Relative Bioavailability of Silybin A and Silybin B From 2 Multiconstituent Dietary Supplement Formulations Containing Milk Thistle Extract: A Single-dose Study

Publication date: Available online 19 December 2017
Source:Clinical Therapeutics
Author(s): Wen-Yi Li, Guo Yu, Renee M. Hogan, Rajesh Mohandas, Reginald F. Frye, Eric Gumpricht, John S. Markowitz
PurposeThe purpose of this study was to compare the bioavailability between 2 milk thistle–containing dietary supplements, Product B and IsaGenesis, in healthy volunteers.MethodsBioavailability between Product B, originally formulated as a powdered capsule, and IsaGenesis, reformulated as a soft gel, were compared by measuring silybin A and silybin B as surrogate pharmacokinetic markers for differences in absorption and bioavailability. For this randomized, open-label, crossover pharmacokinetic study, 12 healthy volunteers consumed a single-dose serving of each supplement separated by at least a 7-day washout period. Serial blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and analyzed via LC-MS/MS.FindingsRapid absorption and elimination of silybin A and silybin B have been observed after oral administration of both Product B and IsaGenesis. However, the absorption rate and extent, as indicated by mean the Cmax and mean plasma AUC, were significantly higher for the IsaGenesis soft gel formulation. The dose-corrected mean Cmax was 365% and 450% greater for silybin A and B, respectively, relative to powdered Product B. The time to Tmax was reached, on average, at least 1 hour earlier with IsaGenesis relative to Product B for both silybin A and silybin B.ImplicationsThe IsaGenesis soft gel formulation provided substantially greater absorption and bioavailability of silybin A and silybin B relative to the powdered Product B supplement. ClinicalTrials.gov Identifier: NCT02529605.



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Exposure– and Dose–response Analyses in Dose Selection and Labeling of FDA-approved Biologics

Publication date: Available online 19 December 2017
Source:Clinical Therapeutics
Author(s): Ken Ogasawara, Christopher D. Breder, Dora H. Lin, G. Caleb Alexander
PurposeBiological drug products, or products derived from living cells, represent an increasingly important part of the pharmaceutical market. Despite this, little is known about how sponsors determine the dose to be studied in registrational trials or to be proposed in labeling for biologics. We examined how exposure–response and dose–response analyses were used to determine dosing in pivotal trials or the labeling for all biologics approved by the Center for Drug Evaluation and Research, the US Food and Drug Administration (FDA) between 2003 and 2016.MethodsWe extracted relevant characteristics of each biologic from its review package by FDA. We used descriptive statistics to characterize the rationale for the selected dose(s) in registration trials, with a particular focus on the role of exposure–response/dose–response analyses. We also examined how exposure–response/dose–response analyses were used to support the labeling dose and the basis for postmarketing requirements or commitments related to dose optimization.FindingsA total of 79 biologics license applications were examined. Dose selection in registrational trials was more often attributed to clinical efficacy (73% of applications) than to clinical safety (42%). The dosing of products whose dose was apparently selected based on clinical efficacy was often (72%) determined by the dose–response relationship. In support of doses that were described in labeling, exposure–response analyses for efficacy were performed more commonly (53%) than dose–response analyses (21%). This trend was apparent after 2012.ImplicationsThis is the first study to summarize the justification of dose selection and the labeled dose of biologics approved by the FDA. Dose–response analyses have been often used as the rationale for dose selection of registrational studies, although exposure–response analyses are becoming more prevalent in support of the dosing guidelines in labeling.



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Mobile contingency management as an adjunctive treatment for co-morbid cannabis use disorder and cigarette smoking

Publication date: April 2018
Source:Addictive Behaviors, Volume 79
Author(s): Jean C. Beckham, Kelsie A. Adkisson, Jeffrey Hertzberg, Nathan A. Kimbrel, Alan J. Budney, Robert S. Stephens, Scott D. Moore, Patrick S. Calhoun
IntroductionCannabis is the most widely used illicit drug in the U.S. with 19.8 million current users. Population-based data indicate that almost all cannabis users (90%) have a lifetime history of tobacco smoking and the majority (74%) currently smoke tobacco. Among cannabis users, smoking tobacco is associated with increased frequency of cannabis use, increased morbidity, and poorer cannabis cessation outcomes. There is a lack of research, however, focused on addressing cessation of both substances simultaneously. The purpose of the current pilot study was to evaluate the feasibility and acceptability of a multi-component tobacco/cannabis abstinence treatment.MethodsFive participants completed Abstinence Reinforcement Therapy, an intervention that included five sessions of cognitive-behavioral telephone counseling for tobacco/cannabis, pharmacotherapy for smoking cessation, and five weeks of mobile contingency management to remain abstinent from tobacco and cannabis.ResultsFeasibility of recruitment, retention and treatment completion was high. Satisfaction with the treatment was also high.ConclusionResults support the feasibility and acceptability of this approach with dual cannabis and tobacco users and suggest that further research examining the efficacy of this approach is warranted.



