bluuebunny/crossref_metadata_2025 huggingface dataset:
Riluzole activates TRPC5 channels independently of PLC activity
Authors: Richter Julia M , Schaefer Michael , Hill Kerstin
Published: October 2013

Background and Purpose

The transient receptor potential channel C5 (TRPC5) is a Ca2+‐permeable cation channel, which is predominantly expressed in the brain. TRPC5 is activated in a PLC‐dependent manner by, as yet, unidentified endogenous messengers. Recently, modulators of TRPC5, like Ca2+, pH and phospholipids, have been identified. However, the role of TRPC5 in vivo is only poorly understood. Novel specific modulators of TRPC5 might help to elucidate its function.

Experimental Approach

Novel modulators of TRPC5 were identified in a compound screening of approved drugs and natural compounds. The potency and selectivity of TRPC5‐activating compounds were determined by fluorometric calcium imaging. The biophysical properties of channel activation by these compounds were analysed using electrophysiological measurements.

Key Results

Riluzole was identified as a novel activator of TRPC5 (EC50 9.2 ± 0.5 μM) and its mechanism of action was shown to be independent of G protein signalling and PLC activity. Riluzole‐induced TRPC5 currents were potentiated by La3+ and, utilizing TRPC5 mutants that lack La3+ binding sites, it was confirmed that riluzole and La3+ activate TRPC5 by different mechanisms. Recordings of excised inside‐out patches revealed a relatively direct effect of riluzole on TRPC5.

Conclusions and Implications

Riluzole can activate TRPC5 heterologously expressed in HEK293 cells as well as those endogenously expressed in the U‐87 glioblastoma cell line. Riluzole does not activate any other member of the TRPC family and could, therefore, despite its action on other ion channels, be a useful pharmacological tool for identifying TRPC5‐specific currents in immortalized cell lines or in acutely isolated primary cells.
Hypoxia modulates the activity of a series of clinically approved tyrosine kinase inhibitors
Authors: Ahmadi M , Ahmadihosseini Z , Allison S J , Begum S , Rockley K , Sadiq M , Chintamaneni S , Lokwani R , Hughes N , Phillips R M
Published: October 2013

Background and Purpose

Hypoxia in tumours is known to cause resistance to conventional chemotherapeutic drugs. In contrast, little is known about the effects of hypoxia on targeted anti‐cancer drugs. This study evaluated the effect of hypoxia on a series of clinically approved tyrosine kinase inhibitors (TKIs).

Experimental Approach

The effect of hypoxia (0.1% oxygen) on the activity of conventional cytotoxic drugs (5‐fluorouracil, doxorubicin and vinblastine), the hypoxia‐activated prodrug tirapazamine and 9 TKIs was determined in a panel of cell lines. Where hypoxia had a marked effect on chemosensitivity, Western blot analysis was conducted to determine the effect of hypoxia on target expression and the effect of TKIs on cell signalling response under aerobic and hypoxic conditions.

Key Results

Three patterns of chemosensitivity were observed: resistance under hypoxia, equitoxic activity against hypoxic and aerobic cells, and preferential cytotoxicity to hypoxic cells. Significant hypoxia selectivity (independent of HIF1) was observed in the case of dasatinib and this correlated with the ability of dasatinib to inhibit phosphorylation of Src at tyrosine 530. Sorafenib was significantly less effective under hypoxic conditions but resistance did not correlate with hypoxia‐induced changes in Raf/MEK/ERK signalling.

Conclusions and Implications

Hypoxia influences the activity of TKIs but in contrast to conventional cytotoxic drugs, preferential activity against hypoxic cells can occur. The search for hypoxia‐targeted therapies has been long and fruitless and this study suggests that some clinically approved TKIs could preferentially target the hypoxic fraction of some tumour types.
Andrographolide exerts anti‐hepatitis C virus activity by up‐regulating haeme oxygenase‐1 via the p38 MAPK/Nrf2 pathway in human hepatoma cells
Authors: Lee Jin‐Ching , Tseng Chin‐Kai , Young Kung‐Chia , Sun Hung‐Yu , Wang Shainn‐Wei , Chen Wei‐Chun , Lin Chun‐Kuang , Wu Yu‐Hsuan
Published: October 2013

Background and Purpose

This study aimed to evaluate the anti‐hepatitis C virus (HCV) activity of andrographolide, a diterpenoid lactone extracted from Andrographis paniculata, and to identify the signalling pathway involved in its antiviral action.

Experimental Approach

Using HCV replicon and HCVcc infectious systems, we identified anti‐HCV activity of andrographolide by measuring protein and RNA levels. A reporter activity assay was used to determine transcriptional regulation of anti‐HCV agents. A specific inhibitor and short hairpin RNAs were used to investigate the mechanism responsible for the effect of andrographolide on HCV replication.

Key Results

In HCV replicon and HCVcc infectious systems, andrographolide time‐ and dose‐dependently suppressed HCV replication. When combined with IFN‐α, an inhibitor targeting HCV NS3/4A protease (telaprevir), or NS5B polymerase (PSI‐7977), andrographolide exhibited a significant synergistic effect. Andrographolide up‐regulated the expression of haeme oxygenase‐1 (HO‐1), leading to increased amounts of its metabolite biliverdin, which was found to suppress HCV replication by promoting the antiviral IFN responses and inhibiting NS3/4A protease activity. Significantly, these antiviral effects were attenuated by an HO‐1‐specific inhibitor or HO‐1 gene knockdown, indicating that HO‐1 contributed to the anti‐HCV activity of andrographolide. Andrographolide activated p38 MAPK phosphorylation, which stimulated nuclear factor erythroid 2‐related factor 2 (Nrf2)–mediated HO‐1 expression, and this was found to be associated with its anti‐HCV activity.

