Design,Synthesis, Molecular Docking,and Biological Evaluation of New Emodin Anthraquinone Derivatives as Potential Antitumor Substances

The emodin anthraquinone derivatives are generally used in traditional Chinese medicine due to their various pharmacological activities. In the present study, a series of emodin anthraquinone derivatives have been designed and synthesized, among which 1,3‐dihydroxy‐6,8‐dimethoxyanthracene‐9,10‐dione is a natural compound that has been synthesized for the very first time, and 1,3‐dimethoxy‐5,8‐dimethylanthracene‐9,10‐dione is a compound that has never been reported earlier. Interestingly, while total seven of these compounds showed neuraminidase inhibitory activity in influenza virus with inhibition rate more than 50 %, specific four compounds exhibited significant inhibition of tumor cell proliferation. The further results demonstrate that 1,3‐dimethoxy‐5,8‐dimethylanthracene‐9,10‐dione showed the best anticancer activity among all the synthesized compounds by inducing highest apoptosis rate to HCT116 cancer cells and arresting their G0/G1 cell cycle phase, through elevation of intracellular level of reactive oxygen species (ROS). Moreover, the binding of 1,3‐dimethoxy‐5,8‐dimethylanthracene‐9,10‐dione with BSA protein has thoroughly been investigated. Altogether, this study suggests the neuraminidase inhibitory activity and antitumor potential of the new emodin anthraquinone derivatives.     

Conformational analysis of an acyclic tetrapeptide: ab‐initio structure determination from X‐ray powder diffraction,Hirshfeld surface analysis and electronic structure

A terminally protected acyclic tetrapeptide has been synthesized, and the crystal structure of its hydrated form, Boc‐Tyr‐Aib‐Tyr‐Ile‐OMe·2H₂O ( 1 ), has been determined directly from powder X‐ray diffraction data. The backbone conformation of tetrapeptide ( 1 ) exhibiting two consecutive β‐turns is stabilized by two 4 → 1 intramolecular N―H · · · O hydrogen bonds. In the crystalline state, the tetrapeptide molecules are assembled through water‐mediated O―H · · · O hydrogen bonds to form two‐dimensional molecular sheets, which are further linked by intermolecular C―H · · · O hydrogen bonds into a three‐dimensional supramolecular framework. The molecular electrostatic potential (MEP) surface of ( 1 ) has been used to supplement the crystallographic observations. The nature of intermolecular interactions in ( 1 ) has been analyzed quantitatively through the Hirshfeld surface and two‐dimensional fingerprint plot. The DFT optimized molecular geometry of ( 1 ) agrees closely with that obtained from the X‐ray structure analysis. The present structure analysis of Boc‐Tyr‐Aib‐Tyr‐Ile‐OMe·2H₂O ( 1 ) represents a case where ab‐initio crystal structure of an acyclic tetrapeptide with considerable molecular flexibility has been accomplished from laboratory X‐ray powder diffraction data. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.     

Ethnic conflict and the United Nations

The United Nations [UN] is an organization of states. As such it can be expected to represent the interests of its members and uphold a state‐centric view of international politics. For this reason it has been suggested that the organization cannot respond positively to ethnic conflicts within states, or across state borders. However, since such ethnic conflicts can be a threat to international peace and security and to internationally accepted norms of behaviour, the UN cannot always remain indifferent. In fact, it has become involved in ethnic conflicts in several ways. It has dispatched peace‐keeping operations to Cyprus and Lebanon, which try to keep apart the warring factions. The UN has been involved in peace‐making in ethnic conflicts through mediation and Security Council and General Assembly resolutions. It has also engaged in peace‐building, which involves efforts to change both socio‐economic conditions and the mutually hostile attitudes of the parties to violent ethnic conflict. Finally, even though the UN, unlike the League of Nations, has not been prepared to adopt a system of minority‐rights protection, it has been involved in the issue of group rights in at least three areas. These are the Genocide Convention, the work of the Sub‐Commission for the Prevention of Discrimination and the Protection of Minorities, and the issue of the right of national self‐determination.     