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User-identified electronic cigarette behavioral strategies and device characteristics for cigarette smoking reduction

Publication date: April 2018
Source:Addictive Behaviors, Volume 79
Author(s): Eric K. Soule, Sarah F. Maloney, Mignonne C. Guy, Thomas Eissenberg, Pebbles Fagan
BackgroundThere is limited evidence on how cigarette smokers use electronic cigarettes (ECIGs) for smoking cessation and reduction. This study used concept mapping, a participatory mixed-methods research approach, to identify ECIG use behaviors and device characteristics perceived to be associated with cigarette smoking cessation or reduction.MethodsCurrent ECIG users aged 18–64 were recruited from seven cities selected randomly from U.S. census tract regions. Participants were invited to complete concept mapping tasks: brainstorming, sorting and rating (n=72). During brainstorming, participants generated statements in response to a focus prompt ("A SPECIFIC WAY I HAVE USED electronic cigarettes to reduce my cigarette smoking or a SPECIFIC WAY electronic cigarettes help me reduce my cigarette smoking is…") and then sorted and rated the statements. Multidimensional scaling and hierarchical cluster analyses were used to generate a cluster map that was interpreted by the research team.ResultsEight thematic clusters were identified: Convenience, Perceived Health Effects, Ease of Use, Versatility and Variety, Advantages of ECIGs over Cigarettes, Cigarette Substitutability, Reducing Harms to Self and Others, and Social Benefits. Participants generated several statements that related to specific behavioral strategies used when using ECIGs for smoking reduction/complete switching behaviors such as making rapid transitions from smoking to ECIG use or using certain ECIG liquids or devices. Former smokers rated the Perceived Health Effects cluster and several behavioral strategy statements higher than current smokers.ConclusionsThese results help to identify ECIG use behaviors and characteristics perceived by ECIG users to aid in cigarette smoking cessation or reduction.



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The Anatomy of Friendship

Publication date: January 2018
Source:Trends in Cognitive Sciences, Volume 22, Issue 1
Author(s): R.I.M. Dunbar
Friendship is the single most important factor influencing our health, well-being, and happiness. Creating and maintaining friendships is, however, extremely costly, in terms of both the time that has to be invested and the cognitive mechanisms that underpin them. Nonetheless, personal social networks exhibit many constancies, notably in their size and their hierarchical structuring. Understanding the processes that give rise to these patterns and their evolutionary origins requires a multidisciplinary approach that combines social and neuropsychology as well as evolutionary biology.



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Editors, Contents, Cover details

Publication date: January 2018
Source:Trends in Cognitive Sciences, Volume 22, Issue 1





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Cyclization of PLP139-151 peptide reduces its encephalitogenic potential in experimental autoimmune encephalomyelitis

Publication date: Available online 19 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Athanasios Lourbopoulos, Minos-Timotheos Matsoukas, Maria Katsara, George Deraos, Aggeliki Giannakopoulou, Roza Lagoudaki, Nikolaos Grigoriadis, John Matsoukas, Vasso Apostolopoulos
We report the novel synthesis of cyclic PLP139-151 (cPLP) and its application in SJL/J mice to study its encephalitogenic effects. Our results indicate that the cPLP analog is minimally encephalitogenic when administered to induce experimental autoimmune encephalomyelitis (low disease burden, minimal inflammatory, demyelinating and axonopathic pathology compared to its linear counterpart). Proliferation assays confirmed the low stimulatory potential of the cPLP compared to linPLP (2.5-fold lower proliferation) as well as inducing lower antibody responses. Molecular modeling showed a completely different TCR recognition profile of cPLP in regard to linPLP, where H¹⁴⁷ replaces W¹⁴⁴ and F¹⁵¹-K¹⁵⁰ replace H¹⁴⁷ as TCR contacts, which may explain the difference on each peptide's response.