Conclusions and Implications

Our results demonstrate that andrographolide has the potential to control HCV replication and suggest that targeting the Nrf2–HO‐1 signalling pathway might be a promising strategy for drug development.
Involvement of midkine in neuroblastoma tumourigenesis
Authors: Kishida S , Kadomatsu K
Published: October 2013

Midkine is highly expressed in various cancers, including neuroblastoma, one of the most malignant paediatric solid tumours known. Also, it has been shown to be useful as a tumour marker, a prognosis factor and a target of molecular therapy. Several molecular tools (e.g. siRNA, antibodies and RNA aptamer) have been used to establish a midkine‐targeted therapy. The involvement of midkine in tumourigenesis has been demonstrated in vivo in a mouse neuroblastoma model, where targeting it with an RNA aptamer was shown to be an effective treatment for xenografted tumours. Chemoresistance is one of the notable phenotypes regulated by midkine in various cancer cell types. In pancreatic tumours and glioma cells, midkine is expressed in chemoresistant cells and is involved in the survival of these cells in the presence of anticancer drugs. In contrast to these tumours, midkine was found to be expressed in every neuroblastoma cell line tested and the knockdown of midkine alone was sufficient to suppress their growth. These results indicate that neuroblastoma cells are highly dependent on midkine and that a midkine‐targeted therapy could exert a significant effect in these cells. However, to achieve a midkine‐targeted therapy for high‐risk neuroblastoma patients, the further refinement of the RNA aptamer or antibody as tools and the elucidation of midkine signalling are immediate issues that need to be resolved. Regarding the latter, although it has been shown that Notch2 functions as a receptor in neuroblastoma cells, it is likely that other receptors (e.g. anaplastic lymphoma kinase) are also involved in midkine signalling.

Linked Articles

This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐4
PDGF and TGF‐β promote tenascin‐C expression in subepithelial myofibroblasts and contribute to intestinal mucosal protection in mice
Authors: Islam M S , Kusakabe M , Horiguchi K , Iino S , Nakamura T , Iwanaga K , Hashimoto H , Matsumoto S , Murata T , Hori M , Ozaki H
Published: October 2013

Background and Purpose

Tenascin‐C (TnC) is a multi‐domain extracellular matrix glycoprotein that is expressed at a high level during embryogenesis but is almost absent during normal postnatal life. This multi‐domain complex molecule is reported to associate with both pro‐inflammatory and anti‐inflammatory signalling cascades. In this study, we examined how TnC modulated intestinal inflammation.

Experimental Approach

TnC pathophysiology was evaluated in cultures of rat intestinal subepithelial myofibroblasts (ISEMF) and intestinal epithelial cells. Wild‐type and TnC(−/−) mice were treated with dextran sodium sulfate (DSS) to induce colitis.

Key Results

DSS‐induced colitis in mice markedly increased TnC in the damaged mucosal areas and up‐regulated mRNA for TnC, pro‐inflammatory cytokines and growth factors (PDGF‐B and TGF‐β1). In addition, 2,4,6‐trinitrobenzene sulfonic acid‐induced colitis and SAMP1/Yit mice, a model of spontaneous Crohn's disease, also exhibited increased mucosal TnC in colon and ilea respectively. PDGF receptor‐α (PDGFRα) positive ISEMF were the primary TnC‐producing cells in colon tissues. Accordingly, ISEMF collected from the rat colon constitutively expressed both TnC and PDGFRα. PDGF‐BB and TGF‐β1 up‐regulated both TnC mRNA and protein levels in ISEMF. Knock‐down of TnC gene increased susceptibility to DSS‐induced colitis, compared with TnC(+/+) littermates. TnC(−/−) mice showed marked abrasion of intestinal mucosal barrier and increased inflammatory scores. Moreover, TnC accelerated both trans‐well migration and wound healing in epithelial cells.

Conclusions and Implications

The pharmacological profiles of PDGF‐BB and TGF‐β in colitis tissues and ISEMF suggest that increased TnC production during inflammation contributed to epithelial cell migration, remodelling and protection of intestinal barriers.
Novel analogues of chlormethiazole are neuroprotective in four cellular models of neurodegeneration by a mechanism with variable dependence on GABAA receptor potentiation
Authors: VandeVrede Lawren , Tavassoli Ehsan , Luo Jia , Qin Zhihui , Yue Lan , Pepperberg David R , Thatcher Gregory R
Published: October 2013

Background and Purpose

Chlormethiazole (CMZ), a clinical sedative/anxiolytic agent, did not reach clinical efficacy in stroke trials despite neuroprotection demonstrated in numerous animal models. Using CMZ as a lead compound, neuroprotective methiazole (MZ) analogues were developed, and neuroprotection and GABAA receptor dependence were studied.

Experimental Approach

Eight MZs were selected from a novel library, of which two were studied in detail. Neuroprotection, glutamate release, intracellular calcium and response to GABA blockade by picrotoxin were measured in rat primary cortical cultures using four cellular models of neurodegeneration. GABA potentiation was assayed in oocytes expressing the α1β2γ2 GABAA receptor.

