Editorial board

Publication date: 15 January 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2





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SRC2-3 binds to vitamin D receptor with high sensitivity and strong affinity

Publication date: 15 January 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
Author(s): Daichi Egawa, Toshimasa Itoh, Akira Kato, Saori Kataoka, Yasuaki Anami, Keiko Yamamoto
Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and regulates the expression of target genes through ligand binding. To express the target gene, coactivator binding to the VDR/ligand complex is essential. Although there are many coactivators in living cells, precise interactions between coactivators and VDR have not been clarified. Here, we synthesized two coactivator peptides, DRIP205-2 and SRC2-3, evaluated their affinity for the ligand-binding domain (LBD) of VDR using 1α,25-dihydroxyvitamin D3, partial agonist 1, and antagonist 2 by surface plasmon resonance (SPR), and assessed their interaction modes with VDR-LBD using X-ray crystallographic analysis. This study showed that the SRC2-3 peptide is more sensitive to the ligands (agonist, partial agonist, and antagonist) and shows more intimate interactions with VDR-LBD than DRIP205-2 peptide.

Graphical abstract

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Editorial Advisory Board

Publication date: February 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 2





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Contents

Publication date: February 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 2





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Masthead

Publication date: February 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 2





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Calendar

Publication date: February 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 2





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A Randomized Controlled Trial to Compare e-Feedback Versus “Standard” Face-to-Face Verbal Feedback to Improve the Acquisition of Procedural Skill

Publication date: Available online 23 December 2016
Source:Journal of Surgical Education
Author(s): Wissam Al-Jundi, Mohamed Elsharif, Melanie Anderson, Phillip Chan, Jonathan Beard, Shah Nawaz
BackgroundConstructive feedback plays an important role in learning during surgical training. Standard feedback is usually given verbally following direct observation of the procedure by a trained assessor. However, such feedback requires the physical presence of expert faculty members who are usually busy and time-constrained by clinical commitments. We aim to evaluate electronic feedback (e-feedback) after video observation of surgical suturing in comparison with standard face-to-face verbal feedback.MethodsA prospective, blinded, randomized controlled trial comparing e-feedback with standard verbal feedback was carried out in February 2015 using a validated pro formas for assessment. The study participants were 38 undergraduate medical students from the University of Sheffield, UK. They were recorded on video performing the procedural skill, completed a self-evaluation form, and received e-feedback on the same day (group 1); observed directly by an assessor, invited to provide verbal self-reflection, and then received standard verbal feedback (group 2). In both groups, the feedback was provided after performing the procedure. The participants returned 2 days later and performed the same skill again. Poststudy questionnaire was used to assess the acceptability of each feedback among the participants.ResultsOverall, 19 students in group 1 and 18 students in group 2 completed the study. Although there was a significant improvement in the overall mean score on the second performance of the task for all participants (first performance mean 11.59, second performance mean 15.95; p ≤ 0.0001), there was no difference in the overall mean improvement score between group 1 and group 2 (4.74 and 3.94, respectively; p = 0.49). The mean overall scores for the e-feedback group at baseline recorded by 2 independent investigators showed good agreement (mean overall scores of 12.84 and 11.89; Cronbach α = 0.86). Poststudy questionnaire demonstrated that both e-feedback and standard verbal feedback achieved high mean Likert grades as recorded by the participants (4.42 [range: 2-5] and 4.71 [range: 4-5], respectively; p = 0.274).Conclusione-Feedback after watching a video recording appears to be acceptable and is not quantitatively different than standard feedback in improving suturing skills among novice trainees. Video assessment of procedural skills is reliable.



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Understanding Resident Performance, Mindfulness, and Communication in Critical Care Rotations

Publication date: Available online 23 December 2016
Source:Journal of Surgical Education
Author(s): Kevin Real, Katelyn Fields-Elswick, Andrew C. Bernard
ObjectiveEvidence from the medical literature suggests that surgical trainees can benefit from mindful practices. Surgical educators are challenged with the need to address resident core competencies, some of which may be facilitated by higher levels of mindfulness. This study explores whether mindful residents perform better than their peers as members of the health care team.DesignThis study employed a multiphase, multimethod design to assess resident mindfulness, communication, and clinical performance.SettingAcademic, tertiary medical center.ParticipantsResidents (N = 51) working in an intensive care unit. In phase I, medical residents completed a self-report survey of mindfulness, communication, emotional affect, and clinical decision-making. In phase II, resident performance was assessed using independent ratings of mindfulness and clinical decision-making by attending physicians and registered nurses.ResultsIn phase 1, a significant positive relationship was found between resident performance and mindfulness, positive affect (PA), and communication. In phase 2, attending physicians/registered nurses' perceptions of residents' mindfulness were positively correlated with communication and inversely related to negative affect (NA). The top quartile of residents for performance and mindfulness had the lowest NA. Higher-rated residents underestimated their performance/mindfulness, whereas those in the lowest quartile overestimated these factors.ConclusionsThis study offers a number of implications for medical resident education. First, mindfulness was perceived to be a significant contributor to self-assessments of competency and performance. Second, both PA and NA were important to mindfulness and performance. Third, communication was associated with resident performance, mindfulness, and PA. These implications suggest that individual characteristics of mindfulness, communication, and affect, all potentially modifiable, influence care quality and safety. To improve low performers, surgical educators could screen and identify residents with inaccurate self-assessments. Residents open to feedback will improve faster and develop awareness toward situations and interactions with patients, colleagues, attending physicians, and staff.



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Facile synthesis of carbon dot and residual carbon nanobeads: Implications for ion sensing, medicinal and biological applications

Publication date: Available online 24 December 2016
Source:Materials Science and Engineering: C
Author(s): Rohit Ranganathan Gaddam, Sudip Mukherjee, Neelambaram Punugupati, D Vasudevan, Chitta Ranjan Patra, Ramanuj Narayan, KVSN Raju
Synthesis of carbon dots (Cdots) via chemical route involves disintegration of carbon materials into nano-domains, wherein, after extraction of Cdots, the remaining carbon material is discarded. The present work focuses on studying even the leftover carbon residue namely, carbon nanobeads (CNBs) as an equally important material for applications on par with that of carbon dot. It employs oxidative treatment of carbonised gum olibanum resin (GOR) to produce the carbons namely Cdots and CNBs (as the residue). The Cdots (~5–10nm) exhibit blue-green fluorescence with an optical absorption at ~300nm unlike the CNBs (40–50nm) which fail to exhibit fluorescence. The fluorescence behaviour exhibited by Cdots were utilized for heavy metal ion sensing of Pb²⁺, Hg²⁺ and Cd²⁺ ions in aqueous media. Interestingly, both Cdots and CNBs are biocompatible to normal cell lines but cytotoxic to cancer cell lines, observed during several in vitro experiments (cell viability assay, cell cycle assay, apoptosis assay, ROS determination assay, caspase-9 activity assay). Additionally, Cdots exhibit bright green fluorescence in B16F10 cells. The Cdots and CNB's demonstrate multifunctional activities (sensor, cellular imaging and cancer therapy) in biomedical applications.

Graphical abstract

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Radiosurgical Target Distance from the Root Entry Zone in the Treatment of Trigeminal Neuralgia

Publication date: Available online 23 December 2016
Source:Practical Radiation Oncology
Author(s): Justin Sharim, Wei-Lun Lo, Won Kim, Srinivas Chivukula, Stephen Tenn, Tania Kaprealian, Nader Pouratian
PurposeStereotactic radiosurgery (SRS) provides a noninvasive treatment modality to patients with medically refractory trigeminal neuralgia. The root entry zone (REZ) has been proposed to be an ideal stereotactic target due to its partial makeup of centrally produced myelin, conferring a theoretical increased sensitivity to irradiation, as well as increased susceptibility to neurovascular conflict, making it the site in which nociceptive signals likely arise. The aim of this study is to determine if there is a statistically and clinically significant difference in pain relief or facial hypesthesia following SRS based on distance of the stereotactic isocenter from REZ.MethodsPatients undergoing Novalis radiosurgery for the treatment of trigeminal neuralgia with at least three months follow-up were included in this study. Post-operative outcomes were stratified by Barrow Neurological Institute (BNI) score for pain relief and BNI facial numbness score for facial hypesthesia.ResultsSixty-seven patients met inclusion criteria and were included in this study. BNI score of I-IIIa was attained in 82% of patients at 3months and 65% at 1year following SRS. Distance from isocenter to REZ varied from 0 to 8.6mm, with mean 1.94±1.62mm. Logistic regression of target-REZ distance against pain relief outcome (patients with score I-IIIa and IIIb-V) was insignificant at 3months (p=0.988), 6months (p=0.925), 9months (p=0.845), and 12months (p=0.547) post-operatively. Furthermore, no significant correlation was found with logistic regression of target-REZ distance with pain relief outcome (patients with score I and score II-IV) (p=0.544).ConclusionsThe current analysis suggests that distance from REZ does not correlate with degree of post-operative pain relief or facial hypesthesia. Thus, targeting specific regions within the trigeminal nerve in relation to these anatomical characteristics may not afford any advantage from this perspective.SummaryStereotactic radiosurgery provides a noninvasive treatment modality to patients with medically refractory trigeminal neuralgia.The trigeminal REZ is a commonly used target due to its theoretical increased sensitivity to irradiation and neurovascular conflict.The current analysis suggests that distance from REZ does not correlate with degree of post-operative pain relief or facial hypesthesia. Targeting specific regions within the trigeminal nerve in relation to these anatomical characteristics may not afford any advantage from this perspective.



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Curative brachytherapy for prostate cancer in African-Caribbean patients: A retrospective analysis of 370 consecutive cases

Publication date: Available online 23 December 2016
Source:Brachytherapy
Author(s): V. Atallah, N. Leduc, M. Creoff, P. Sargos, T. Taouil, P. Escarmant, V. Vinh-Hung
PurposeProstate cancer is the most frequent malignancy in African-Caribbean men, a population sharing common genetic traits with African-American (AA) but presenting also genomic and epidemiologic specificities. Despite socioeconomic disparities with French mainland, all patients were treated within the French state–financed equal-access health care system. In this study, we report biochemical outcomes of patients treated by brachytherapy in our department from 2005 to 2014 in an African-Caribbean population.Methods and MaterialsThree hundred seventy consecutive patients receiving ¹²⁵I brachytherapy as a curative treatment for early-stage (localized) disease between 2005 and 2014 were recorded. Selected patients presented with low-risk disease: initial prostate-specific antigen (PSA) <10 ng/mL, clinical stage ≤ T2c, and Gleason score <7. Patients with intermediate risk of recurrence were also included on a case-to-case basis with prostate-specific antigen <15 or Gleason score 7 (3 + 4). Biochemical failure free–survival was defined according to the American Society for Radiation Oncology nadir+2 definition.ResultsThe 3-year and 5-year biochemical failure free–survival for the entire cohort were 98.3% and 91.6%, respectively. For patients with low- and intermediate-risk disease, the 5-year BBFS rates were 92.1% and 90.8%, respectively. In univariate and multivariate analyses, only Gleason score (<7 vs. 7; p =  0.030 vs. p < 0.05) was a significant predictor of biochemical failure. The overall rate of late and acute Grade 2 or higher genitourinary toxicity was 12.6% and 10.3%.ConclusionsIn this large single-center series, brachytherapy achieved excellent rates of medium-term biochemical control in both low and selected intermediate-risk localized prostate cancer in African-Caribbean patients. Brachytherapy seems to be an excellent choice of treatment, with excellent outcomes and limited morbidity for African-Caribbean populations.