Effective Anomerisation of 2′‐Deoxyadenosine Derivatives During Disaccharide Nucleoside Synthesis

The formation of a disaccharide nucleoside (11) by O3′‐glycosylation of 5′‐O‐protected 2′‐deoxyadenosine or its N ⁶‐benzoylated derivative has been observed to be accompanied by anomerisation to the corresponding α‐anomeric product (12). The latter reaction can be explained by instability of the N‐glycosidic bond of purine 2′‐deoxynucleosides in the presence of Lewis acids. An independent study on the anomerisation of partly blocked 2′‐deoxyadenosine has been carried out. Additionally, transglycosylation has been utilized in the synthesis of 3′‐O‐β‐d‐ribofuranosyl‐2′‐deoxyadenosines and its α‐anomer.     

Overall picture of an emerging neonatal infectious disease induced by a superantigenic exotoxin mainly produced by methicillin‐resistant Staphylococcus aureus

Since 1992, many neonates in neonatal intensive care units in Japan have been developing fever and systemic exanthema. Immunological analyses of neonates with these symptoms has revealed that the bacterial superantigen, toxic shock syndrome toxin‐1 (TSST‐1) is the cause. The name neonatal TSS‐like exanthematous disease (NTED) has been applied to this condition. The most striking clinical finding has been that none of the term neonates have developed shock or died of NTED. The timing of NTED epidemics has coincided with the spread of emerging TSST‐1‐producing methicillin‐resistant Staphylococcus aureus clones in Japan. The low frequency of pregnant women with positive anti‐TSST‐1 antibody titers could be one reason for the spread of NTED in Japan. Neonates have immune tolerance against TSST‐1 and may actively suppress the immune response to NTED with interleukin‐10. According to the T cell responses in infants or young children with diseases induced by TSST‐1, the pathophysiology of TSST‐1‐related diseases may be age‐dependent. The precise mechanism of anergy and deletion of specific T cells stimulated with TSST‐1 should be investigated in neonates infected with NTED. Both NTED and TSS might provide good models for analyzing the mechanism(s) of neonatal immune tolerance and the age‐dependence of human immunity. This disease has not only become representative of diseases caused by superantigens, but has also yielded a considerable amount of evidence about human immune reactions against superantigens.     

Synthesis and Antioxidant Activity of Carane and Pinane Based Sulfenimines and Sulfinimines

The synthesis of sulfenimines and sulfinimines has been carried out with 10‐hydroxyisocamphylthiol. The configuration of the compounds has been deduced by methods of NMR, DFT calculations and X‐ray diffraction analysis. The cytotoxic, antioxidant and membrane‐protective activity of the synthesized compounds as well as of the previously obtained sulfenimines and sulfinimines based on 4‐caranethiol have been determined.     

Review article: Commercialization of whole‐plant systems for biomanufacturing of protein products: evolution and prospects

Technology for enabling plants to biomanufacture nonnative proteins in commercially significant quantities has been available for just over 20 years. During that time, the agricultural world has witnessed rapid commercialization and widespread adoption of transgenic crops enhanced for agronomic performance (herbicide‐tolerance, insect‐resistance), while plant‐made pharmaceuticals (PMPs) and plant‐made industrial products (PMIPs) have been limited to experimental and small‐scale commercial production. This difference in the rate of commercial implementation likely reflects the very different business‐development challenges associated with ‘product’ technologies compared with ‘enabling’ (‘platform’) technologies. However, considerable progress has been made in advancing and refining plant‐based production of proteins, both technologically and in regard to identifying optimal business prospects. This review summarizes these developments, contrasting today’s technologies and prospective applications with those of the industry’s formative years, and suggesting how the PM(I)P industry’s evolution has generated a very positive outlook for the ‘plant‐made’ paradigm.     