Key Results

Neuroprotection against a range of insults was retained even with substantial chemical modification. Dependence on GABAA receptor activity was variable: at the extremes, neuroprotection by GN‐28 was universally sensitive to picrotoxin, while GN‐38 was largely insensitive. In parallel, effects on extracellular glutamate and intracellular calcium were associated with GABAA dependence. Consistent with these findings, GN‐28 potentiated α1β2γ2 GABAA function, whereas GN‐38 had a weak inhibitory effect. Neuroprotection against moderate dose oligomeric Aβ1–42 was also tolerant to structural changes.

Conclusions and Implications

The results support the concept that CMZ does not contain a single pharmacophore, rather that broad‐spectrum neuroprotection results from a GABAA‐dependent mechanism represented by GN‐28, combined with a mechanism represented in GN‐38 that shows the least dependence on GABAA receptors. These findings allow further refinement of the neuroprotective pharmacophore and investigation into secondary mechanisms that will assist in identifying MZ‐based compounds of use in treating neurodegeneration.
The structural role of receptor tyrosine sulfation in chemokine recognition
Authors: Ludeman Justin P , Stone Martin J
Published: October 2013

Tyrosine sulfation is a post‐translational modification of secreted and transmembrane proteins, including many GPCRs such as chemokine receptors. Most chemokine receptors contain several potentially sulfated tyrosine residues in their extracellular N‐terminal regions, the initial binding site for chemokine ligands. Sulfation of these receptors increases chemokine binding affinity and potency. Although receptor sulfation is heterogeneous, insights into the molecular basis of sulfotyrosine (sTyr) recognition have been obtained using purified, homogeneous sulfopeptides corresponding to the N‐termini of chemokine receptors. Receptor sTyr residues bind to a shallow cleft defined by the N‐loop and β3‐strand elements of cognate chemokines. Tyrosine sulfation enhances the affinity of receptor peptides for cognate chemokines in a manner dependent on the position of sulfation. Moreover, tyrosine sulfation can alter the selectivity of receptor peptides among several cognate chemokines for the same receptor. Finally, binding to receptor sulfopeptides can modulate the oligomerization state of chemokines, thereby influencing the ability of a chemokine to activate its receptor. These results increase the motivation to investigate the structural basis by which tyrosine sulfation modulates chemokine receptor activity and the biological consequences of this functional modulation.

Linked Articles

This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐5
Melatonin MT1 and MT2 receptors display different molecular pharmacologies only in the G‐protein coupled state
Authors: Legros Céline , Devavry Séverine , Caignard Sarah , Tessier Clémence , Delagrange Philippe , Ouvry Christine , Boutin Jean A , Nosjean Olivier
Published: October 2013

Background and Purpose

Melatonin receptors have been extensively characterized regarding their affinity and pharmacology, mostly using 2‐[125I]‐melatonin as a radioligand. Although [3H]‐melatonin has the advantage of corresponding to the endogenous ligand of the receptor, its binding has not been well described.

Experimental Approach

We characterized [3H]‐melatonin binding to the hMT1 and hMT2 receptors expressed in a range of cell lines and obtained new insights into the molecular pharmacology of melatonin receptors.

Key Results

The binding of [3H]‐melatonin to the hMT1 and hMT2 receptors displayed two sites on the saturation curves. These two binding sites were observed on cell membranes expressing recombinant receptors from various species as well as on whole cells. Furthermore, our GTPγS/NaCl results suggest that these sites on the saturation curves correspond to the G‐protein coupled and uncoupled states of the receptors, whose pharmacology was extensively characterized.

Conclusions and Implications

hMT1 and hMT2 receptors spontaneously exist in two states when expressed in cell lines; these states can be probed by [3H]‐melatonin binding. Overall, our results suggest that physiological regulation of the melatonin receptors may result from complex and subtle mechanisms, a small difference in affinity between the active and inactive states of the receptor, and spontaneous coupling to G‐proteins.
The protein Ocular albinism 1 is the orphan GPCR GPR143 and mediates depressor and bradycardic responses to DOPA in the nucleus tractus solitarii
Authors: Hiroshima Y , Miyamoto H , Nakamura F , Masukawa D , Yamamoto T , Muraoka H , Kamiya M , Yamashita N , Suzuki T , Matsuzaki S , Endo I , Goshima Y
Published: October 2013

Background and Purpose

L‐DOPA is generally considered to alleviate the symptoms of Parkinson's disease by its conversion to dopamine. We have proposed that DOPA is itself a neurotransmitter in the CNS. However, specific receptors for DOPA have not been identified. Recently, the gene product of ocular albinism 1 (OA1) was found to exhibit DOPA‐binding activity. Here, we have investigated whether OA1 is a functional receptor of DOPA in the nucleus tractus solitarii (NTS).

Experimental Approach

We examined immunohistochemical expression of OA1 in the NTS, and the effects of DOPA microinjected into the depressor sites of NTS on blood pressure and heart rate in anaesthetized rats, with or without prior knock‐down of OA1 in the NTS, using shRNA against OA1.

Key Results

Using a specific OA1 antibody, OA1‐positive cells and nerve fibres were found in the depressor sites of the NTS. OA1 expression in the NTS was markedly suppressed by microinjection into the NTS of adenovirus vectors carrying the relevant shRNA sequences against OA1. In animals treated with OA1 shRNA, depressor and bradycardic responses to DOPA, but not those to glutamate, microinjected into the NTS were blocked. Bilateral injections into the NTS of DOPA cyclohexyl ester, a competitive antagonist against OA1, suppressed phenylephrine‐induced bradycardic responses without affecting blood pressure responses.