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Psychological and Neural Mechanisms Associated with Effort-Related Cardiovascular Reactivity and Cognitive Control: An Integrative Approach

Publication date: Available online 23 December 2016
Source:International Journal of Psychophysiology
Author(s): Nicolas Silvestrini
Numerous studies have assessed cardiovascular (CV) reactivity as a measure of effort mobilization during cognitive tasks. However, psychological and neural processes underlying effort-related CV reactivity are still relatively unclear. Previous research reliably found that CV reactivity during cognitive tasks is mainly determined by one region of the brain, the dorsal anterior cingulate cortex (dACC), and that this region is systematically engaged during cognitively demanding tasks. The present integrative approach builds on the research on cognitive control and its brain correlates that shows that dACC function can be related to conflict monitoring and integration of information related to task difficulty and success importance—two key variables in determining effort mobilization. In contrast, evidence also indicates that executive cognitive functioning is processed in more lateral regions of the prefrontal cortex. The resulting model suggests that, when automatic cognitive processes are insufficient to sustain behavior, the dACC determines the amount of required and justified effort according to task difficulty and success importance, which leads to proportional adjustments in CV reactivity and executive cognitive functioning. These propositions are discussed in relation to previous findings on effort-related CV reactivity and cognitive performance, new predictions for future studies, and relevance for other self-regulatory processes.



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The influence of self-construal type on outcome evaluation: Evidence from event-related potentials

Publication date: Available online 23 December 2016
Source:International Journal of Psychophysiology
Author(s): Xiangru Zhu, Haiyan Wu, Suyong Yang, Ruolei Gu
Recent studies have revealed a close relationship between the self and reward networks. One of our previous studies has found that outcome evaluation (including the processing of reward and punishment) is modulated by self-reflection. A question remaining unclear is how different types of self-construal influence outcome evaluation. Self-construal refers to the way in which people perceive themselves to be linked (or not) with other people. Two subtypes of self-construal have been identified: independent self and interdependent self. In the present study, 27 normal adults read essays that contained independent or interdependent pronouns (i.e., I or we) and then performed a gambling task while brain event-related potentials (ERPs) were recorded. The ERP analysis focused on the feedback-related negativity (FRN) and the P3 component. Outcome feedback evoked a larger FRN in the independent self-priming condition than in the interdependent self-priming condition. In contrast, the P3 amplitude was insensitive to self-construal manipulation. The present findings suggest that different types of transient self-construal manifest differently in outcome evaluation processes, supporting the existence of a close link between the self and reward networks.



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Dietary Assessment in the MetaCardis Study: Development and Relative Validity of an Online Food Frequency Questionnaire

Publication date: Available online 23 December 2016
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Eric O. Verger, Patrice Armstrong, Trine Nielsen, Rima Chakaroun, Judith Aron-Wisnewsky, Rikke Juul Gøbel, Tatjana Schütz, Fabien Delaere, Nicolas Gausseres, Karine Clément, Bridget A. Holmes
BackgroundThe European study MetaCardis aims to investigate the role of the gut microbiota in health and cardiometabolic diseases in France, Germany, and Denmark. To evaluate long-term diet–disease relationships, a food frequency questionnaire (FFQ) was found to be the most relevant dietary assessment method for the MetaCardis study.ObjectiveThe objectives of this study were to describe the development of three semiquantitative online FFQs used in the MetaCardis study—one FFQ per country—and to assess the relative validity of the French MetaCardis FFQ.DesignThe layout and format of the MetaCardis FFQ was based on the European Prospective Investigation of Cancer (EPIC)-Norfolk FFQ and the content was based on relevant European FFQs. Portion size and nutrient composition were derived from national food consumption surveys and food composition databases. To assess the validity of the French MetaCardis FFQ, a cross-sectional study design was utilized.Participants/settingThe validation study included 324 adults recruited between September 2013 and June 2015 from different hospitals in Paris, France.Main outcome measuresFood intakes were measured with both the French MetaCardis FFQ and 3 consecutive self-administered web-based 24-hour dietary recalls (DRs).Statistical analyses performedSeveral measures of validity of the French MetaCardis FFQ were evaluated: estimations of food groups, energy, and nutrient intakes from the DRs and the FFQ, Spearman and Pearson correlations, cross-classification, and Bland-Altman analyses.ResultsThe French MetaCardis FFQ tended to report higher food, energy, and nutrient intakes compared with the DRs. Mean correlation coefficient was 0.429 for food, 0.460 for energy, 0.544 for macronutrients, 0.640 for alcohol, and 0.503 for micronutrient intakes. Almost half of participants (44.4%) were correctly classified within tertiles of consumption, whereas 12.9% were misclassified in the opposite tertile. Performance of the FFQ was relatively similar after stratification by sex.ConclusionsThe French MetaCardis FFQ was found to have an acceptable level of validity and may be a useful instrument to rank individuals based on their food and nutrient intakes.



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The Influence of Alertness on the Spatial Deployment of Visual Attention is Mediated by the Excitability of the Posterior Parietal Cortices

With a reduced level of alertness, healthy individuals typically show a rightward shift when deploying visual attention in space. The impact of alertness on the neural networks governing visuospatial attention is, however, poorly understood. By using a transcranial magnetic stimulation twin-coil approach, the present study aimed at investigating the effects of an alertness manipulation on the excitability of the left and the right posterior parietal cortices (PPCs), crucial nodes of the visuospatial attentional network. Participants' visuospatial attentional deployment was assessed with a free visual exploration task and concurrent eye tracking. Their alertness level was manipulated through the time of the day, that is, by testing chronotypically defined evening types both during their circadian on- and off-peak times. The results revealed an increased excitability of the left compared with the right PPC during low alertness. On the horizontal dimension, these results were accompanied by a significant rightward shift in the center and a bilateral narrowing in the periphery of the visual exploration field, as well as a central upward shift on the vertical dimension. The findings show that the manipulation of non-spatial attentional aspects (i.e., alertness) can affect visuospatial attentional deployment and modulate the excitability of areas subtending spatial attentional control.

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Age- and Sex-Dependent Impact of Repeated Social Stress on Intrinsic and Synaptic Excitability of the Rat Prefrontal Cortex

Stress is implicated in psychiatric illnesses that are characterized by impairments in cognitive functions that are mediated by the medial prefrontal cortex (mPFC). Because sex and age determine stress vulnerability, the effects of repeated social stress occurring during early adolescence, mid-adolescence, or adulthood on the cellular properties of male and female rat mPFC Layer V neurons in vitro were examined. Repeated resident–intruder stress produced age- and sex-specific effects on mPFC intrinsic and synaptic excitability. Mid-adolescents were particularly vulnerable to effects on intrinsic excitability. The maximum number of action potentials (APs) evoked by increasing current intensity was robustly decreased in stressed male and female mid-adolescent rats compared with age-matched controls. These effects were associated with stress-induced changes in AP half-width, amplitude, threshold, and input resistance. Social stress at all ages generally decreased synaptic excitability by decreasing the amplitude of spontaneous excitatory postsynaptic potentials. The results suggest that whereas social stress throughout life can diminish the influence of afferents driving the mPFC, social stress during mid-adolescence additionally affects intrinsic characteristics of mPFC neurons that determine excitability. The depressant effects of social stress on intrinsic and synaptic mPFC neurons may underlie its ability to affect executive functions and emotional responses, particularly during adolescence.

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Memory-Guided Stumbling Correction in the Hindlimb of Quadrupeds Relies on Parietal Area 5

In complex environments, tripping over an unexpected obstacle evokes the stumbling corrective reaction, eliciting rapid limb hyperflexion to lift the leg over the obstruction. While stumbling correction has been characterized within a single limb in the cat, this response must extend to both forelegs and hindlegs for successful avoidance in naturalistic settings. Furthermore, the ability to remember an obstacle over which the forelegs have tripped is necessary for hindleg clearance if locomotion is delayed. Therefore, memory-guided stumbling correction was studied in walking cats after the forelegs tripped over an unexpected obstacle. Tactile input to only one foreleg was often sufficient in modulating stepping of all four legs when locomotion was continuous, or when hindleg clearance was delayed. When obstacle height was varied, animals appropriately scaled step height to obstacle height. As tactile input without foreleg clearance was insufficient in reliably modulating stepping, efference, or proprioceptive information about modulated foreleg stepping may be important for producing a robust, long-lasting memory. Finally, cooling-induced deactivation of parietal area 5 altered hindleg stepping in a manner indicating that animals no longer recalled the obstacle over which they had tripped. Altogether, these results demonstrate the integral role area 5 plays in memory-guided stumbling correction.

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Neurexins 1-3 Each Have a Distinct Pattern of Expression in the Early Developing Human Cerebral Cortex

Neurexins (NRXNs) are presynaptic terminal proteins and candidate neurodevelopmental disorder susceptibility genes; mutations presumably upset synaptic stabilization and function. However, analysis of human cortical tissue samples by RNAseq and quantitative real-time PCR at 8–12 postconceptional weeks, prior to extensive synapse formation, showed expression of all three NRXNs as well as several potential binding partners. However, the levels of expression were not identical; NRXN1 increased with age and NRXN2 levels were consistently higher than for NRXN3. Immunohistochemistry for each NRXN also revealed different expression patterns at this stage of development. NRXN1 and NRXN3 immunoreactivity was generally strongest in the cortical plate and increased in the ventricular zone with age, but was weak in the synaptogenic presubplate (pSP) and marginal zone. On the other hand, NRXN2 colocalized with synaptophysin in neurites of the pSP, but especially with GAP43 and CASK in growing axons of the intermediate zone. Alternative splicing modifies the role of NRXNs and we found evidence by RNAseq for exon skipping at splice site 4 and concomitant expression of KHDBRS proteins which control this splicing. NRXN2 may play a part in early cortical synaptogenesis, but NRXNs could have diverse roles in development including axon guidance, and intercellular communication between proliferating cells and/or migrating neurons.