Graphical abstract

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Erratum to “Structure-activity relationships among DNA ligase inhibitors; characterization of a selective uncompetitive DNA ligase I inhibitor” [DNA Repair 60C (2017) 29–39]

Publication date: Available online 19 December 2017
Source:DNA Repair
Author(s): Timothy R.L. Howes, Annahita Sallmyr, Rhys Brooks, George E. Greco, Darin E. Jones, Yoshihiro Matsumoto, Alan E. Tomkinson




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Histopathological regression predicts treatment outcome in locally advanced esophagogastric adenocarcinoma

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): Silvia Spoerl, Alexander Novotny, Salah-Eddin Al-Batran, Florian Lordick, Peter Thuss-Patience, Claudia Pauligk, Bernhard Haller, Marcus Feith, Sylvie Lorenzen
BackgroundNeoadjuvant chemotherapy (neoCTx) improves survival outcomes of patients with localised esophagogastric adenocarcinoma (EGA). This analysis evaluates the predictive value of histopathological response after neoCTx.MethodsA total of 461 patients with locally advanced EGA (≥T2 and/or N+) who received neoCTx followed by surgery were analysed: 314 (68.1%) with intestinal, 94 (20.4%) with diffuse and 53 (11.5%) with mixed histological type according to Lauren classification. Histopathological response evaluation was available for 363 patients and performed locally. This analysis evaluates the predictive value of histopathological subtype on histopathological response after neoCTx. Response was correlated with survival.ResultsMedian patients' age was 63 years, 79.8% were male. Tumours were localised in the stomach in 32.5% and EG junction in 67.5% of the patients. With a median follow-up of 49.4 months, median disease-free (DFS) and overall survival (OS) were 38.0 and 66.4 months, respectively.Pathological complete response (TRG1a) was 8.8% and combined complete and subtotal regression (TRG1a/b) was 27.3% for all patients. Around 9.2% of patients with intestinal type had a TRG1a compared with 6.2% with diffuse and 10.8% with mixed type. TRG1a/b rate was higher in intestinal (31.0%) than in diffuse (15.4%) and in mixed type (21.6%).For patients with intestinal type, 3-year DFS was 78.4% with TRG1a and 54.3% with other regression grades (p = 0.031). All patients with diffuse and mixed type and TRG1a were disease free after 3 years compared with 31.1% (p = 0.056) and 47.7% (p = 0.044) with other regression grades.ConclusionHistopathological subtype is predictive for histopathological response and outcome after neoCTx, with the highest response rates in intestinal differentiated EGA.



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The Danish Head and Neck Cancer fast-track program: a tertiary cancer centre experience

Publication date: Available online 19 December 2017
Source:European Journal of Cancer
Author(s): Anders B. Roennegaard, Tine Rosenberg, Kristine Bjørndal, Jens Ahm Sørensen, Jørgen Johansen, Christian Godballe
IntroductionDuring the 1990s, all Nordic countries except for Denmark experienced a general increase in 5-year survival rates for cancer patients. In 2007, the Danish National Board of Health in collaboration with national multidisciplinary cancer groups and the Danish regions initiated fast-track clinical pathway solutions.ObjectivesThe objectives of this study were 1) to present the setup of the head and neck cancer (HNC) fast-track program at Odense University Hospital (OUH) as an example of the Danish model and 2) to present patient characteristics, diagnostic outcome, cancer detection rate, and duration of the fast-track patient courses.Materials and methodsFrom 1st July 2012 to 1st September 2015, all patients referred to the HNC fast-track program at OUH for diagnostics and treatment were consecutively included in the study resulting in 3165 patient courses.ResultsThe overall malignancy detection rate was 40.6% and for HNC it was 29.2%. The overall median fast-track course duration was 12 days (range 0–74). Overall 2990 (94.5%) of 3165 patients completed their fast-track course within the maximally permitted course duration.Discussion and conclusionBased on our findings, it was concluded that: 1) a HNC fast-track program build on pre-booked slots for diagnostics and treatment is feasible and can secure acceptable course durations for more than 90% of patient courses, 2) by using private ENT specialists as a 'filter-function', an acceptable detection rate can be achieved.



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Lipid-polymer hybrid nanocarriers for delivering cancer therapeutics

Publication date: Available online 19 December 2017
Source:Journal of Controlled Release
Author(s): Tushar Date, Vaishnavi Nimbalkar, Jyostna Kamat, Anupama Mittal, Ram I. Mahato, Deepak Chitkara

Graphical abstract

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Current and future technological advances in transdermal gene delivery

Publication date: Available online 19 December 2017
Source:Advanced Drug Delivery Reviews
Author(s): Xianfeng Chen
Transdermal gene delivery holds significant advantages as it is able to minimize the problems of systemic administration such as enzymatic degradation, systemic toxicity, and poor delivery to target tissues. This technology has the potential to transform the treatment and prevention of a range of diseases. However, the skin poses a great barrier for gene delivery because of the "bricks-and-mortar" structure of the stratum corneum and the tight junctions between keratinocytes in the epidermis. This review systematically summarizes the typical physical and chemical approaches to overcome these barriers and facilitate gen delivery via skin for applications in vaccination, wound healing, skin cancers and skin diseases. Next, the advantages and disadvantages of different approaches are discussed and the insights for future development are provided.