Conclusion and Implications

OA1 acted as a functional receptor for DOPA in the NTS, mediating depressor and bradycardic responses. Our results add to the evidence for a central neurotransmitter role for DOPA, without conversion to dopamine.
In vivo delivery of siRNA targeting vasohibin‐2 decreases tumor angiogenesis and suppresses tumor growth in ovarian cancer
Authors: Koyanagi Takahiro , Suzuki Yasuhiro , Saga Yasushi , Machida Shizuo , Takei Yuji , Fujiwara Hiroyuki , Suzuki Mitsuaki , Sato Yasufumi
Published: October 2013

Vasohibin‐2 (VASH2) is a homolog of vasohibin‐1 and exhibits pro‐angiogenic activity. We recently reported that VASH2 is expressed in certain ovarian cancers and promotes tumor growth through angiogenesis. To further demonstrate the effectiveness of molecular targeting of VASH2 for anticancer treatment, we applied in vivo delivery of siRNA targeting VASH2 (siVASH2) using atelocollagen to a xenograft model of ovarian cancer. We inoculated mice s.c. with DISS and SKOV‐3, two representative human ovarian serous adenocarcinoma cell lines. When tumors were measurable, we initiated treatment with control or siVASH2 mixed with atelocollagen, which enveloped the whole tumor. Treatment with siVASH2 significantly inhibited s.c. tumor growth by abrogating tumor angiogenesis. We confirmed that expression of VASH2 mRNA in the tumor was downregulated by siVASH2 treatment. In addition, the siVASH2‐treated tumor contained more blood vessels covered with pericytes, indicating that knockdown of VASH2 contributes to the normalization of tumor blood vessels. Based on these results, VASH2 may be a promising molecular target for ovarian cancer treatment.
Amurensin G enhances the susceptibility to tumor necrosis factor‐related apoptosis‐inducing ligand‐mediated cytotoxicity of cancer stem‐like cells of HCT‐15 cells
Authors: Lee Su‐Hoon , Kim Mi‐Ju , Kim Dong‐Wan , Kang Chi‐Dug , Kim Sun‐Hee
Published: October 2013

Cancer stem cells (CSCs) are resistant to radiotherapy and chemotherapy and play a significant role in cancer recurrence. Design of better treatment strategies that can eliminate or otherwise control CSC populations in tumors is necessary. In this study, the sensitivity to tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced cytotoxicity and the effect of amurensin G, a novel sirtuin 1 (SIRT1) inhibitor, were examined using the CSC‐enriched fraction of HCT‐15 human colon cancer cells. Cancer stem cell‐enriched HCT‐15 colony cells were paradoxically less sensitive to doxorubicin, and more sensitive to TRAIL‐induced cytotoxicity, than their parental cells. Also, CD44+ HCT‐15 cells were more susceptible to TRAIL‐mediated cytotoxicity than CD44− HCT‐15 cells, possibly due to increased levels of death receptors DR4 and DR5 as well as c‐Myc, and decreased levels of c‐FLIPL/S in CD44+ cells compared with CD44− HCT‐15 cells. The combination effect of amurensin G on TRAIL‐mediated cytotoxicity was much more apparent in CD44+ cells than in CD44− HCT‐15 cells, and this was associated with more prominent downregulation of c‐FLIPL/S in CD44+ cells than in CD44− HCT‐15 cells. These results indicate that HCT‐15 colony or CD44+ cells, which may have CSC properties, are more sensitive to TRAIL than parental or CD44− HCT‐15 cells. Amurensin G may be effective in eliminating colon CSCs and be applicable to potentiate the sensitivity of colon CSCs to TRAIL.
Plasma miR‐21 is a novel diagnostic biomarker for biliary tract cancer
Authors: Kishimoto Tomoya , Eguchi Hidetoshi , Nagano Hiroaki , Kobayashi Shogo , Akita Hirofumi , Hama Naoki , Wada Hiroshi , Kawamoto Koichi , Tomokuni Akira , Tomimaru Yoshito , Umeshita Koji , Doki Yuichiro , Mori Masaki
Published: October 2013

Biliary tract cancer (BTC) has a generally poor prognosis. Furthermore, it is difficult to distinguish BTC from benign biliary disease (BBD) with commonly used modalities. Therefore, a novel biomarker to facilitate cancer detection is highly desirable. Recent studies have reported the use of circulating microRNAs (miRNAs) as biomarkers for cancers. The purpose of this study was to evaluate whether circulating miRNA‐21 (miR‐21) could be used as a biomarker for BTC. Plasma samples were obtained from 94 BTC patients, 50 healthy volunteers (HVs), and 23 BBD patients. miR‐21 levels in the samples were measured by qRT‐PCR. Plasma miR‐21 levels in patients with BTC were significantly higher than in HVs or in patients with BBD (P < 0.0001 for both). Receiver–operator curve (ROC) curve analysis in differentiating BTC patients from HVs indicated that area under the curve (AUC), optimal sensitivity and specificity was 0.93, 85.1% and 100%, respectively, and those in differentiating BTC patients from BBD patients was 0.83, 72.3%, 91.3%, respectively. Validation of these results indicated that the negative predictive value, positive predictive value, sensitivity, specificity, and accuracy in differentiating BTC patients from HVs was 76.6%, 98.6%, 84.0%, 98.0%, and 88.9%, respectively, and those in differentiating BTC patients from BBD patients was 42.2%, 93.0%, 71.2%, 82.6%, and 72.6%, respectively. These sets of values were improved by combining miR‐21 and CA19‐9 measurements. Plasma miR‐21 is a novel diagnostic biomarker for BTC, and may be useful in distinguishing between BTC and BBD patients.
Effectiveness of Novel 5‐(5‐amino‐1‐aryl‐1H‐pyrazol‐4‐yl)‐1H‐tetrazole Derivatives Against Promastigotes and Amastigotes of Leishmania amazonensis
Authors: dos Santos Faiões Viviane , Leon Leonor L. , Canto‐Cavalheiro Marilene M. , Torres‐Santos Eduardo C. , Bernardino Alice M. R. , Vegi Percilene F. , dos Santos Maurício S.
Published: October 2013