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Traditional uses, phytochemistry and pharmacology of wild banana (Musa acuminata Colla): A review

Publication date: 20 January 2017
Source:Journal of Ethnopharmacology, Volume 196
Author(s): Nimisha Sarah Mathew, Pradeep Singh Negi
Ethnopharmacological relevanceMusa acuminata, the wild species of banana is a plant of the tropical and subtropical regions. Over the past few decades, the health benefits of M. acuminata have received much attention. All parts of the plant including fruits, peel, pseudostem, corm, flowers, leaves, sap and roots have found their use in the treatment of many diseases in traditional medicine. Literature review have indicated use of M. acuminata in the treatment of various diseases such as fever, cough, bronchitis, dysentery, allergic infections, sexually transmitted infections, and some of the non-communicable diseases. The reported pharmacological activities of M. acuminata include antioxidant, antidiabetic, immunomodulatory, hypolipidemic, anticancer, and antimicrobial especially anti-HIV activity. This review presents information on the phytochemicals and pharmacological studies to validate the traditional use of different parts of M. acuminata in various diseases and ailments. A comprehensive assessment of the biological activities of M. acuminata extracts is included and possible mechanisms and phytochemicals involved have also been correlated to provide effective intervention strategies for preventing or managing diseases.Materials and methodsA literature search was performed on M. acuminata using ethnobotanical textbooks, published articles in peer-reviewed journals, local magazines, unpublished materials, and scientific databases such as Pubmed, Scopus, Web of Science, ScienceDirect, and Google Scholar. The Plant List, Promusa, Musalit, the Integrated Taxonomic Information System (ITIS) databases were used to validate the scientific names and also provide information on the subspecies and cultivars of M. acuminata.Result and discussionThe edible part of M. acuminata provides energy, vitamins and minerals. All other parts of the plant have been used in the treatment of many diseases in traditional medicine. The rich diversity of phytochemicals present in them probably contributes to their beneficial effects, and validates the role of M. acuminata plant parts used by various tribes and ethnic groups across the geographical areas of the world.ConclusionThis review presents information on phytochemicals and pharmacological activities of M. acuminata plant parts. Pharmacological studies support the traditional uses of the plant, and probably validate the uses of M. acuminata by the indigenous people to treat and heal many infections and diseases. Some studies on animal models have been carried out, which also provide evidence of efficacy of the M. acuminata plant as a therapeutic agent. These observations suggest that M. acuminata plant parts possesses pluripharmacological properties, and can be used in designing potent therapeutic agents. However, individual bioactive constituent(s) from different parts of this plant need further investigations to confirm various pharmacological claims, and to explore the potential of M. acuminata in the development of drugs and use in functional foods.

Graphical abstract

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Control of stress-induced depressive disorders by So-ochim-tang-gamibang, a Korean herbal medicine

Publication date: 20 January 2017
Source:Journal of Ethnopharmacology, Volume 196
Author(s): Jung Eun Choi, Dae-Myung Park, Eunho Chun, Jeong June Choi, Ji Hye Seo, Seunghyung Kim, Jaemin Son, Moonho Do, Sun Yeou Kim, Yang-Chun Park, In Chul Jung, Mirim Jin
Ethnopharmacological relevanceSo-ochim-tang-gamibang (SOCG) is a Korean herbal medicine formula that has been applied to treat depressive moods and depression associated somatoform pain. This decoction consists of Cyperus rotundus L. (Cyperi Rhizoma), Lindera aggregata (Sims) Kosterm. (Linderae Radix), Aquilaria agallochum (Lour.) Roxb. ex Finl. (Aquilariae Resinatum Lignum), Glycyrrhiza uralensis Fisch. (Glycyrrhizae Radix) Platycodon grandiflorum (Jacq.) A. DC. (Platycodi Radix), and Citrus aurantium L. (Aurantii Fructus). The aim of this study is to assess antidepressant-like effects of SOCG and to investigate its possible cellular and molecular mechanisms.Material and methodsUsing chronic restraint stress animal model, effects of SOCG on depressive-like behaviors, corticosterone, and hippocampal expressions of a neurotrophic factor and an apoptotic marker, were investigated. Mice were exposed to restraint stress 6h per day over a period of two weeks, and orally administrated either SOCG (30, 100, or 300mg/kg/day). The depressive-like behaviors were analyzed by forced swimming test and open field test. The serum levels of corticosterone were measured by enzyme-linked immunosorbent assay. Expressions of caspase-3 and BDNF in the hippocampus were analyzed by immunofluorescence. Further, effects of SOCG were examined in corticosterone-treated PC12 cells. Cellular toxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays. Real-time PCR was applied to investigate the cellular expression levels of Bax, Bcl-2, and BDNF. The levels of caspase-3 and BDNF were examined by Western blotting.ResultsAdministration of SOCG not only reduced immobility time of restraint-stressed mice in a dose-dependent manner, but also significantly increased the distance mice moved and the number of crossings in the open field test. Further, SOCG significantly reduced the serum level of corticosterone and expression of caspase-3, while increased expression of BDNF in vivo. SOCG increased cell viability in corticosterone treated PC12 cells, which was accompanied by decreased caspase-3 expression and the ratio of Bax/Bcl-2 mRNA expression as well as increased BDNF expression in vitro.ConclusionsTaken together, our data suggested that SOCG may have potential as an antidepressant agent controlling depressive behaviors and corticosterone-induced neuronal damage caused by chronic stress.

Graphical abstract

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Concurrent bullatine A enhances morphine antinociception and inhibits morphine antinociceptive tolerance by indirect activation of spinal κ-opioid receptors

Publication date: 20 January 2017
Source:Journal of Ethnopharmacology, Volume 196
Author(s): Qian Huang, Ming-Li Sun, Yuan Chen, Xin-Yan Li, Yong-Xiang Wang
Ethnopharmacological relevanceBullatine A, a C20-diterpenoid alkaloid and one of the major effective ingredients in Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao), can block pain hypersensitivity in a variety of rodent models through expression of spinal microglial dynorphin A.Aim of the studyTo assess the interaction between bullatine A and morphine on antinociception in acute nociception and pain hypersensitivity states, with the exogenous synthetic dynorphin A as a comparisonMaterials and methodsSpinal nerve ligation-induced neuropathic rats and naïve mice were used for assessing the acute and chronic interactions of bullatine A/dynorphin A with morphine.ResultsSingle subcutaneous injection of bullatine A or dynorphin A(1−17) did not either alter formalin- and thermally (hot-plate and water immersion tests)-induced acute nociception or potentiate morphine antinociception in naïve mice. In contrast, bullatine A dose-dependently inhibited formalin-induced tonic pain with the efficacy of 54% inhibition and the half-effective dose of 0.9mg/kg. Concurrent bullatine A additively enhanced morphine antinociception. In neuropathic rats, the antinociceptive effects of multiple bidaily intrathecal injections of bullatine A and dynorphin A remained consistent over 13 days, whereas morphine produced progressive and complete tolerance to antinociception, which was completely inhibited by concurrent bullatine A and dynorphin A. A single intrathecal injection of bullatine A and dynorphin A immediately reversed established morphine tolerance in neuropathic rats, although the blockade was a less degree in the thermally induced mouse acute nociceptive tests. The inhibitory effects of bullatine A and dynorphin A on morphine tolerance were immediately and completely attenuated by intrathecal dynorphin A antibody and/or selective κ-opioid receptor antagonist GNTI.ConclusionThese results suggest that bullatine A produces antinociception without induction of tolerance and inhibits morphine antinociceptive tolerance, and provide pharmacological basis for concurrent bullatine A and morphine treatment for chronic pain and morphine analgesic tolerance.

Graphical abstract

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An ex vivo evaluation of the efficacy of andrographolide in modulating differential expression of transcription factors and target genes in periodontal cells and its potential role in treating periodontal diseases

Publication date: 20 January 2017
Source:Journal of Ethnopharmacology, Volume 196
Author(s): R Ambili, Prasanthila Janam, P.S. Saneesh Babu, Manu Prasad, D. Vinod, P.R. Anil Kumar, T.V. Kumary, S. Asha Nair, M. Radhakrishna Pillai
Ethanopharmacological relevanceAndrographolide is a herbal extract traditionally used in South Asian countries for treating inflammatory diseases.Aim of the studyTo evaluate the efficacy of andrographolide in management of periodontal disease which is a highly prevalent oral disease.Materials and MethodsPeriodontal ligament fibroblasts (PDLF) were cultured from healthy and diseased periodontium using explant culture methods. The safe dose of AG was determined using MTT assay. LPS (lipopolysaccharide) of the most important periodontopathogen, P gingivalis was used to activate NF-κB and STAT3 in PDLF. The efficacy of AG in inhibiting NF-κB and STAT3 was analyzed using immunofluorescence. Down regulation of expression of target genes of these transcription factors related to inflammation and bone resorption were analyzed using real time PCR.ResultsAG up to the concentration of 25μM was found to be safe as determined by MTT assay. Statistically significant activation of NF-κB and STAT3 in cultured PDLF was observed in diseased group compared to healthy controls before and after LPS challenge. 5μM AG pretreatment significantly inhibited activation of NF-κB and STAT3 and down regulated expression of inflammatory and bone resorptive genes in cultured PDLF.ConclusionsThe findings of the present study propose the adjunctive use of a novel herbal drug andrographolide as a promising host modulation agent for periodontal therapy by inhibiting NF-κB and STAT3 activation and inhibition of inflammation and bone resorption related genes.

Graphical abstract

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The potential of aqueous extracts of Bellucia dichotoma Cogn. (Melastomataceae) to inhibit the biological activities of Bothrops atrox venom: A comparison of specimens collected in the states of Pará and Amazonas, Brazil

Publication date: 20 January 2017
Source:Journal of Ethnopharmacology, Volume 196
Author(s): Valéria Mourão de Moura, Luana Yamille Andrade de Souza, Noranathan da Costa Guimarães, Ilia Gilmara Carvalho dos Santos, Patrícia Danielle Oliveira de Almeida, Ricardo Bezerra de Oliveira, Rosa Helena Veras Mourão, Maria Cristina Dos-Santos
Ethnopharmacological importanceThe effectiveness of aqueous extract of Bellucia dichotoma Cogn. (Melastomataceae) specimems collected in Santarém, PA, against some biological activities of Bothrops atrox venom (BaV) has been scientifically proven. Here, we analyzed the components and assessed the anti-snakebite potential of aqueous extracts of bark of B. dichotoma collected in Manaus, AM, (AEBd-MAO) and Santarém, PA, (AEBd-STM), both in Brazil.Materials and methodsThe phytochemical profiles of the aqueous extracts were identified using thin layer chromatography (TLC), and the concentrations of phenolics were determined by colorimetric assay. The inhibitory potential of the extracts was tested against the phospholipase A2, coagulant and gelatinolytic activities of BaV in vitro and its defibrinating and edema-inducing activities in vivo. Interaction between BaV and the extracts was investigated using SDS-Page electrophoresis and Western blotting. Extract cytotoxicity and antioxidant potential were assessed using the human fibroblast cell line MRC-5 and the DPPH assay in cell culture, respectively.ResultsWhile there was no difference between the phytochemical profiles of the extracts, AEBd-MAO had higher concentrations of total phenolics, total tannins and hydrolysable tannins. The extracts inhibited 100% of the phospholipase and coagulant activity of BaV when pre-incubated. Without pre-incubation, however, there was no reduction in phospholipase activity, although significant inhibition of coagulant activity was observed. In the doses used in folk medicine, without pre-incubation, both extracts inhibited 100% of the coagulant activity of BaV. In vivo, the extracts were unable to inhibit the defibrinating activity of the venom but were effective in inhibiting its edema-inducing activity. In the profiles of the extracts pre-incubated with BaV, not all the protein bands revealed by SDS-PAGE and Western blot were observed. Both extracts had a high antioxidant potential and neither had a cytotoxic effect.ConclusionAlthough the concentrations of phenolics in each extract were different, the anti-snakebite potential was similar for the concentrations of extract tested. Our findings are of importance for the quality control of this raw material, which, once tested in accordance with Brazilian National Health Surveillance Agency recommendations, may be suitable for use as a phytomedicine to complement treatment of the local effects induced by Bothrops venoms.