Differential in radiosensitizing potency of enantiomers of the fatty acid synthase inhibitor C75

The elevated activity of fatty acid synthase has been reported in a number of cancer types. Inhibition of this enzyme has been demonstrated to induce cancer cell death and reduce tumor growth. In addition, the fatty acid synthase inhibitor drug C75 has been reported to synergistically enhance the cancer‐killing ability of ionizing radiation. However, clinical use of C75 has been limited due to its producing weight loss, believed to be caused by alterations in the activity of carnitine palmitoyltransferase‐1. C75 is administered in the form of a racemic mixture of (−) and (+) enantiomers that may differ in their regulation of fatty acid synthase and carnitine palmitoyltransferase‐1. Therefore, we assessed the relative cancer‐killing potency of different enantiomeric forms of C75 in prostate cancer cells. These results suggest that (−)‐C75 is the more cytotoxic enantiomer and has greater radiosensitizing capacity than (+)‐C75. These observations will stimulate the development of fatty acid synthase inhibitors that are selective for cancer cells and enhance the tumor‐killing activity of ionizing radiation, while minimizing weight loss in cancer patients.     

TUG1: a pivotal oncogenic long non‐coding RNA of human cancers

Long non‐coding RNAs (lncRNAs) are a group greater than 200 nucleotides in length. An increasing number of studies has shown that lncRNAs play important roles in diverse cellular processes, including proliferation, differentiation, apoptosis, invasion and chromatin remodelling. In this regard, deregulation of lncRNAs has been documented in human cancers. TUG1 is a recently identified oncogenic lncRNA whose aberrant upregulation has been detected in different types of cancer, including B‐cell malignancies, oesophageal squamous cell carcinoma, bladder cancer, hepatocellular carcinoma and osteosarcoma. In these malignancies, knock‐down of TUG1 has been shown to suppress cell proliferation, invasion and/or colony formation. Interestingly, TUG1 has been found to be downregulated in non‐small cell lung carcinoma, indicative of its tissue‐specific function in tumourigenesis. Pertinent to clinical practice, TUG1 may act as a prognostic biomarker for tumours. In this review, we summarize current knowledge concerning the role of TUG1 in tumour progression and discuss mechanisms associated with it.     

Reconciliation and third‐party affiliation in carrion crows

Conflicts are costly because they can damage social relationships. To buffer conflicts, various species use post‐conflict behaviour, such as reconciliation or third‐party affiliation. Both behaviours have predominantly been studied in non‐human primates. However, recently, studies revealed post‐conflict behaviour in other mammalian and some bird species (e.g., corvids). While third‐party affiliation has been reported in several corvid species, reconciliation has only rarely been observed. The social structure of the studied groups has been postulated as a reason for the absence of reconciliation. Here, we investigated whether post‐conflict behaviours in corvids indeed mirror the relationship structure. We studied the behaviour of a newly established group of juvenile carrion crows (Corvus corone corone), where pair bonds had not yet been established. We applied a combination of observations and food monopolisation experiments to quantify the use of post‐conflict behaviours. Provisioning food in one or two pieces induced different patterns of aggression during feeding and differently affected the affiliation patterns after feeding. Specifically, victims of severe aggression affiliated with third parties after conflicts in the two‐piece condition, while aggressors affiliated with victims of mild aggression in the one‐piece condition. We thus provide the first evidence that a corvid species, crows, flexibly engage in both third‐party affiliation and reconciliation.     

Mass spectrometry‐compatible silver staining of histones resolved on acetic acid‐urea‐Triton PAGE

Acetic acid‐Urea‐Triton (AUT) PAGE is commonly used method to separate histone variants and their post‐translationally modified forms. Coomassie staining is the preferred method for protein visualization; however, its sensitivity is less than that of silver staining. Though silver staining of histones in AUT‐PAGE has been reported, the method is time‐consuming, dependent on prior staining by Amido black and has not been reported suitable for mass spectrometry. Here, we propose ‘SDS‐Silver’ method for rapid, sensitive and mass spectrometry‐compatible staining of histones resolved on AUT‐PAGE.     

