Characteristics of mucin hypersecretion in different inflammatory patterns based on endotypes of chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is usually accompanied by mucin hypersecretion that can lead to mucus accumulation and impair nasal mucociliary clearance, thus exacerbating airway inflammation. Abnormal mucin hypersecretion is regulated by different T helper (Th) cytokines, which are associated with different endotype-driven inflammatory responses. Therefore, it is of great significance to understand how these factors regulate mucin hypersecretion to provide precise treatment strategies for different endotypes of CRS. BODY: Thus far, the most common endotypes of CRS are classified as type 1, type 2, or type 3 immune responses based on innate and adaptive cell-mediated effector immunity, and the representative Th cytokines in these immune responses, such as IFN-γ, TNF-α, IL-4, IL-5, IL-13, IL-10, IL-17, and IL-22, play an important regulatory role in mucin secretion. We reviewed all the related literature in the PubMed database to determine the expression of these Th cytokines in CRS and the role they play in the regulation of mucin secretion. CONCLUSION: We believe that the main Th cytokines involved in specific endotypes of CRS play a key role in regulating abnormal mucin secretion, which contributes to better understanding of the pathogenesis of CRS and provides therapeutic targets for airway inflammatory diseases associated with mucin hypersecretion.

Early-Age Mechanical Characteristics and Microstructure of Concrete Containing Mineral Admixtures under the Environment of Low Humidity and Large Temperature Variation.

The application of concrete containing mineral admixtures was attempted in Northwest China in this study, where the environment has the characteristics of low humidity and large temperature variation. The harsh environment was simulated by using an environmental chamber in the laboratory and four types of concrete were prepared, including ordinary concrete and three kinds of mineral admixture concretes with different contents of fly ash and blast-furnace slag. These concretes were cured in the environmental chamber according to the real curing conditions during construction. The compression strength, fracture properties, SEM images, air-void characteristics, and X-ray diffraction features were researched at the early ages of curing before 28 d. The results showed that the addition of fly ash and slag can improve the compression strength and fracture properties of concrete in the environment of low humidity and large temperature variation. The optimal mixing of mineral admixture was 10% fly ash and 20% slag by replacing the cement in concrete, which can improve the compression strength, initial fracture toughness, unstable fracture toughness, and fracture energy by 23.9%, 25.2%, 45.3%, and 22.6%, respectively, compared to ordinary concrete. Through the analysis of the microstructure of concrete, the addition of fly ash and slag can weaken the negative effects of the harsh environment of low humidity and large temperature variation on concrete microstructure and cement hydration.

A Novel Method of Emergency Situation Detection for a Brain-Controlled Vehicle by Combining EEG Signals With Surrounding Information.

In this paper, to address the safety of brain-controlled vehicles under emergency situations, we propose a novel method of emergency situation detection by fusing driver electroencephalography (EEG) signals with surrounding information. We first build a novel EEG-based detection model of driver emergency braking intention. We then recognize emergency situations by fusing the result of the proposed EEG-based intention detection model with that of the obstacle detection model based on surrounding information. The real-time detection system of driver emergency braking intention is implemented on an embedded system, and the driver-and-hardware-in-the-loop-experiment of the proposed detection method of emergency situations is performed. Experimental results show that the proposed method can detect emergency situations with the system accuracy of 94.89%, false alarm rate of 0.05%, and response time of 540 ms. This paper has important values in the future development of brain-controlled vehicles, human-centric advanced driver assistant systems, and self-driving vehicles and opens a new avenue on how cognitive neuroscience may be applied to human-machine integration.

Cimicifuga species identification by high performance liquid chromatography-photodiode array/mass spectrometric/evaporative light scattering detection for quality control of black cohosh products.

Black cohosh has become one of the most important herbal products in the US dietary supplements market. It is manufactured from roots and rhizomes of Cimicifuga racemosa (Ranunculaceae). Botanical identification of the raw starting material is a key step in the quality control of black cohosh preparations. The present report summarizes a fingerprinting approach based on high performance liquid chromatography-photodiode array/mass spectrometric/evaporative light scattering detection (HPLC-PDA/MS/ELSD) that has been developed and validated using a total of 10 Cimicifuga species. These include three North American species, Cimicifuga racemosa, Cimicifuga americana, Cimicifuga rubifolia, and seven Asian species, Cimicifuga acerina, Cimicifuga biternat, Cimicifuga dahurica, Cimicifuga heracleifolia, Cimicifuga japonica, Cimicifuga foetida, and Cimicifuga simplex. The chemotaxonomic distinctiveness of the HPLC fingerprints allows identification of all 10 Cimicifuga species. The triterpene glycoside cimigenol-3-O-arabinoside (3), cimifugin (12), and cimifugin-3-O-glucoside (18) were determined to be suitable species-specific markers for the distinction of C. racemosa from the other Cimicifuga species. In addition to identification, the fingerprint method provided insight into chemical interconversion processes occurring between the diverse triterpene glycosides contained in black cohosh. The reported method has proven its usefulness in the botanical standardization and quality control of black cohosh products.