Graphical abstract

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Geniposide attenuates ANIT-induced cholestasis through regulation of transporters and enzymes involved in bile acids homeostasis in rats

Publication date: 20 January 2017
Source:Journal of Ethnopharmacology, Volume 196
Author(s): Lingling Wang, Guixin Wu, Feihua Wu, Nan Jiang, Yining Lin
Ethnopharmacological relevanceGeniposide (GE) is one of the major iridoid glycosides isolated from the fruit of Gardenia jasminoides Ellis that has been used to treat hepatic disorders including cholestasis. However, the underlying mechanisms for GE ameliorating the reduction in bile acids accumulation by α-naphthylisothiocyanate (ANIT) remain unclear.Aim of the studyThe purpose of this study is to characterize the efficacy of GE in regulation of bile acids uptake, synthesis, metabolism, and transport in ANIT-induced rats.Materials and methodsSprague–Dawley rats were orally administrated with vehicle, GE (25, 50, and 100mg/kg), and ursodeoxycholic acid (UDCA) (60mg/kg) once daily for seven days. On the fifth day, a single dose of ANIT (75mg/kg) was administrated via oral gavage. Blood biochemical determination, bile flow rate and liver histopathology were measured to evaluate the protective effect of GE. The mRNA expressions and protein levels of transporters and enzymes involved in bile acids homeostasis were determined by quantitative real-time polymerase chain reaction (PCR) and western blot to study the underlying mechanism of GE against ANIT-induced rats.ResultsGE (25, 50, and 100mg/kg, po) dose-dependently prevented ANIT-induced changes in serum markers for liver injury. GE treatment reduced basolateral bile acids uptake via repression of OATP2 (P<0.05). Bile acids biosynthesis was decreased through down-regulation of CYP7A1, CYP8B1, and CYP27A1 (P<0.05). GE significantly increased canalicular bile acids secretion via BSEP (P<0.05), subsequently stimulating bile flow during cholestasis. GE also markedly enhanced mRNA level of basolateral transporter OSTβ (P<0.01). Bile acids transported to the plasma were cleared into the urine, resulting in down-regulation of plasma bile acids. However, GE did not alter the mRNA levels of CYP3A2, UGT1A1 and SULT2A1. Furthermore, the gene and protein expression analysis demonstrated activation of FXR, PXR, and SHP after GE administration.ConclusionGE attenuates ANIT-induced hepatotoxicity and cholestasis in rats, due to regulation enzymes and transporters responsible for bile acids homeostasis.

Graphical abstract

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Effects of ZnSO4-induced peripheral anosmia on zebrafish behavior and physiology

Publication date: 1 March 2017
Source:Behavioural Brain Research, Volume 320
Author(s): Murilo S. Abreu, Ana C.V.V. Giacomini, Rubens Rodriguez, Allan V. Kalueff, Leonardo J.G. Barcellos
Olfaction plays a key role in modulating behavioral and physiological responses of various animal species, including fishes. Olfactory deficits can be induced in fish experimentally, and utilized to examine the role of olfaction in their normal and pathological behaviors. Here, we examine whether experimental anosmia, evoked by ZnSO4 in adult zebrafish can be associated with behavioral and/or physiological responses. We show that experimental ZnSO4-induced anosmia caused acute, but not prolonged, anxiogenic-like effects on zebrafish behavior tested in the novel tank test. The procedure also elevated whole-body cortisol levels in zebrafish. Moreover, ZnSO4 treatment, but not sham, produced damage to olfactory epithelium, inducing overt basal cell vacuolization and intercellular edema. The loss of olfaction, assessed by the fish food preference behavior in the aquatic Y-maze, was present 1h, but not 24h, after the treatment. Collectively, this suggests that transient experimental anosmia by ZnSO4 modulates zebrafish behavior and olfaction, which can be used to evoke and assess their stress-related anxiety-like states.



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Human umbilical cord mesenchymal stem cells transplantation improves cognitive function in Alzheimer’s disease mice by decreasing oxidative stress and promoting hippocampal neurogenesis

Publication date: 1 March 2017
Source:Behavioural Brain Research, Volume 320
Author(s): YuanBo Cui, ShanShan Ma, ChunYan Zhang, Wei Cao, Min Liu, DongPeng Li, PengJu Lv, Qu Xing, RuiNa Qu, Ning Yao, Bo Yang, FangXia Guan
Stem cell transplantation represents a promising therapy for central nervous system injuries, but its application to Alzheimer's disease (AD) is still limited and the potential mechanism for cognition improvement remains to be elucidated. In the present study, we used Tg2576 mice which express AD-like pathological forms of amyloid precursor protein (APP) to investigate the effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) intravenous transplantation on AD mice. Interestingly, hUC-MSCs transplantation significantly ameliorated cognitive function of AD mice without altering Aβ levels in hippocampus. Remarkably, hUC-MSCs transplantation reduced oxidative stress in hippocampus of AD mice by decreasing the level of malondialdehyde (MDA), increasing the level of nitric oxide (NO), enhancing the activity of superoxide dismutase (SOD) and neuronal nitric oxide synthase (nNOS). The mechanisms underlying the improved cognitive function may be linked to hippocampal neurogenesis and an up-regulation of neuronal synaptic plasticity related proteins levels including silent information regulator 1 (Sirt1), brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN). Taken together, our findings suggest that hUC-MSCs can improve cognition of AD mice by decreasing oxidative stress and promoting hippocampal neurogenesis. These results suggest that modulating hUC-MSCs to generate excess neuroprotective factors could provide a viable therapy to treat AD.



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Dynamic changes in sleep pattern during post-partum in normal pregnancy in rat model

Publication date: 1 March 2017
Source:Behavioural Brain Research, Volume 320
Author(s): Neelima Sivadas, Arathi Radhakrishnan, B.S. Aswathy, Velayudhan Mohan Kumar, Kamalesh K. Gulia
To develop an animal model for studies on peri-partum sleep disorders, sleep patterns in female Wistar rats during pregnancy, post-partum and after weaning, were assessed and associated adaptive changes in their anxiety were examined. Adult nulliparous female rats, maintained in standard laboratory conditions with ad libitum food and water, were surgically implanted with electroencephalogram and electromyogram electrodes under anaesthesia for objective assessment of sleep-wakefulness (S-W). After post-surgical recovery, three control recordings of S-W were taken for 24h before the animals were kept for mating. After confirmation of pregnancy, S-W recordings were acquired during different days of pregnancy, post-partum lactation/nursing days, and also after weaning. Their anxiety levels were tested in the elevated plus maze. During pregnancy, sleep increased primarily due to increase in light non-REM sleep during dark period. There was an increase in non-REM sleep delta power after parturition, though the sleep was fragmented, especially during daytime. Simultaneous behavioural recording showed increased anxiety during third trimester of pregnancy and gradual reversal of it after parturition. This is the first report where diurnal and nocturnal variations in S-W and delta power, along with adaptive changes in anxiety, were studied before, during and after pregnancy. This study also provides an animal model for drug trials and studies on sleep disorders during peri-partum window.



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Effects of chronic methamphetamine on psychomotor and cognitive functions and dopamine signaling in the brain

Publication date: 1 March 2017
Source:Behavioural Brain Research, Volume 320
Author(s): Panayotis K. Thanos, Ronald Kim, Foteini Delis, Mark J. Rocco, Jacob Cho, Nora D. Volkow
Methamphetamine (MA) studies in animals usually involve acute, binge, or short-term exposure to the drug. However, addicts take substantial amounts of MA for extended periods of time. Here we wished to study the effects of MA exposure on brain and behavior, using an animal model analogous to this pattern of MA intake. MA doses, 4 and 8mg/kg/day, were based on previously reported average daily freely available MA self-administration levels. We examined the effects of 16 week MA treatment on psychomotor and cognitive function in the rat using open field and novel object recognition tests and we studied the adaptations of the dopaminergic system, using in vitro and in vivo receptor imaging. We show that chronic MA treatment, at doses that correspond to the average daily freely available self-administration levels in the rat, disorganizes open field activity, impairs alert exploratory behavior and anxiety-like state, and downregulates dopamine transporter in the striatum. Under these treatment conditions, dopamine terminal functional integrity in the nucleus accumbens is also affected. In addition, lower dopamine D1 receptor binding density, and, to a smaller degree, lower dopamine D2 receptor binding density were observed. Potential mechanisms related to these alterations are discussed.



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The ability for cocaine and cocaine-associated cues to compete for attention

Publication date: 1 March 2017
Source:Behavioural Brain Research, Volume 320
Author(s): Kyle K. Pitchers, Taylor R. Wood, Cari J. Skrzynski, Terry E. Robinson, Martin Sarter
In humans, reward cues, including drug cues in individuals experiencing addiction, are especially effective in biasing attention towards them, so much so they can disrupt ongoing task performance. It is not known, however, whether this happens in rats. To address this question, we developed a behavioral paradigm to assess the capacity of an auditory drug (cocaine) cue to evoke cocaine-seeking behavior, thus distracting thirsty rats from performing a well-learned sustained attention task (SAT) to obtain a water reward. First, it was determined that an auditory cocaine cue (tone-CS) reinstated drug-seeking equally in sign-trackers (STs) and goal-trackers (GTs), which otherwise vary in the propensity to attribute incentive salience to a localizable drug cue. Next, we tested the ability of an auditory cocaine cue to disrupt performance on the SAT in STs and GTs. Rats were trained to self-administer cocaine intravenously using an Intermittent Access self-administration procedure known to produce a progressive increase in motivation for cocaine, escalation of intake, and strong discriminative stimulus control over drug-seeking behavior. When presented alone, the auditory discriminative stimulus elicited cocaine-seeking behavior while rats were performing the SAT, but it was not sufficiently disruptive to impair SAT performance. In contrast, if cocaine was available in the presence of the cue, or when administered non-contingently, SAT performance was severely disrupted. We suggest that performance on a relatively automatic, stimulus-driven task, such as the basic version of the SAT used here, may be difficult to disrupt with a drug cue alone. A task that requires more top-down cognitive control may be needed.