In this research, a series of substituted 5‐(5‐amino‐1‐aryl‐1H‐pyrazol‐4‐yl)‐1H‐tetrazoles were synthesized and evaluated for in vitro antileishmanial activity. Among the derivatives, examined compounds 3b and 3l exhibited promising activity against promastigotes and amastigotes forms of Leishmania amazonensis. The cytotoxicity of these compounds was evaluated on murine cells, giving access to the corresponding selectivity index (SI).
Antimicrobial Activity and SAR Study of New Gemini Imidazolium‐Based Chlorides
Authors: Pałkowski Łukasz , Błaszczyński Jerzy , Skrzypczak Andrzej , Błaszczak Jan , Kozakowska Karolina , Wróblewska Joanna , Kożuszko Sylwia , Gospodarek Eugenia , Krysiński Jerzy , Słowiński Roman
Published: October 2013

A series of 70 new 3,3′(α,ω‐dioxaalkyl)bis(1‐alkylimidazolium) chlorides were synthesized. They were characterized with respect to surface active properties and antimicrobial activity against the following pathogens: Staphylococcus aureus, Enterococcus faecalis, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa, Candida krusei, and Candida albicans. In this article, besides description of the synthesis, we characterize a set of features of these compounds, concerning their structure (described by the length of the dioxaalkan spacer and the length of the alkyl substituent in the aromatic ring) and surface active properties (critical micelle concentration, value of surface tension at critical micelle concentration, value of surface excess, molecular area of a single particle, and free energy of adsorption of molecule). Then, we present a SAR study for Staphylococcus aureus, as one of the most widespread pathogenic strains, conducted with the help of the Dominance‐based Rough Set Approach (DRSA), that involves identification of relevant features and relevant combinations of features being in strong relationship with a high antimicrobial activity of the compounds. The SAR study shows, moreover, that the antimicrobial activity is dependent on the type of substituents and their position at the chloride moiety, as well as on the surface active properties of the compounds.
Discovery of Synthetic Leishmania Inhibitors by Screening of a 2‐Arylbenzothiophene Library
Authors: Bonano Vivian I. , Yokoyama‐Yasunaka Jenicer K. U. , Miguel Danilo C. , Jones Scott A. , Dodge Jeffrey A. , Uliana Silvia R. B.
Published: October 2013

Tamoxifen has been shown to be active in vitro against Leishmania and effective in the treatment for leishmaniasis in murine models. Through the screening of a compound library of estrogen receptor modulator analogs, we identified the major characteristics required for antileishmanial activity. To overcome the difficulties presented by tamoxifen's propensity for E/Z isomerization, we used the 2‐arylbenzothiophene compound BTP as a more stable alternative. Directed screening of a small compound library based on BTP led to active compounds against Leishmania. Subsequent structure–activity data for the synthetic 2‐arylbenzothiophenes evaluated in this study indicate that optimal antileishmanial potency is dependent on the presence of two basic side chains. In addition, the primary structural features required for estrogen receptor binding, the phenols, are not required for inhibiting parasitic growth. Significantly, the most active antileishmanial benzothiophenes lack the pharmacophore for estrogen receptor activity and therefore address potential concerns about the undesirable effects of using selective estrogen receptor modulators in women and children with leishmaniasis. Three compounds selected from the screening have shown consistent activity against all species and stages of Leishmania in vitro although improvements in selectivity are needed. These compounds represent viable starting points for further optimization as antileishmanial agents.
1‐Thia‐4,7‐diaza‐spiro[4.4]nonane‐3,6‐dione: A Structural Motif for 5‐hydroxytryptamine 6 Receptor Antagonism
Authors: Hostetler Greg , Dunn Derek , McKenna Beth A. , Kopec Karla , Chatterjee Sankar
Published: October 2013

A series of potent 5‐hydroxytryptamine 6 (5‐HT6) receptor antagonists based on 1‐thia‐4,7‐diaza‐spiro[4.4]nonane‐3,6‐dione motif has been disclosed. Enantiomers of potent racemate compound 8a (Ki = 26 nm) displayed difference in activity (Ki of 15 nm versus 855 nm) signaling the influence of the stereochemistry of the chiral center on potency. In addition, the potent enantiomer displayed significant selectivity in biological activities over several related family members.
Synthesis and Evaluation of Novel Oleanolic Acid Derivatives as Potential Antidiabetic Agents
Authors: Zhang Liying , Jia Xiaojian , Dong Jizhe , Chen Dongyin , Liu Jun , Zhang Luyong , Wen Xiaoan
Published: October 2013