LC/TIS-MS fingerprint profiling of Cimicifuga species and analysis of 23-Epi-26-deoxyactein in Cimicifuga racemosa commercial products.

In this study, a liquid chromatography (LC)/turbo ion spray (TIS)-mass spectrometry (MS) method was developed to examine the chromatography or "fingerprint profile" of seven Cimicifuga herbs and six Cimicifuga racemosa (black cohosh) commercial products. Triterpene glycoside components were selected as chemical markers for analysis because they have appeared as a major compound group in Cimicifuga species. LC/MS chromatograms unveiled the patterns of C. racemosa, Cimicifuga dahurica, Cimicifuga foetida, Cimicifuga heracleifolia, Cimicifuga japonica, Cimicifuga acerina, and Cimicifuga simplex, which are very different from each other. 23-Epi-26-deoxyactein was found only in C. racemosa, C. dahurica, and C. foetida. A highly selective and sensitive LC/MS/MS method for quantitative analysis of 23-epi-26-deoxyactein with detection levels up to 2.5 ng in these samples was also developed and was applied to six commercial C. racemosa products. C. racemosa and its six commercial products contained about 6-15% of 23-epi-26-deoxyactein in total triterpene glycosides. On the other hand, the estimated amount of total triterpene glycosides in other commercial products was either greater or lesser than what the manufacturers claimed. The technique and LC/MS profiles generated in this study provide a reliable and reproducible method that can be readily utilized for botanical identification of Cimicifuga plants, for examination and validation of its commercial products, and for "chemical" quality control in the manufacture of black cohosh products.

Montacin and cis-montacin, two new cytotoxic monotetrahydrofuran annonaceous acetogenins from Annona montana.

Two new monotetrahydrofuran Annonaceous acetogenins, montacin (1), and cis-montacin (2), along with four known acetogenins, annonacin, cis-annonacin, annomontacin, and cis-annomontacin, were isolated from the seeds of Annona montana. The structures of the new isolates were elucidated by spectral and chemical methods. The new acetogenins exhibited moderate in vitro cytotoxic activity against the 1A9 human ovarian cancer cell line. Interestingly, when Ca(2+) was present, compounds 1 and 2 became 3- to 10-fold more active against 1A9 cells and the PTX10 subline.

Antitumor agents. 234. Design, synthesis, and biological evaluation of novel 4beta-[(4' '-benzamido)-amino]-4'-o-demethyl-epipodophyllotoxin derivatives.

A series of 4beta-[(4' '-benzamido)-amino]-4'-O-demethyl-epipodophyllotoxin derivatives (11-23) were designed to enhance DNA topoisomerase II inhibition, overcome drug resistance, and modulate water solubility of etoposide (1) analogues. The target compounds were synthesized and evaluated for their effects against DNA topoisomerase II and KB or 1-resistant KB-7d tumor cells in tissue culture. As compared with 1, most compounds showed superior inhibition against both KB and KB-7d cells. Nine compounds (13-18, 20-22) induced higher levels of cellular protein-linked DNA breaks than did 1. Ten compounds selected from these and related derivatives were further examined for their antitumor spectra and drug-resistance profiles. Like 1, these compounds selectively inhibited the growth of KB (nasopharyngeal) and 1A9 (ovarian) tumor cells. More notably, they retained inhibitory activity against etoposide-, camptothecin-, and paclitaxel-resistant KB or 1A9 subclones. In general, these C(4)-modified new derivatives exhibited superior activity profiles, particularly against drug-resistant cell lines, to those of 1. Preliminary metabolism studies on compounds 16 and 20 revealed that 20 was relatively resistant to metabolism by rat serum and liver enzymes, while 16 was metabolically unstable.

Antitumor agents. Part 235: Novel 4'-ester etoposide analogues as potent DNA topoisomerase II inhibitors with improved therapeutic potential.

Eight 4'-ester epipodophyllotoxin derivatives (9-16) were designed and synthesized with the aim to overcome drug-resistance and improve water-solubility simultaneously. These compounds were superior to etoposide (1) in causing cellular protein-linked DNA breaks and inhibiting KB and 1-resistant KB-7d cell replication. Compounds 9 and 10 showed significant inhibitory activity against DNA topoisomerase II in vitro. Compound 10 also exhibited an in vitro DNA cleavage pattern similar to that of GL-331 (5). A hypothetical model on the action mode of 1-analogues is proposed based on the results.

Antitumor agents. 217. Curcumin analogues as novel androgen receptor antagonists with potential as anti-prostate cancer agents.