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Suboptimal choice in rats: Incentive salience attribution promotes maladaptive decision-making

Publication date: 1 March 2017
Source:Behavioural Brain Research, Volume 320
Author(s): Jonathan J. Chow, Aaron P. Smith, A. George Wilson, Thomas R. Zentall, Joshua S. Beckmann
Stimuli that are more predictive of subsequent reward also function as better conditioned reinforcers. Moreover, stimuli attributed with incentive salience function as more robust conditioned reinforcers. Some theories have suggested that conditioned reinforcement plays an important role in promoting suboptimal choice behavior, like gambling. The present experiments examined how different stimuli, those attributed with incentive salience versus those without, can function in tandem with stimulus-reward predictive utility to promote maladaptive decision-making in rats. One group of rats had lights associated with goal-tracking as the reward-predictive stimuli and another had levers associated with sign-tracking as the reward-predictive stimuli. All rats were first trained on a choice procedure in which the expected value across both alternatives was equivalent but differed in their stimulus-reward predictive utility. Next, the expected value across both alternatives was systematically changed so that the alternative with greater stimulus-reward predictive utility was suboptimal in regard to primary reinforcement. The results demonstrate that in order to obtain suboptimal choice behavior, incentive salience alongside strong stimulus-reward predictive utility may be necessary; thus, maladaptive decision-making can be driven more by the value attributed to stimuli imbued with incentive salience that reliably predict a reward rather than the reward itself.



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Conspecific alarm substance differently alters group behavior of zebrafish populations: Putative involvement of cholinergic and purinergic signaling in anxiety- and fear-like responses

Publication date: 1 March 2017
Source:Behavioural Brain Research, Volume 320
Author(s): Julia Canzian, Barbara D. Fontana, Vanessa A. Quadros, Denis B. Rosemberg
The zebrafish (Danio rerio) is an emergent model organism for assessing fear and anxiety-like phenotypes. The short fin wild type (WT), and leopard (leo) are two zebrafish populations that present several behavioral differences, in which leo displays pronounced defensive responses. Mounting evidence suggests a modulatory role for cholinergic and purinergic signaling in fear and anxiety, but the involvement of these neurotransmitter systems in the behavioral profile of zebrafish is obscure. Here we tested whether the acute exposure to conspecific alarm substance (AS), an experimental protocol that induces fear, alters shoaling behavior, diving response, acetylcholinesterase (AChE) activity, and nucleotide hydrolysis in brain tissue of WT and leo. When four fish were concomitantly exposed to AS extracted from a donor fish of similar phenotype, both populations presented a significant increase of erratic movements without changes in freezing bouts. An increased shoal cohesion and a decreased vertical distribution were observed only in WT exposed to AS. The respective population also revealed a significant increase in AChE and ecto-5′-nucleotidase activities after the exposure period. The comparison of basal endpoints between populations showed that leo displays a higher social cohesion, few vertical transitions and enhanced AChE and ecto-5′-nucleotidase activities. In conclusion, we suggest that the effects of AS on defensive behaviors depend on the population, indicating the existence of distinct neurochemical mechanisms involved. Furthermore, this report shows the first evidence of a potential role of cholinergic and purinergic systems in fear- and anxiety-like responses of zebrafish populations.

Graphical abstract

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Genetically engineered and self-assembled oncolytic protein nanoparticles for targeted cancer therapy

Publication date: March 2017
Source:Biomaterials, Volume 120
Author(s): Joong-jae Lee, Jung Ae Kang, Yiseul Ryu, Sang-Soo Han, You Ree Nam, Jong Kook Rho, Dae Seong Choi, Sun-Woong Kang, Dong-Eun Lee, Hak-Sung Kim
The integration of a targeted delivery with a tumour-selective agent has been considered an ideal platform for achieving high therapeutic efficacy and negligible side effects in cancer therapy. Here, we present engineered protein nanoparticles comprising a tumour-selective oncolytic protein and a targeting moiety as a new format for the targeted cancer therapy. Apoptin from chicken anaemia virus (CAV) was used as a tumour-selective apoptotic protein. An EGFR-specific repebody, which is composed of LRR (Leucine-rich repeat) modules, was employed to play a dual role as a tumour-targeting moiety and a fusion partner for producing apoptin nanoparticles in E. coli, respectively. The repebody was genetically fused to apoptin, and the resulting fusion protein was shown to self-assemble into supramolecular repebody-apoptin nanoparticles with high homogeneity and stability as a soluble form when expressed in E. coli. The repebody-apoptin nanoparticles showed a remarkable anti-tumour activity with negligible side effects in xenograft mice through a cooperative action of the two protein components with distinct functional roles. The repebody-apoptin nanoparticles can be developed as a systemic injectable and tumour-selective therapeutic protein for targeted cancer treatment.

Graphical abstract

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Fabrication of injectable high strength hydrogel based on 4-arm star PEG for cartilage tissue engineering

Publication date: March 2017
Source:Biomaterials, Volume 120
Author(s): Jianqi Wang, Fengjie Zhang, Wing Pui Tsang, Chao Wan, Chi Wu
Hydrogels prepared from poly(ethylene glycol) (PEG) are widely applied in tissue engineering, especially those derived from a combination of functional multi-arm star PEG and linear crosslinker, with an expectation to form a structurally ideal network. However, the poor mechanical strength still renders their further applications. Here we examined the relationship between the dynamics of the pre-gel solution and the mechanical property of the resultant hydrogel in a system consisting of 4-arm star PEG functionalized with vinyl sulfone and short dithiol crosslinker. A method to prepare mechanically strong hydrogel for cartilage tissue engineering is proposed. It is found that when gelation takes place at the overlap concentration, at which a slow relaxation mode just appears in dynamic light scattering (DLS), the resultant hydrogel has a local maximum compressive strength ∼20 MPa, while still keeps ultralow mass concentration and Young's modulus. Chondrocyte-laden hydrogel constructed under this condition was transplanted into the subcutaneous pocket and an osteochondral defect model in SCID mice. The in vivo results show that chondrocytes can proliferate and maintain their phenotypes in the hydrogel, with the production of abundant extracellular matrix (ECM) components, formation of typical chondrocyte lacunae structure and increase in Young's modulus over 12 weeks, as indicated by histological, immunohistochemistry, gene expression analyses and mechanical test. Moreover, newly formed hyaline cartilage was observed to be integrated with the host articular cartilage tissue in the defects injected with chondrocytes/hydrogel constructs. The results suggest that this hydrogel is a promising candidate scaffold for cartilage tissue engineering.



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Targeting the PD-1/PD-L1 Axis in Non-Small-Cell Lung Cancer

Publication date: Available online 23 December 2016
Source:Current Problems in Cancer
Author(s): Rajiv Kumar, Dearbhaile Collins, Saoirse Dolly, Fiona McDonald, Mary E.R. O′Brien, Timothy A. Yap
The last decade has witnessed rapid advances in the discovery and development of immune checkpoint inhibitors in cancer medicine, particularly drugs targeting programmed cell death 1 and programmed cell death ligand-1 in non-small cell lung cancer. The proven antitumor efficacy coupled with low rates of drug-related toxicities observed, albeit idiosyncratic, with these novel immunotherapeutics, have led to the registration of multiple programmed cell death 1 and programmed cell death ligand-1 inhibitors, such as nivolumab, pembrolizumab and atezolizumab, in second-line advanced non-small cell lung cancer, while durvalumab and avelumab are in late phase clinical testing. Moreover, pembrolizumab has shown a survival advantage in the first-line setting, however nivolumab failed to show a survival benefit possibly relating to patient selection on the basis of PD-L1 expression. Current patient selection is based on PD-L1 expression, using the relevant companion diagnostic test, where patients with strong PD-L1 expression being more likely to respond to these novel agents. Ongoing clinical research is now focused on the development of programmed cell death 1 and programmed cell death ligand-1 inhibitor monotherapy in neo-adjuvant and adjuvant non-small cell lung cancer. There is also much interest in using these drugs as a therapeutic backbone for rational combinations with other treatment modalities, including cytotoxic chemotherapies in the first line non-small cell lung cancer, other immunotherapies such as cytotoxic T-lymphocyte-associated protein-4 antagonists, molecularly targeted agents, including EGFR and ALK inhibitors, and radiotherapy. Concurrent treatment with radiotherapy is of particular interest due to the potential for the abscopal effect, whereby using radiotherapy to facilitate systemic treatment.



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Indocyanine Green Fluorescence Imaging in Hepatobiliary Surgery

Publication date: Available online 23 December 2016
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Ali Majlesara, Mohammad Golriz, Mohammadreza Hafezi, Arash Saffari, Esther Wild, Lena Maier-Hein, Beat P. Müller-Stich, Arianeb Mehrabi
Indocyanine green (ICG) is a fluorescent dye that has been widely used for fluorescence imaging during hepatobiliary surgery. ICG is injected intravenously, selectively taken up by the liver, and then secreted into the bile. The catabolism and fluorescence properties of ICG permit a wide range of visualization methods in hepatobiliary surgery. We have characterized the applications of ICG during hepatobiliary surgery into: 1) liver mapping, 2) cholangiography, 3) tumor visualization, and 4) partial liver graft evaluation. In this literature review, we summarize the current understanding of ICG use during hepatobiliary surgery.Intra-operative ICG fluorescence imaging is a safe, simple, and feasible method that improves the visualization of hepatobiliary anatomy and liver tumors. Intravenous administration of ICG is not toxic and avoids the drawbacks of conventional imaging. In addition, it reduces post-operative complications without any known side effects. ICG fluorescence imaging provides a safe and reliable contrast for extra-hepatic cholangiography when detecting intra-hepatic bile leakage following liver resection. In addition, liver tumors can be visualized and well-differentiated hepatocellular carcinoma tumors can be accurately identified. Moreover, vascular reconstruction and outflow can be evaluated following partial liver transplantation. However, since tissue penetration is limited to 5 to 10mm, deeper tissue cannot be visualized using this method. Many instances of false positive or negative results have been reported, therefore further characterization is required.



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Ulk1 protects against ethanol-induced neuronal stress and cognition-related behavioral deficits

Publication date: Available online 23 December 2016
Source:Neuroscience Research
Author(s): Akiko Sumitomo, Keisho Ueta, Sayaka Mauchi, Kazuko Hirai, Kouta Horike, Takatoshi Hikida, Takeshi Sakurai, Akira Sawa, Toshifumi Tomoda
Alcoholism is a psychiatric condition that develops through neuroadaptations in response to neuronal stresses caused by chronic ethanol intake. Neurons can adapt to ethanol-induced metabolic changes by activating cellular protective mechanisms, including autophagy. Here we show that expression of Ulk1, a gene critical to the regulation of autophagy, was affected in the prefrontal cortex (PFC) of mice following chronic intermittent ethanol (CIE) exposure. Consequently, overall levels of Ulk1 activity in the PFC were downregulated, leading to accumulation of p62, a protein that serves as a target for autophagic degradation. In addition, Ulk1-null mice demonstrated decline in the exploratory activity, deficits in the ability to recognize novel objects following CIE exposure, and reduced rate of voluntary ethanol drinking. The data suggest the neuroprotective role for Ulk1-mediated autophagy in the suppression of neuropsychiatric manifestation during ethanol exposure.