Antidiabetic agents simultaneously inhibiting hepatic glucose production and stimulating hepatic glucose consumption could apply a better control over hyperglycemia. A series of oleanolic acid derivatives with bulky substituents at C‐3 position were designed and synthesized in order to search for this kind of agents. All of the compounds were evaluated biologically in vitro using glycogen phosphorylase and HepG2 cells. The results indicated that several derivatives exhibited moderate‐to‐good inhibitory activities against glycogen phosphorylase. Compound 8g showed the best inhibition with an IC50 value of 5.4 μm. Moreover, most of the derivatives were found to increase the glucose consumption in HepG2 cells in a dose‐dependent manner. The possible binding mode of compound 8g with glycogen phosphorylase was also explored by docking study. 8g was found to have hydrogen bonding interactions with Arg193, Arg310, and Arg60 of the allosteric site.
Effect of HA14‐1 on Apoptosis‐Regulating Proteins in HeLa Cells
Authors: Rehman Kanwal , Tariq Muhammad , Akash Muhammad S. H. , Gillani Zeeshan , Qazi Mehmood H.
Published: October 2013

Overexpression of Bcl‐2 has been recognized in various malignancies. Recently, HA14‐1, a Bcl‐2 antagonist, has been identified for its anti‐apoptotic effect. However, mode of action of HA14‐1 still remains to be elucidated. In this study, we examined HA14‐1 binding efficiency with receptor proteins through molecular docking. Cell viability using HeLa cells was evaluated through MTT assay after exposure to different concentration of HA14‐1. Moreover, after HA14‐1 exposure, expressions of tumor suppressor protein (p53), BH3‐only protein (Puma) and apoptosis‐associated proteins were analyzed by Western blotting. From the results, it was found that HA14‐1 occupied all three domains; BH1, BH2, and BH3 within the hydrophobic pocket of Bcl‐2. However, HA14‐1 occupied only BH1 and BH3 of Bcl‐xl, conversely, no such stable bond was observed for Bax and Bak. ARG107 and TYR101 were the amino acids involved in the binding of HA14‐1 to Bcl‐2 and Bcl‐xl, respectively. Additionally, decrease in Bcl‐2 and Bcl‐xl expression along with increase in p53 and Puma expression after exposure to HA14‐1 was observed. The results suggested p53 pathway to be the probable mechanism of action for the induction of apoptosis in HeLa cell by downregulating the effect of anti‐apoptotic proteins suggesting that HA14‐1 may provide therapeutic potential for the treatment of human cervical cancer.
A comparison of Child Health Programmes recommended for preschool children in selected high‐income countries
Authors: Wood Rachael , Blair Mitch
Published: October 2013

Background

The UK Child Health Programme (CHP) aims to ensure that children attain their development and health potential. It comprises a series of proactive child health reviews incorporating growth and development surveillance and health promotion; routine immunizations; and certain screening tests, and is offered to all children. The evidence underpinning different elements of the CHP varies from robust to sparse, and consequently there is uncertainty about optimal programme design. This study aimed to compare the CHP currently recommended in the UK with that recommended in selected other high‐income countries in order to inform ongoing CHP policy development.

Methods

The CHP recommended for preschool children in the UK was compared with that in Australia; Canada; the USA; and Sweden using a combination of literature review, focused website searches, and consultation with experts in the countries studied. Delivery, content, and uptake of child health reviews, immunizations, and screening were considered.

Results

All the countries studied recommend CHP services including child health reviews, immunizations, and screening to their preschool populations. Despite this superficial uniformity, considerable variation exists between countries in the detail of CHP delivery and content. The UK programme is relatively narrow in scope, offering the fewest child health reviews, a relatively restricted immunization programme (although some expansion is planned), and limited newborn bloodspot screening. Internationally comparable data on the uptake/coverage of CHP services are patchy: the available information suggests substantial variation between and within countries in the uptake of child health reviews.

Conclusions

In the absence of uncontested evidence on the ‘ideal’ CHP for preschool children, demonstrating variation between countries in recommended programmes provides valuable contextual information for policy makers. Further work looking at relationships between CHP services and children's outcomes would add further value.
Longitudinal associations between breastfeeding and observed mother–child interaction qualities in early childhood
Authors: Papp L. M.
Published: October 2013

Background

Despite extensive literature on the role of breastfeeding in maternal and child health and cognitive development, few studies have systematically tested whether breastfeeding predicts children's socio‐emotional outcomes. The present study examined associations between trajectories of breastfeeding and observed parent–child interaction qualities of maternal sensitivity, child positivity, and child negativity from 6 months to 3 years of age.

Methods

Data were drawn from the NICHD Study of Early Child Care and Youth Development (n = 1306 US families). Hierarchical linear modelling accounted for demographic and early characteristics, including home environment, maternal depression, and observed global relationship quality.

Results

Breastfeeding was associated with increases in observed maternal sensitivity over time, even after the effects of demographic and early characteristics were controlled. Accounting for the covariates, breastfeeding was not associated with child behaviour (i.e. positivity, negativity) in mother–child interaction across early childhood.

Conclusions

Improved relationship quality, specifically through changes in maternal behaviour, may be another advantage experienced by breastfeeding mothers and children.
Understanding the healthcare experiences of teenaged cancer patients and survivors
Authors: Farjou G. , Sinha R. , Dix D. , Shahbaz A. , Klaassen R. J. , Klassen A. F.
Published: October 2013

Background

Despite literature supporting a client and family‐centred approach to healthcare delivery in paediatric facilities, there is little information about healthcare delivery from the perspective of teenagers in the oncology setting. The objective of this study is to describe the healthcare experiences of teenagers with cancer.