SnoN functions as a tumour suppressor by inducing premature senescence

SnoN represses TGF‐β signalling to promote cell proliferation and has been defined as a proto‐oncogene partly due to its elevated expression in many human cancer cells. Although the anti‐tumourigenic activity of SnoN has been suggested, the molecular basis for this has not been defined. We showed here that high levels of SnoN exert anti‐oncogenic activity by inducing senescence. SnoN interacts with the promyelocytic leukaemia (PML) protein and is recruited to the PML nuclear bodies where it stabilizes p53, leading to premature senescence. Furthermore, overexpression of SnoN inhibits oncogenic transformation induced by Ras and Myc in vitro and significantly blocks papilloma development in vivo in a carcinogen‐induced skin tumourigenesis model. The few papillomas that were developed displayed high levels of senescence and spontaneously regressed. Our study has revealed a novel Smad‐independent pathway of SnoN function that mediates its anti‐oncogenic activity.     

Epitope motif of an anti‐nitrotyrosine antibody specific for tyrosine‐nitrated peptides revealed by a combination of affinity approaches and mass spectrometry

Nitration of tyrosine residues has been shown to be an important oxidative modification in proteins and has been suggested to play a role in several diseases such as atherosclerosis, asthma, lung and neurodegenerative diseases. Detection of nitrated proteins has been mainly based on the use of nitrotyrosine‐specific antibodies. In contrast, only a small number of nitration sites in proteins have been unequivocally identified by MS. We have used a monoclonal 3‐NT‐specific antibody, and have synthesized a series of tyrosine‐nitrated peptides of prostacyclin synthase (PCS) in which a single specific nitration site at Tyr‐430 had been previously identified upon reaction with peroxynitrite 17 . The determination of antibody‐binding affinity and specificity of PCS peptides nitrated at different tyrosine residues (Tyr‐430, Tyr‐421, Tyr‐83) and sequence mutations around the nitration sites provided the identification of an epitope motif containing positively charged amino acids (Lys and/or Arg) N‐terminal to the nitration site. The highest affinity to the anti‐3NT‐antibody was found for the PCS peptide comprising the Tyr‐430 nitration site with a K_D of 60 nM determined for the peptide, PCS(424‐436‐Tyr‐430NO₂); in contrast, PCS peptides nitrated at Tyr‐421 and Tyr‐83 had substantially lower affinity. ELISA, SAW bioaffinity, proteolytic digestion of antibody‐bound peptides and affinity‐MS analysis revealed highest affinity to the antibody for tyrosine‐nitrated peptides that contained positively charged amino acids in the N‐terminal sequence to the nitration site. Remarkably, similar N‐terminal sequences of tyrosine‐nitration sites have been recently identified in nitrated physiological proteins, such as eosinophil peroxidase and eosinophil‐cationic protein. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.     

β‐Hydroxybutyrate exacerbates lipopolysaccharide/ d‐galactosamine‐induced inflammatory response and hepatocyte apoptosis in mice

β‐Hydroxybutyrate (BHB), one of ketone body, has been traditionally regarded as an alternative carrier of energy, but recent studies found that BHB plays versatile roles in inflammation. It has been previously reported that the level BHB declined in mice with lipopolysaccharide (LPS)/d ‐galactosamine (d ‐Gal)‐induced liver damage, but the pathological significance remains unclear. In the present study, the pathophysiological roles of BHB in LPS/d ‐Gal‐induced hepatic damage has been investigated. The results indicated pretreatment with BHB further enhanced LPS/d ‐Gal‐induced elevation of aspartate aminotransferase and alanine aminotransferase, exacerbated the histological abnormalities and increased the mortality. Pretreatment with BHB upregulated the level of tumor necrosis factor α and interleukin‐6 in plasma, promoted the activities of caspase‐3, caspase‐8, and caspase‐9 and increased the count of terminal deoxynucleotidyl transferase dUTP nick end labeling‐positive cells. In addition, post‐insult supplement with BHB also potentiated LPS/d ‐Gal‐induced apoptotic liver damage. Therefore, BHB might be a detrimental factor in LPS/d ‐Gal‐induced liver injury via enhancing the inflammation and the apoptosis in the liver.     