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Highway to Cell

Publication date: Available online 23 December 2016
Source:Microbes and Infection
Author(s): Sophia Häfner




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Parkin and PINK1 functions in oxidative stress and neurodegeneration

Publication date: Available online 23 December 2016
Source:Brain Research Bulletin
Author(s): Sandeep K. Barodia, Rose B. Creed, Matthew S. Goldberg
Loss-of-function mutations in the genes encoding Parkin and PINK1 are causally linked to autosomal recessive Parkinson's disease (PD). Parkin, an E3 ubiquitin ligase, and PINK1, a mitochondrial-targeted kinase, function together in a common pathway to remove dysfunctional mitochondria by autophagy. Presumably, deficiency for Parkin or PINK1 impairs mitochondrial autophagy and thereby increases oxidative stress due to the accumulation of dysfunctional mitochondria that release reactive oxygen species. Parkin and PINK1 likely have additional functions that may be relevant to the mechanisms by which mutations in these genes cause neurodegeneration, such as regulating inflammation, apoptosis, or dendritic morphogenesis. Here we briefly review what is known about functions of Parkin and PINK1 related to oxidative stress and neurodegeneration.



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Inotropic support against early brain injury improves cerebral hypoperfusion and outcomes in a murine model of subarachnoid hemorrhage

Publication date: Available online 23 December 2016
Source:Brain Research Bulletin
Author(s): Tomoko Mutoh, Tatsushi Mutoh, Kazuhiro Nakamura, Kazumasu Sasaki, Yasuko Tatewaki, Tatsuya Ishikawa, Yasuyuki Taki
Early brain injury/ischemia is a recent therapeutic target that contributes to triggering delayed cerebral ischemia (DCI) in the setting of subarachnoid hemorrhage (SAH). This study aimed to determine the role of dobutamine for inotropic cardiac support in improving cerebral blood flow (CBF) and outcomes after experimental SAH, mediated by hypoxia-inducible factor (HIF). Thirty-one mice were subjected to SAH by endovascular perforation, and assigned to either 2% isoflurane postconditioning performed between 1 and 2.5h after SAH induction or concomitant intravenous dobutamine infusion (15μg/kg/min) with or without HIF inhibitor 2-methoxyestradiol (2ME2) (10mg/kg) administered intraperitoneally. Neurobehavioral function was assessed daily by neurological scores and open field testing. DCI was defined 3days later by detecting a new infarction on MRI. Global CBF depression was notable early after SAH, but dobutamine showed significant improvement in CBF, lower incidence of DCI, and better recovery of neuroscores and open field test variables compared with isoflurane postconditioning (P<0.05). CBF over the entire brain on day 1 predicted DCI with a cut-off of 36.5mL/100g/min (80% specificity and 67% sensitivity), with a better area under the curve (0.83 versus 0.75) than the hemispheric CBF measured on the perforated side. The dobutamine-mediated outcomes were attenuated (P<0.05) by 2ME2 pretreatment. The data suggest that cardiac support with dobutamine improves global CBF depression induced by early brain injury, leading to reduced prevalence of DCI and better functional outcomes after experimental SAH, in which HIF may be acting as a critical mediator.



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Manuscript title: Acute Effects of Aceclofenac, COX-2 inhibitor, on Penicillin-Induced Epileptiform Activity

Publication date: Available online 23 December 2016
Source:Brain Research Bulletin
Author(s): Mehmet Taşkıran, Abdulkadir Taşdemir, Nusret Ayyıldız
PurposeThe effects of COX-2 inhibitors on seizure activity are controversial. The aim of the current study was to determine the post-treatment effect of aceclofenac on penicillin-induced experimental epilepsy.MethodsMale Wistar rats were used in all experiments (n=24). The seizure activity was triggered by penicillin. Aceclofenac was injected intraperitoneally at doses of 10mg/kg and 20mg/kg.ResultsIntraperitoneal administration of 10 and 20mg/kg aceclofenac doses, exhibited proconvulsant properties on seizure activity on rats. The mean spike frequency and amplitude of aceclofenac 10mg/kg were 41.89±2.12 spike/min and 0.619±0.094mV, respectively. The mean spike frequency and amplitude of aceclofenac 20mg/kg were 35.26±2.72 spike/min and 0.843±0.089mV, respectively.ConclusionThe results indicated that not all of the COX-2 inhibitors may have anticonvulsant or proconvulsant features on patients with epilepsy susceptibility and must be used with great care. It was also suggested that not only cyclooxygenase metabolic pathway but also lipoxygenase pathway should be considered together in further detailed studies.

Graphical abstract

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Electroencephalographic frontal synchrony and caudal asynchrony during painful hand immersion in cold water

Publication date: Available online 23 December 2016
Source:Brain Research Bulletin
Author(s): Joshua Levitt, Hyunwoo J. Choo, Kelsey A. Smith, Brian W. LeBlanc, Carl Y. Saab
Recent studies in our laboratory showed that cortical theta oscillations correlate with pain in rodent models. In this study, we sought to validate our pre-clinical data using EEG recordings in humans during immersion of the hand in ice cold water, a moderately noxious stimulus. Power spectral analysis shows that an increase in pain score is associated with an increase in power amplitude within a frequency range of 6–7Hz at the frontal (Fz) electrode. These results are consistent with our previous pre-clinical animal studies and the clinical literature. We also report a novel reduction in power at the caudal (O1) electrode within a broader 3–30Hz rand and decreased coherence between Fz and C3, C4 electrodes within the theta (4–8Hz) and low beta (13–21Hz) bands, while coherence (an indirect measure of functional connectivity) between Fz and O1 increased within the theta and alpha (8–12Hz) bands. We argue that pain is associated with EEG frontal synchrony and caudal asynchrony, leading to the disruption of cortico-cortical connectivity.



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Anti-apoptotic and angiogenic effects of intelectin-1 in rat cerebral ischemia

Publication date: Available online 23 December 2016
Source:Brain Research Bulletin
Author(s): Naibing Gu, Yaru Dong, Ye Tian, Zhengli Di, Zhiqin Liu, Mingze Chang, Xiaotao Jia, Yihua Qian, Weiping Zhang
Ischemic stroke is an acute life-threatening disease, which causes neurological dysfunction. The formation of new blood vessels around the infarct is vital to the restoration of perfusion and healing of brain tissue. Studies have shown that intelectin-1 (omentin) promotes endothelial cell function and angiogenesis in response to ischemia and inhibits apoptosis in rats with unilateral hind limb surgery. In the present study, we investigated the neuroprotective role of intelectin-1 following focal cerebral ischemia. We specifically assessed the effect of increased expression of intelectin-1 in promoting angiogenesis and reducing apoptosis. The treatment was administered using a lentiviral vector, 7days prior to surgery. The surgery was performed using the established middle cerebral artery occlusion (MCAO) model in rats, and the outcome was evaluated 7days after injury. Our results demonstrated a significant reduction in brain infarction volume following LV-intelectin-1 treatment. Additionally, CD34 and capillary density were increased in the cerebral ischemic penumbra. Real-time PCR and Western blot revealed an increased expression of intelectin-1, and phosphorylation of eNOS and AKT with enhanced expression of bcl-2 in brain tissues. These data suggest that the successful delivery of LV-intelectin-1 ameliorated ischemic brain injury. It promoted endothelial cell function and revascularization, and inhibited apoptosis in response to ischemia by stimulating the Akt-eNOS signaling pathway.



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A novel immunosensing platform for highly sensitive prostate specific antigen detection based on dual-quenching of photocurrent from CdSe sensitized TiO2 electrode by gold nanoparticles decorated polydopamine nanospheres

Publication date: 15 May 2017
Source:Biosensors and Bioelectronics, Volume 91
Author(s): Yu-Xiang Dong, Jun-Tao Cao, Yan-Ming Liu, Shu-Hui Ma
Herein, a novel photoelectrochemical (PEC) immunosensing platform for highly sensitive detection of prostate specific antigen (PSA) was constructed based on dual-quenching of photocurrent from CdSe sensitized TiO2 electrode by gold nanoparticles decorated dopamine–melanin nanospheres (AuNPs-Dpa-melanin CNSs). In this proposal, CdSe sensitized TiO2 was used as photoelectrochemical matrix and the functional AuNPs-Dpa-melanin CNSs were used as signal quenching element. The dual quenching of the gold nanoparticles decorated Dpa-melanin CNSs to the CdSe sensitized TiO2 was achieved as follows: (i) the strong energy transfer between the CdSe quantum dots (QDs) and Au NPs diminishes the photocurrent signal of CdSe QDs; (ii) the steric hindrance of AuNPs-Dpa-melanin CNSs partly obstructs the diffusion of the electron donor, i.e. ascorbic acid, to the surface of photoelectrode, which make the depleting efficiency of the photogenerated holes decrease, leading to a declined photocurrent intensity. On the basis of the dual quenching effect of AuNPs-Dpa-melanin CNSs, a competitive immunosensing platform for PSA was designed upon the specific binding of anti-PSA to PSA and PSA functionalized AuNPs-Dpa-melanin CNSs conjugates. This proposed immunosensor possesses wide linear range from 1.0×10^–11gmL⁻¹ to 1.0×10⁻⁷gmL⁻¹ with the detection limit of 2.7pgmL⁻¹. Moreover, the applicability of the present method was demonstrated in the determination of PSA in human serum. The strategy creates new paradigms for PSA and other tumor markers detection and demonstrates high sensitivity, good specificity, and satisfied applicability in complex biological samples.



http://ift.tt/2i1DvcF

Kanamycin detection based on the catalytic ability enhancement of gold nanoparticles

Publication date: 15 May 2017
Source:Biosensors and Bioelectronics, Volume 91
Author(s): Chengke Wang, Dan Chen, Qingqing Wang, Rong Tan
In this paper, we demonstrated that kanamycin could enhance the peroxidase-like activity of citrate-capped gold nanoparticles (AuNPs) through two steps: the attachment of kanamycin onto AuNPs through −NH2 (on kanamycin) and −COOH (on AuNPs) interactions; and the specifically interaction between glucoside on kanamycin and AuNPs which changes the surface property of AuNPs, and produced •OH radicals and Au³⁺ in the solution, and catalyzed the chromogenic reactions between 3, 3′, 5, 5′-tetramethylbenzidine (TMB) and H2O2. Based on this principle, a novel method for kanamycin detection has been developed. This method exhibited high sensitivity and selectivity, as low as 0.1nM kanamycin could be detected with a linear range from 0.1nM to 20nM and 20nM to 300nM, respectively. This method was also successfully applied for the detection of kanamycin content in milk and meat samples.