Methods

As part of a larger study on teen‐centred care delivery in paediatric oncology, a survey included several open‐ended questions to learn about the following: (1) what teenagers liked about the cancer care they received; (2) what they disliked about the cancer care received; and (3) what they would include if they could design the perfect cancer centre for teenagers. The survey was completed by 200 teenagers (aged 12–20 years) from three paediatric hospitals inCanada. Answers to these questions were coded and developed into themes and subthemes using a thematic analysis approach.

Results

The number of patients providing answers was 89% for question 1, 63% for question 2 and 68.5% for question 3. Likes and dislikes were conceptualized in terms of four key themes as follows: (1) staff at the treatment centre; (2) the cancer care they received; (3) the treatment centre itself; and (4) social activities. The most common suggestions for the perfect cancer centre included having access to better entertainment, more social opportunities to interact with peers, and a more comfortable environment for themselves and their families.

Conclusion

Understanding teenagers' experiences in the paediatric oncology setting provides information that could be used to shape the delivery of healthcare in a way that is tailored to their needs. Further research in this area is required in order to improve existing oncology care.
Addressing Important Questions in the Field of Adolescent Purpose
Authors: Hill Patrick L. , Burrow Anthony L. , Sumner Rachel
Published: October 2013

In this review, we discuss three questions about the importance of studying purpose as a construct relevant to adolescence. We consider how finding a purpose can help youth answer questions such as “Who am I?” and “Where am I going?” and summarize the benefits of finding a purpose during adolescence. Purposeful youth are more agentic and driven in their lives, as well as happier and less susceptible to risks common in adolescence. We conclude by identifying areas that merit study, including the need to understand which contexts best scaffold the development of purpose among youth and the need for experimental research to strengthen causal claims.
Age‐Related Changes in Spreading Activation During Infancy
Authors: Barr Rachel , Walker Joanne , Gross Julien , Hayne Harlene
Published: October 2013

The concept of spreading activation describes how retrieval of one memory cues retrieval of other memories that are associated with it. This study explored spreading activation in 6‐, 12‐, and 18‐month‐old infants. Infants (n = 144) learned two tasks within the same experimental session; one task, deferred imitation (DI), is typically remembered longer than the other task, visual recognition memory (VRM). At all ages, retrieval of the DI memory facilitated retrieval of the VRM memory, but the conditions under which this spreading activation occurred changed as a function of age. The implications of these findings are discussed in relation to the development of mnemonic networks during infancy and the value of studying infants for our understanding of memory more generally.
Deconstructing Building Blocks: Preschoolers' Spatial Assembly Performance Relates to Early Mathematical Skills
Authors: Verdine Brian N. , Golinkoff Roberta M. , Hirsh‐Pasek Kathryn , Newcombe Nora S. , Filipowicz Andrew T. , Chang Alicia
Published: October 2013

This study focuses on three main goals: First, 3‐year‐olds' spatial assembly skills are probed using interlocking block constructions (N = 102). A detailed scoring scheme provides insight into early spatial processing and offers information beyond a basic accuracy score. Second, the relation of spatial assembly to early mathematical skills was evaluated. Spatial skill independently predicted a significant amount of the variability in concurrent mathematical performance. Finally, the relation between spatial assembly skill and socioeconomic status (SES), gender, and parent‐reported spatial language was examined. While children's performance did not differ by gender, lower SES children were already lagging behind higher SES children in block assembly. Furthermore, lower SES parents reported using significantly fewer spatial words with their children.
Cultural Socialization and Ethnic Pride Among Mexican‐Origin Adolescents During the Transition to Middle School
Authors: Hernández Maciel M. , Conger Rand D. , Robins Richard W. , Bacher Kelly Beaumont , Widaman Keith F.
Published: October 2013

The relation between cultural socialization and ethnic pride during the transition to middle school was examined for 674 fifth‐grade students (50% boys; Mage = 10.4 years) of Mexican origin. The theoretical model guiding the study proposes that parent–child relationship quality is a resource in the transmission of cultural values from parent to child and that parental warmth promotes the child's positive response to cultural socialization. Results showed that mother and father cultural socialization predicted youth ethnic pride and that this relation was stronger when parents were high in warmth. The findings highlight the positive role parent cultural socialization may play in the development of adolescent ethnic pride. Furthermore, findings reveal the role of parent–child relationship quality in this process.
A Gentle Introduction to Bayesian Analysis: Applications to Developmental Research
Authors: van de Schoot Rens , Kaplan David , Denissen Jaap , Asendorpf Jens B. , Neyer Franz J. , van Aken Marcel A.G.
Published: October 2013

Bayesian statistical methods are becoming ever more popular in applied and fundamental research. In this study a gentle introduction to Bayesian analysis is provided. It is shown under what circumstances it is attractive to use Bayesian estimation, and how to interpret properly the results. First, the ingredients underlying Bayesian methods are introduced using a simplified example. Thereafter, the advantages and pitfalls of the specification of prior knowledge are discussed. To illustrate Bayesian methods explained in this study, in a second example a series of studies that examine the theoretical framework of dynamic interactionism are considered. In the Discussion the advantages and disadvantages of using Bayesian statistics are reviewed, and guidelines on how to report on Bayesian statistics are provided.
Preschoolers Selectively Infer History When Explaining Outcomes: Evidence From Explanations of Ownership, Liking, and Use
Authors: Nancekivell Shaylene E. , Friedman Ori
Published: October 2013

