prospective studies on diet and cancer.     

Prediction of methionine oxidation risk in monoclonal antibodies using a machine learning method

ABSTRACT

Monoclonal antibodies (mAbs) have become a major class of protein therapeutics that target a spectrum of diseases ranging from cancers to infectious diseases. Similar to any protein molecule, mAbs are susceptible to chemical modifications during the manufacturing process, long-term storage, and in vivo circulation that can impair their potency. One such modification is the oxidation of methionine residues. Chemical modifications that occur in the complementarity-determining regions (CDRs) of mAbs can lead to the abrogation of antigen binding and reduce the drug’s potency and efficacy. Thus, it is highly desirable to identify and eliminate any chemically unstable residues in the CDRs during the therapeutic antibody discovery process. To provide increased throughput over experimental methods, we extracted features from the mAbs’ sequences, structures, and dynamics, used random forests to identify important features and develop a quantitative and highly predictive in silico methionine oxidation model.     

A new adduct of iriflophene and flavonoid from Sedum aizoon L.

A new adduct of iriflophene and flavonoid, 1, 8, 10, 10b-tetrahydroxy-3-methoxy-5a-(3,4-dihydr- oxyphenyl)-9-(4-hydroxybenzoyl)-5a,10b-dihydro-11H-benzofuro[2,3-b]chromen-11-one (1), together with six known compounds were isolated from the EtOH extract from Sedum aizoon L. Their chemical structures were elucidated by analyses of spectral data. The chemotaxonomic analysis of the compounds was discussed, compounds 1–4 provide important chemotaxonomic markers for S. aizoon.