http://ift.tt/2hhwpC1

Nitrogen-doped graphene quantum dots-labeled epitope imprinted polymer with double templates via the metal chelation for specific recognition of cytochrome c

Publication date: 15 May 2017
Source:Biosensors and Bioelectronics, Volume 91
Author(s): Yun-Jing Yan, Xi-Wen He, Wen-You Li, Yu-Kui Zhang
A novel fluorescent sensor nitrogen-doped graphene quantum dots (N-GQDs)/SiO2/molecular imprinting polymer（N-GQDs/SiO2/MIP）was fabricated by surface imprinting and epitope imprinting to recognize and detect the target protein cytochrome c (Cyt C) with fluorescence quenching. In the polymerization process, the C- and N-terminal nonapeptides of Cyt C were selected as the double templates which were fixed by functional monomer (zinc acrylate) through metal chelation and steady six-membered ring. The linear range of fluorescence quenching for this receptor towards Cyt C was 0.20–60μM, and the detection limit was 0.11μM. The precision for six times replicate determination of Cyt C at 30μM was 1.20%, and the imprinting factor (IF) was 3.06. The recoveries of the material to Cyt C in urine were 99.3–114.0%. In brief, this work proposed a strategy to prepare a new type fluorescent imprinting polymer based on N-GQDs and provided an attractive perspective for the detection of protein by using the combination of N-GQDs and molecular imprinting technique.



http://ift.tt/2hhvO3b

Chemiluminescence cloth-based glucose test sensors (CCGTSs): A new class of chemiluminescence glucose sensors

Publication date: 15 May 2017
Source:Biosensors and Bioelectronics, Volume 91
Author(s): Huijie Li, Cuiling Liu, Dan Wang, Chunsun Zhang
Chemiluminescence (CL) has been widely applied in many fields, but it is rarely used in a very simple, economical but effective way. In this work, for the first time, the CL cloth-based glucose test sensors (CCGTSs) are developed as a new class of CL glucose sensors, with no need for complicated, expensive device fabrication and peripheral equipment. When integrated with desirable hydrophobic barrier in the flow channel and gravity/capillary flow induced by a difference in height between the loading zone and the detection zone, a single cloth-based device can perform the whole CL process involving two steps of enzyme reactions. The wax screen-printing approach is used to fabricate ultra-cheap CCGTSs, the glucose detection involves the enzymatic oxidation of glucose to gluconic acid and H2O2 followed by the horseradish peroxidase (HRP)-catalyzed oxidation of luminol by H2O2, and the emitted CL signals are heightened with p-iodophenol (PIP) and imaged using an inexpensive, portable CCD camera. Under optimized conditions, glucose can be determined over the range of 0.1–100mM, with a detection limit of 0.0948mM and an analysis time of less than 5.5min. Finally, the applicability and validity of the CCGTSs are demonstrated for the measurement of glucose in clinical urine and serum samples. Thus, the proposed sensors could provide great promise in applications in many areas, and may facilitate the achievement of point-of-care testing.



http://ift.tt/2i1v29t

Fabrication of injectable high strength hydrogel based on 4-arm star PEG for cartilage tissue engineering

Publication date: March 2017
Source:Biomaterials, Volume 120
Author(s): Jianqi Wang, Fengjie Zhang, Wing Pui Tsang, Chao Wan, Chi Wu
Hydrogels prepared from poly(ethylene glycol) (PEG) are widely applied in tissue engineering, especially those derived from a combination of functional multi-arm star PEG and linear crosslinker, with an expectation to form a structurally ideal network. However, the poor mechanical strength still renders their further applications. Here we examined the relationship between the dynamics of the pre-gel solution and the mechanical property of the resultant hydrogel in a system consisting of 4-arm star PEG functionalized with vinyl sulfone and short dithiol crosslinker. A method to prepare mechanically strong hydrogel for cartilage tissue engineering is proposed. It is found that when gelation takes place at the overlap concentration, at which a slow relaxation mode just appears in dynamic light scattering (DLS), the resultant hydrogel has a local maximum compressive strength ∼20 MPa, while still keeps ultralow mass concentration and Young's modulus. Chondrocyte-laden hydrogel constructed under this condition was transplanted into the subcutaneous pocket and an osteochondral defect model in SCID mice. The in vivo results show that chondrocytes can proliferate and maintain their phenotypes in the hydrogel, with the production of abundant extracellular matrix (ECM) components, formation of typical chondrocyte lacunae structure and increase in Young's modulus over 12 weeks, as indicated by histological, immunohistochemistry, gene expression analyses and mechanical test. Moreover, newly formed hyaline cartilage was observed to be integrated with the host articular cartilage tissue in the defects injected with chondrocytes/hydrogel constructs. The results suggest that this hydrogel is a promising candidate scaffold for cartilage tissue engineering.



http://ift.tt/2i1zLId

RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer

Publication date: Available online 22 December 2016
Source:Cancer Cell
Author(s): Anne T. Schneider, Jérémie Gautheron, Maria Feoktistova, Christoph Roderburg, Sven H. Loosen, Sanchari Roy, Fabian Benz, Peter Schemmer, Markus W. Büchler, Ueli Nachbur, Ulf P. Neumann, Rene Tolba, Mark Luedde, Jessica Zucman-Rossi, Diana Panayotova-Dimitrova, Martin Leverkus, Christian Preisinger, Frank Tacke, Christian Trautwein, Thomas Longerich, Mihael Vucur, Tom Luedde
Receptor-interacting protein kinase 1 (RIPK1) represents an essential signaling node in cell death and inflammation. Ablation of Ripk1 in liver parenchymal cells (LPC) did not cause a spontaneous phenotype, but led to tumor necrosis factor (TNF)-dependent hepatocyte apoptosis and liver injury without affecting inducible nuclear factor κB (NF-κB) activation. Loss of Ripk1 induced the TNF-dependent proteasomal degradation of the E3-ligase, TNF receptor-associated factor 2 (TRAF2), in a kinase-independent manner, thereby activating caspase-8. Moreover, loss of both Ripk1 and Traf2 in LPC not only resulted in caspase-8 hyperactivation but also impaired NF-κB activation, promoting the spontaneous development of hepatocellular carcinoma. In line, low RIPK1 and TRAF2 expression in human HCCs was associated with an unfavorable prognosis, suggesting that RIPK1 collaborates with TRAF2 to inhibit murine and human hepatocarcinogenesis.

Teaser

Schneider et al. show that RIPK1 deficiency in liver parenchymal cells (LPC) enhances TNF-induced TRAF2 degradation, leading to liver injury. Loss of both RIPK1 and TRAF2 in LPC promotes hepatocellular carcinoma (HCC) development. In human HCC, low RIPK1 and TRAF2 expression is associated with poor outcome.


http://ift.tt/2i1zUvi

Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics

Publication date: Available online 22 December 2016
Source:Cancer Cell
Author(s): Kristopher A. Sarosiek, Cameron Fraser, Nathiya Muthalagu, Patrick D. Bhola, Weiting Chang, Samuel K. McBrayer, Adam Cantlon, Sudeshna Fisch, Gail Golomb-Mello, Jeremy A. Ryan, Jing Deng, Brian Jian, Chris Corbett, Marti Goldenberg, Joseph R. Madsen, Ronglih Liao, Dominic Walsh, John Sedivy, Daniel J. Murphy, Daniel Ruben Carrasco, Shenandoah Robinson, Javid Moslehi, Anthony Letai
It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities.

Graphical abstract

Teaser

To explain how pediatric, compared with adult, cancer patients have a higher risk for treatment-associated toxicities, Sarosiek et al. find that many tissues in children and young mice are primed for apoptosis, whereas adult tissues are not due to differences in the expression of apoptotic proteins.


http://ift.tt/2hhy7TZ

FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase

Publication date: Available online 22 December 2016
Source:Cancer Cell
Author(s): Zejuan Li, Hengyou Weng, Rui Su, Xiaocheng Weng, Zhixiang Zuo, Chenying Li, Huilin Huang, Sigrid Nachtergaele, Lei Dong, Chao Hu, Xi Qin, Lichun Tang, Yungui Wang, Gia-Ming Hong, Hao Huang, Xiao Wang, Ping Chen, Sandeep Gurbuxani, Stephen Arnovitz, Yuanyuan Li, Shenglai Li, Jennifer Strong, Mary Beth Neilly, Richard A. Larson, Xi Jiang, Pumin Zhang, Jie Jin, Chuan He, Jianjun Chen
N⁶-Methyladenosine (m⁶A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m⁶A in cancer have been limited. Here we show that FTO, as an m⁶A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m⁶A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m⁶A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogenesis and drug response.

Teaser

Li et al. show that FTO, an N⁶-methyladenosine (m⁶A) demethylase, is highly expressed in subtypes of AML, promotes leukemogenesis, and inhibits all-trans-retinoic acid-induced leukemia cell differentiation. FTO exerts its oncogenic role by regulating mRNA targets such as ASB2 and RARA by reducing their m⁶A levels.


http://ift.tt/2hhvCRL

Oxidative stress induces mitotic arrest by inhibiting Aurora A-involved mitotic spindle formation

Publication date: Available online 23 December 2016
Source:Free Radical Biology and Medicine
Author(s): Guang-Fei Wang, Qincai Dong, Yuanyuan Bai, Jing Yuan, Quanbin Xu, Cheng Cao, Xuan Liu
Oxidative stress contributes to the oxidative modification of cellular components, including lipids, proteins and DNA, and results in DNA damage, cell cycle arrest, cellular dysfunction and apoptosis. However, the mechanism underlying oxidative stress-induced mitotic abnormalities is not fully understood. In this study, we demonstrated that exogenous and endogenous reactive oxygen species (ROS) promoted mitotic arrest. Delayed formation and abnormal function of the mitotic spindle, which directly impeded mitosis and promoted abnormal chromosome separation, was responsible for ROS-induced mitotic arrest. As a key regulator of mitotic spindle assembly, Aurora A kinase was hyperphosphorylated in early mitosis under oxidative stress, which may disturb the function of Aurora A in mitotic spindle formation. Our findings identified a mechanism by which ROS regulate mitotic progression and indicated a potential molecular target for the treatment of oxidative stress-related diseases.

Graphical abstract

http://ift.tt/2imnWiL

Assay of superoxide dismutase activity in a plate assay using WST-1

Publication date: Available online 23 December 2016
Source:Free Radical Biology and Medicine
Author(s): Alexander V Peskin, Christine C Winterbourn
One of the most convenient methods for measuring superoxide dismutase activity is a plate assay using xanthine oxidase and the water soluble tetrazolium WST-1. For reliable results with WST-1, certain aspects of the procedure need to be adhered to. This article describes an appropriate protocol that minimizes sources of variability.