Two experiments provide evidence that preschoolers selectively infer history when explaining outcomes and infer past events that could have plausibly happened. In Experiment 1, thirty‐three 3‐year‐olds and thirty‐six 4‐year‐olds explained why a character owns or likes certain objects. In Experiment 2, thirty‐four 4‐year‐olds and thirty‐six 5‐year‐olds explained why a character either owns or is using the objects. Children aged 4 and 5 years, but not 3 years, inferred history when explaining ownership, but not when explaining liking or use. They also tailored their explanations to reflect likelihood, allowing them to infer plausible past events. These findings are informative about the development of children's ability to infer history in their explanations and also suggest that preschoolers appreciate that ownership depends on past investment.
Sociodemographic disparities and behavioral factors in clinical oral health status during pregnancy
Authors: Chung Lisa H. , Gregorich Steven E. , Armitage Gary C. , Gonzalez‐Vargas Judy , Adams Sally H.
Published: October 2013

Objectives

Although oral health (OH) problems are common during pregnancy, little is known about individual characteristics or behaviors relating to clinically assessed OH during pregnancy. This cross‐sectional study describes the clinical OH status of a sample of pregnant women, examines relationships between sociodemographic factors and OH, behavioral factors and OH, and the influence of behavior on the relationships between sociodemographic clusters and OH. Baseline data were utilized from a pilot intervention study promoting OH during pregnancy.

Methods

Participants (n = 99), recruited from CenteringPregnancy® prenatal care groups completed questionnaires addressing race/ethnicity, income, education, dental insurance, oral hygiene practices, and dental care utilization; and clinical examinations for periodontal probing depths (PD), bleeding on probing (BOP), plaque assessment, and visual detection of untreated decay. Chi‐squares and one‐way anovas with Tukey's studentized range test of planned comparisons were conducted to examine bivariable relationships between both sociodemographic and behavioral characteristics to OH status. Multivariable logistic regression analyses tested whether the effects of sociodemographic variables on OH status might be mediated by behaviors, including self‐reported oral hygiene and recent dental visits.

Results

Forty‐five percent of the sample had untreated decay and the mean percentage of sites with BOP = 18%. Bivariable analyses of sociodemographic factors indicated that compared with Whites, Hispanic women had greater % of sites with: BOP, PD ≥5 mm plus BOP, and Plaque Index (PI) scores of ≥2, all P = 0.05; and greater untreated decay (Chi‐square 13.3, P < 0.001). Lower income was related to greater untreated decay (Chi‐square 7.6, P < 0.01). Compared with the highest education level, the lowest level group had higher % BOP, P < 0.05. Public dental insurance (versus private) was associated with greater % BOP, PD ≥5 mm plus BOP, both P < 0.05, and greater untreated decay (Chi‐square 16.9, P < 0.001). Regarding behaviors, lacking a past 6‐month dental visit was related to greater: BOP, PD ≥5 mm plus BOP, and PI ≥2 (F range 6.2–8.7, P < 0.01–0.05); and greater untreated decay (Chi‐square 12.0, P < 0.001). Self‐reported optimal oral hygiene was related to lower % BOP and PD ≥5 mm plus BOP (F range 4.5–6.7, both P < 0.05). Mediation analyses indicated that there were significant indirect effects of racial/ethnic differences on OH outcomes via having a recent dental visit (OR range 1.2–1.9). However, significant differences between the Hispanic and White groups remained.

Conclusions

This study highlights sociodemographic disparities in clinical OH during pregnancy, the importance of dental care, and provides useful findings for tailoring interventions for expectant mothers and their infants.
Recurrent reactions to food among children at paediatric emergency departments
Authors: Vetander M. , Ly D. H. , Håkansson N. , Lilja G. , Nilsson C. , Östblom E. , Wickman M. , Bergström A.
Published: October 2013

Background

Knowledge about repeated food reactions in paediatric emergency departments (ED) is sparse.

Objective

To investigate the incidence and potential risk factors for repeated ED visits for food‐allergic reactions among children with a prior ED visit due to reactions to food.

Methods

A total of 358 children with ED visits at paediatric hospitals in Stockholm due to reactions to foods during 2007 (index‐reaction) were investigated in relation to recurrent reactions until 30 June 2010. Adjusted Cox proportional hazard models were used to compute relative risks (RR) and 95% confidence intervals (CI).

Results

A total of 80 children had 116 ED revisits over a period of 873 patient‐years, yielding an incidence rate of 9 per 100 patient‐years. Known food allergy before the index ED visit in 2007 increased the risk for ED revisits (RR = 2.30, 95% CI 1.35–3.94). Likewise, prescription of adrenaline auto‐injector before the index‐reaction increased the risk (RR = 2.02, 95% CI 1.17–3.49). Twenty‐one percent of the children had more severe reactions at the revisit, 38% less severe and 41% had reactions of comparable severity. However, among 44% of the children with comparable or less severe reaction at revisit, early treatment with adrenaline hampered the classification of change in severity.

Conclusions and Clinical Relevance

Previously known food allergy and prior prescription of adrenaline are significant risk factors for ED revisits among children with a prior ED visit due to reactions to food. Our results indicate that the severity of the index‐reaction cannot be used to predict the severity of the relapse.