Enantioseparation of flurbiprofen enantiomers using chiral ionic liquids by liquid‐liquid extraction

Flurbiprofen is a kind of nonsteroidal anti‐inflammatory drug, which has been widely used in clinic for treatment of rheumatoid arthritis and osteoarthritis. It has been reported that S‐flurbiprofen shows good performance on clinic anti‐inflammatory treatment, while R‐enantiomer almost has no pharmacological activities. It has important practical values to obtain optically pure S‐flurbiprofen. In this work, chiral ionic liquids, which have good structural designability and chiral recognize ability, were selected as the extraction selector by the assistance of quantum chemistry calculations. The distribution behaviors of flurbiprofen enantiomers were investigated in the extraction system, which was composed of organic solvent and aqueous phase containing chiral ionic liquid. The results show that maximum enantioselectivity up to 1.20 was attained at pH 2.0, 25°C using 1,2‐dichloroethane as organic solvent, 1‐butyl‐3‐methylimidazole L‐tryptophan ([Bmim][L‐trp]) as chiral selector. The racemic flurbiprofen initial concentration was 0.2 mmol L^?1, and [Bmim][L‐trp] concentration was 0.02 mol L^?1. Furthermore, the recycle of chiral ionic liquids has been achieved by reverse extraction process of the aqueous phase with chiral selector, which is significant for industrial application of chiral ionic liquids and scale‐up of the extraction process.     

Rational design of a monomeric and photostable far‐red fluorescent protein for fluorescence imaging in vivo

Fluorescent proteins (FPs) are powerful tools for cell and molecular biology. Here based on structural analysis, a blue‐shifted mutant of a recently engineered monomeric infrared fluorescent protein (mIFP) has been rationally designed. This variant, named iBlueberry, bears a single mutation that shifts both excitation and emission spectra by approximately 40 nm. Furthermore, iBlueberry is four times more photostable than mIFP, rendering it more advantageous for imaging protein dynamics. By tagging iBlueberry to centrin, it has been demonstrated that the fusion protein labels the centrosome in the developing zebrafish embryo. Together with GFP‐labeled nucleus and tdTomato‐labeled plasma membrane, time‐lapse imaging to visualize the dynamics of centrosomes in radial glia neural progenitors in the intact zebrafish brain has been demonstrated. It is further shown that iBlueberry can be used together with mIFP in two‐color protein labeling in living cells and in two‐color tumor labeling in mice.     

The role of the C(2) configuration and methyl substitution on the catalytic activity of novel 2,3,3‐ and 2,7,7‐trimethyl‐substituted γ‐aminonorbornan‐2‐ols

A new set of optically active 2,3,3‐ and 2,7,7‐trimethyl‐substituted γ‐aminonorbornan‐2‐ols have been obtained from 2‐methylenenorbornane‐1‐carbonitriles derived from (+)‐camphor and (?)‐fenchone and probed as chiral ligands for the enantioselective addition of diethylzinc to benzaldehyde. This has allowed the study of the structural factors influencing the chirality transfer, such as variation of the relative configuration at C(2) and steric hindrance at C(2), C(3), and C(7) positions of norbornane, which result in the observance of the important role played by the gem‐dimethyl position in γ‐aminonorbornan‐2‐exo‐ols. An empirical rationalization of the obtained experimental results has been realized on the basis of energetically‐favored diastereomeric Noyori‐like transition states. Chirality 2010. © 2010 Wiley‐Liss, Inc.