Graphical abstract

http://ift.tt/2hbcktL

Augmented O-GlcNAc signaling via glucosamine attenuates oxidative stress and apoptosis following contrast-induced acute kidney injury in rats

Publication date: Available online 23 December 2016
Source:Free Radical Biology and Medicine
Author(s): Jiachang Hu, Rongyi Chen, Ping Jia, Yi Fang, Tongqiang Liu, Nana Song, Xialian Xu, Jun Ji, Xiaoqiang Ding
Contrast-induced acute kidney injury (CI-AKI) is an iatrogenic renal injury and associated with substantial morbidity and mortality in susceptible individuals. Despite extensive study of a variety of agents for renal protection, limited strategies have been shown to be effective in the reduction of CI-AKI. O-linked β-N-acetylglucosamine (O-GlcNAc) is a post-translational regulatory modification of intracellular proteins and governs the function of numerous proteins, both cytosolic and nuclear. Increasing evidence suggests that O-GlcNAc levels are increased in response to stress and that acute augmentation of this reaction is cytoprotective. However, the underlying mechanisms by which augmented OGlcNAc signaling provides renoprotection against contrast media insults is still unknown. Here, we investigated the effect of augmented O-GlcNAc signaling via glucosamine on CI-AKI and explored the underlying molecular mechanisms, particularly its relationship with PI3-kinase (PI3K)/Akt signaling. We used a novel and reliable CI-AKI model consisting of 5/6 nephrectomized (NE) rats, and a low-osmolar contrast media (iohexol, 10ml/kg, 3.5gI) injected via the tail vein after dehydration for 48h. The results showed that augmented O-GlcNAc signaling by glucosamine prevented the kidneys against iohexol-induced injury characterized by the attenuation of renal dysfunction, tubular damage, apoptosis and oxidative stress. Furthermore, this renoprotection was blocked by treatment with alloxan, an O-GlcNAc transferase inhibitor. Augmented O-GlcNAc signaling also increased the protein expression levels of phospho-Akt (Ser473, but not Thr308 and Thr450), phospho-GSK-3β, Nrf2, and Bcl-2, and decreased the levels of Bax and cleaved caspase-3. Both alloxan and specific inhibitors of PI3K (Wortmannin and LY294002) blocked the protection of glucosamine via inhibiting Akt signaling pathway. We further identified O-GlcNAcylated Akt through immunoprecipitation and western blot. We confirmed that Akt was modified by O-GlcNAcylation, and glucosamine pretreatment increased the O-GlcNAcylation of Akt. Collectively, the results demonstrate that glucosamine induces renoprotection against CIAKI through augmented O-GlcNAc and activation of PI3K/Akt signaling, making it a promising strategy for preventing CI-AKI.



http://ift.tt/2imqRIi

Syntheses and photovoltaic properties of 6-(2-thienyl)-4H-thieno[3,2-b]indole based conjugated polymers containing fluorinated benzothiadiazole

Publication date: 27 January 2017
Source:Polymer, Volume 109
Author(s): Ina Jeong, Sangmin Chae, Ahra Yi, Juae Kim, Ho Hwan Chun, Jung Hyeong Cho, Hyo Jung Kim, Hongsuk Suh
In this report, a series of copolymers based on 6-(2-thienyl)-4H-thieno[3,2-b]indole (TTI) as an electron-rich unit and fluorinated DTBT as an electron-deficient unit were synthesized, namely PTTIF1 and PTTIF2, and applied to photovoltaic devices. TTI unit was coupled with fluorinated DTBT to utilize the merit of introduction of fluorine atom leading to the lowering of the HOMO energy level while keeping high planarity of the conjugated backbone.The synthesized copolymers show a noticeable change in HOMO energy levels as compared with non-fluorinated polymer (PTTIDTBT-h). Optimized photovoltaic devices of PTTIF2 exhibited power conversion efficiency of 4.36% with decent JSC and FF values, which can be explained by the higher charge transporting ability of PTTIF2 with preferable face-on crystallite population than PTTIF1 in grazing incident wide-angle X-ray scattering (GIWAXS).

Graphical abstract

http://ift.tt/2ipiPKC

Dermoscopic features of squamous cell carcinoma on the lips

Summary

Background

Dermoscopy of cutaneous squamous cell carcinoma (SCC) has already been described. However little is known on the dermoscopic features of lip SCC.

Objectives

to describe the clinic and dermoscopic criteria of lip SCC,

Methods

Clinical and dermoscopic images of lip SCC were retrospectively evaluated for the presence of specific dermoscopic criteria. Cases were collected from Skin Cancer Unit of Reggio Emilia, Italy, Dermatology Unit Second University of Naples, Italy, and First Department of Dermatology of Aristotle University of Thessaloniki, Greece.

Results

We collected 22 lip SCC; the majority were located on the lower lip (90.9%); more than 2/3 of the total series were flat (68.2%). The clinical images revealed that white-yellowish and red colours were almost equally presented and usually combined together. The predominant clinical aspect that characterized lip SCC was the presence of ulceration (90.9%). Dermoscopically, we noticed polymorphous unfocused small size vessels located both peripheral or throughout the lesions. Scales and white structures were observed in all lesions.

Conclusions

The presence of ulceration, scales, polymorphous vessels and white structures are the main dermoscopic features of lip SCC.

This article is protected by copyright. All rights reserved.

http://ift.tt/2hhhUhD

Randomized controlled trial comparing 35% trichloroacetic acid peel and 5-aminolevulinic acid photodynamic therapy for the treatment of multiple actinic keratosis

Summary

Background

Photodynamic therapy (PDT) and chemical peels with trichloroacetic acid (TCA) can be applied to larger skin areas and thus are suitable treatment options for patients with multiple actinic keratosis (AK). Despite its long use TCA has, however, only been investigated rarely in this indication.

Objectives

This randomized, observer-blinded, intrapatient comparison study sought to investigate the efficacy and safety of 35% TCA versus 20% aminolevulinic acid PDT (ALA PDT) in patients with extensive field cancerisation and multiple AK in the face or on the scalp.

Methods

28 patients with at least 5 AK in two comparable anatomical areas on the head were treated with 35% TCA and ALA PDT randomly assigned to each area. Therapeutic efficacy, adverse events and cosmetic outcome were assessed by a blinded investigator at 1, 3, 6 and 12 months after treatment.

Results

After 12-months follow up TCA and ALA PDT reduced the total lesion count, the primary outcome, by 31,9% and 58,0%, respectively (p=0,006). Complete clearance of preexisting AK were 48,8% for TCA and 73,7% for ALA PDT (p=0,011). Treatment failure (Number of AK greater than 50% of the baseline count) was observed in 7 patients (25%) after TCA and in 2 patients (7,1%) after PDT treatment. Treatment-related pain was significantly higher for ALA PDT (VAS 7,5±2,3 vs TCA: 5,1±2,6; p=0,04) whereas scarring (n=6, 21,4%) was only seen in TCA treated patients.

Conclusions

ALA PDT provided better clinical results than TCA in the treatment of patients with extensive field cancerisation and multiple AK.

This article is protected by copyright. All rights reserved.

http://ift.tt/2i1uSPv

A comparison study of clinician-rated atopic dermatitis outcome measures for intermediate to dark skin patients

Abstract

Background

Atopic dermatitis (AD) assessment is more difficult in patients with skin of colour (SOC). We sought to compare the reliability of commonly used outcome measures for assessing AD in SOC patients and evaluated a novel greyscale in this population.

Method

Twenty-five AD patients each attended a one-day scoring exercise based in either Sydney or Melbourne, Australia. Each patient was scored by the same five physicians using the Eczema Area Severity Index (EASI), objective-Scoring Atopic Dermatitis score (oSCORAD), Investigator's Global Assessment (IGA) and a novel greyscale. Patients also completed the Patient-Oriented Eczema Measure (POEM) and quality of life measures. A mexameter was used for measuring baseline melanin indices. Ten random patients were re-scored to test intra-rater reliability.

Results

We included 11 light skinned patients (melanin index ≤200) and 14 SOC patients (melanin index >200) in the cohort. The inter-rater ICCs were: EASI 0.827 (95% CI 0.658-0.941) for light skin and 0.774 (95% CI 0.598-0.906) for SOC; oSCORAD 0.680 (95% CI 0.441-0.880) for light skin and 0.736 (95%CI 0.544-0.889) for SOC; IGA 0.803 (95%CI 0.618-0.932) for light skin and 0.696 (95%CI 0.490-0.868) for SOC; the greyscale had an ICC of 0.776 (95%CI: 0.601-0.907) when replacing the EASI's erythema scale for SOC patients. All scores showed excellent intra-rater reliability for all skin types. Erythema component analysis showed that erythema did not contribute to variability.

Conclusions

EASI showed excellent reliability for patients of all skin colours, and is recommended as the optimal core measure for patients with all skin colours.

This article is protected by copyright. All rights reserved.

http://ift.tt/2hhpkBq

Treatment Patterns and Outcomes among Adults Admitted to Hospital in the United Kingdom (UK) due to Plaque or Erythrodermic Psoriasis

Abstract

The National Institute for Health and Care Excellence (NICE) identified treatment of moderate-to-severe psoriasis as an area for research.^1-2 No recent studies have assessed treatment patterns and outcomes among patients hospitalised for psoriasis in the UK.^3-5

This study evaluated clinician- and patient-reported outcomes, treatment patterns, and hospital length of stay (LOS) in patients admitted to hospital for plaque or erythrodermic psoriasis, and enrolled 61 eligible patients across 9 UK hospital sites from 15 November 2013 to 2 June 2014.

This article is protected by copyright. All rights reserved.

http://ift.tt/2i1pqvY

Painful skin lesions and squamous cell carcinoma predict overall mortality risk in organ transplant recipients: A cohort study

Abstract

Background

Organ transplant recipients have a highly increased risk of cutaneous squamous cell carcinomas. Sensation of pain in cutaneous tumours is a powerful patient-reported warning signal for invasive cutaneous squamous cell carcinomas in organ transplant recipients.

Objectives

The impact of painful compared to painless skin lesions and cutaneous squamous cell carcinoma (SCC) compared to other skin lesions on the overall mortality risk in organ transplant recipients (OTR) was investigated.

Methods

We followed 410 OTR from 10 different centres across Europe and North America during the period between 2008 and 2015. These patients had been enrolled in an earlier study to define clinically meaningful patient-reported warning signals predicting the presence of SCC and had been included if they had a lesion requiring histological diagnosis. Cumulative incidences of overall mortality were calculated using Kaplan-Meier survival analysis and risk factors were analysed with Cox proportional hazard analysis.

Results

There was an increased overall mortality risk in OTR who reported painful compared to painless skin lesions with a hazard ratio adjusted for age, sex, and other relevant factors of 1.6 (95% CI 0.97-2.7). There was also an increased overall mortality risk in OTR diagnosed with SCC compared to other skin lesions with an adjusted hazard ratio of 1.7 (95% CI 1.0-2.8). Mortality due to internal malignancies and systemic infections appeared to prevail in OTR with SCC.

Conclusions

We suggest that OTR have an increased overall mortality risk if they develop painful skin lesions or are diagnosed with cutaneous SCC.

This article is protected by copyright. All rights reserved.

http://ift.tt/2hhnpwG