A number of curcumin analogues were prepared and evaluated as potential androgen receptor antagonists against two human prostate cancer cell lines, PC-3 and DU-145, in the presence of androgen receptor (AR) and androgen receptor coactivator, ARA70. Compounds 4 [5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one], 20 [5-hydroxy-1,7-bis[3-methoxy-4-(methoxycarbonylmethoxy)phenyl]-1,4,6-heptatrien-3-one], 22 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]-5-oxohepta-4,6-dienoic acid ethyl ester], 23 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]5-oxohepta-4,6-dienoic acid], and 39 [bis(3,4-dimethoxyphenyl)-1,3-propanedione] showed potent antiandrogenic activities and were superior to hydroxyflutamide, which is the currently available antiandrogen for the treatment of prostate cancer. Structure-activity relationship (SAR) studies indicated that the bis(3,4-dimethoxyphenyl) moieties, the conjugated beta-diketone moiety, and the intramolecular symmetry of the molecules seem to be important factors related to antiandrogenic activity. The data further suggest that the coplanarity of the beta-diketone moiety and the presence of a strong hydrogen bond donor group were also crucial for the antiandrogenic activity, which is consistent with previous SAR results for hydroxyflutamide analogues. When the pharmacophoric elements of dihydrotestosterone (DHT) and compound 4 are superposed, the resulting construct implies that the curcumin analogues may function as a 17alpha-substituted DHT. Compounds 4, 20, 22, 23, and 39 have been identified as a new class of antiandrogen agents, and these compounds or their new synthetic analogues could be developed into clinical trial candidates to control androgen receptor-mediated prostate cancer growth.

Anti-AIDS agents 49. Synthesis, anti-HIV, and anti-fusion activities of IC9564 analogues based on betulinic acid.

The betulinic acid derivative IC9564 inhibits human immunodeficiency virus (HIV)-1 entry. Among a series of IC9564 derivatives, 5 and 20 were the most promising compounds against HIV infection with EC(50) values of 0.33 and 0.46 microM, respectively. Both compounds inhibited syncytium formation with EC(50) values of 0.40 and 0.33 microM, respectively. The comparable EC(50) values in the two assays suggested that these compounds are fusion inhibitors. The structure-activity relationship data also indicated that a double bond in IC9564 can be eliminated and the statine moiety can be replaced with L-leucine while retaining anti-HIV activity.

Antitumor agents. Part 214: synthesis and evaluation of curcumin analogues as cytotoxic agents.

Fifty-eight curcumin analogues were prepared and evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. Compound was the most potent analogue against several cell lines, including HOS (bone cancer) and 1A9 (breast cancer), with ED50 values of 0.97 and <0.63 microg/mL, respectively.

Interiotherins C and D, two new lignans from Kadsura interior and antitumor-promoting effects of related neolignans on Epstein-Barr virus activation.

Two new lignans, interiotherins C (1) and D (2), together with the known compounds interiorin (3), heteroclitin F (4), neokadsuranin (5), heteroclitin D (6), kadsurin (7), gomisin A (8), schisandrin C (9), interiotherin A (10), angeloylgomisin R (11), gomisin G (12), interiotherin B (13), and gomisin C (14), were isolated from the stems of Kadsura interior. The structures and stereochemistries of the new compounds were determined from mass, CD, and NMR spectral data. Fourteen neolignans were screened as potential antitumor promoters by examining their ability to inhibit Epstein-Barr virus early antigen (EBV-EA) activation (induced by 12-O-tetradecanoylphorbol-13-acetate) in Raji cells. Neokadsuranin (5) and schisandrin C (9) were the most potent compounds. These data suggest that some neolignans might be valuable antitumor promoters or chemopreventors.

Antitumor agents. Part 209: Pheophorbide-a derivatives as photo-Independent cytotoxic agents.

A methanolic crude extract of the plant Garuga pinnata Roxb. (Burseraceae) showed promising cytotoxic activity against a panel of human tumor cell lines in vitro, including KB and its drug-resistant sublines (Ferguson et al. Cancer Res. 1988, 48, 5956). Pheophorbide-a and-b methyl esters (3,4) were isolated as active principles with broad photo-dependent cytotoxic activities in the micromolar range. These findings prompted SAR studies of known and novel pheophorbide-a derivatives as photo-dependent and photo-independent cytotoxic agents. The results showed that zinc-protoporphyrin IX (10), zinc 13(R)-hydroxypheophorbide-a methyl ester (22), and zinc chlorin-e6 trimethyl ester (13) possessed photo-independent cytotoxic activity. Compounds 13 and 22 were the most active cytotoxic agents of the series (mean ED(50) 4.6 +/- 1.0 microM and 5.7 +/- 0.7 microM, respectively) against KB cells incubated in the dark.