Graphical abstract

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Probing the interaction of zero valent iron nanoparticles with blood system by biophysical, docking, cellular, and molecular studies

Publication date: Available online 19 December 2017
Source:International Journal of Biological Macromolecules
Author(s): Babak Abbaszadeh Asl, Leila Mogharizadeh, Niloofar Khomjani, Behnam Rasti, Seyed Pouyan Pishva, Keivan Akhtari, Farnoosh Attar, Mojtaba Falahati
Human exposure to nanoparticles (NPs) is inevitable as NPs become more widely applied and, as a result, nanotoxicology study is now gaining attention. Herein, the interaction of zero valent iron NPs (ZVFe-NPs) with human hemoglobin (Hb) was evaluated using a variety of techniques including fluorescence spectroscopy, far circular dichroism (CD) spectroscopy as well as docking study. Also, the cytotoxicity of ZVFe-NPs on the human lymphocyte cell line as a model of blood system cell line was investigated by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), acridine orange/ethidium bromide (AO/EB) staining, flow cytometry, and real-time PCR assays. Fluorescence studies revealed that ZVFe-NPs bind to Hb via hydrogen bonds and induced conformational changes of Hb in a static denaturation mechanism. CD experiment showed that Hb retained its native structure in the presence of ZVFe-NP. Molecular docking study also demonstrated that polar residues of Hb provide convenient medium to establish hydrogen bonds with water molecules on ZVFe-NP surface. Likewise, it was also revealed that ZVFe-NPs impaired the viability of lymphocyte cells through apoptotic pathway. For NPs to move into the clinical area, it is crucial that nanotoxicology research provide pivotal information about the adverse effect of NPs against biological systems.



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Soft Tissue Sarcoma Response to Two Cycles of Neoadjuvant Chemotherapy

Publication date: Available online 19 December 2017
Source:Academic Radiology
Author(s): Jennifer L. Favinger, Daniel S. Hippe, Darin J. Davidson, Saeed Elojeimy, Eira S. Roth, Antoinette W. Lindberg, Alice S. Ha
Rationale and ObjectivesWhen soft tissue sarcomas are treated with neoadjuvant chemotherapy, the number of cycles of chemotherapy is usually dependent on the tumor's initial response. Popular methods to assess tumor response include Response Evaluation Criteria in Solid Tumors (RECIST) criteria, which rely solely on tumor size, and maximum standardized uptake value (SUVmax) reduction in positron emission tomography (PET), which requires an expensive and high radiation test. We hypothesized that contrast-enhanced magnetic resonance imaging (MRI) may offer a good alternative by providing additional information beyond tumor size.Materials and MethodsFollowing IRB approval, a retrospective review identified patients with soft tissue sarcomas who underwent both PET and MRI before and after two cycles of neoadjuvant chemotherapy. Five readers independently examined the MRI exams for: changes in size, T2 or T1 signal, necrosis and degree of enhancement. Readers then made a subjective binary assessment of tumor response to therapy. Each reader repeated the anonymized randomized reading at least 2 weeks apart. 18 F-FDG PET exams were interpreted by a nuclear medicine specialist. The maximum standardized uptake values (SUVmax) for pre and post-chemotherapy exams were compared. Intra- and inter-reader agreement was assessed using Cohen's kappa and Light's kappa, respectively. .ResultsTwenty cases were selected for this multireader study, of which 9 (45%) were responders and 11 were nonresponders by SUVmax. Using all MRI criteria, 43% were classified as responders based on MRI and 1.5% were classified as responders by RECIST criteria. Using PET as the reference, the sensitivity and the specificity of the MRI diagnosis for response using all findings were 50% and 63%, respectively. There was fair to moderate intrareader (kappa = 0.37) and inter-reader (kappa = 0.48) agreement for the MRI diagnosis of response. None of the individual MRI signal characteristics were significantly different between the PET responders and nonresponders. Additionally, no MRI findings were significantly different between those with and without good clinical responses.ConclusionBy our assessment, there is a poor correlation between tumor response by RECIST criteria and PET SUVmax. In addition, varying MR features did not help in diagnosing tumor response. Imaging of tumor response remains a challenging area that requires further research.



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Advances and new technologies in the treatment of burn injury

Publication date: 1 January 2018
Source:Advanced Drug Delivery Reviews, Volume 123
Author(s): Yiwei Wang, Peter K.M. Maitz




http://ift.tt/2BObuSb

Editorial board members

Publication date: 1 January 2018
Source:Advanced Drug Delivery Reviews, Volume 123





http://ift.tt/2B39T7B

Current and future technological advances in transdermal gene delivery

Publication date: Available online 19 December 2017
Source:Advanced Drug Delivery Reviews
Author(s): Xianfeng Chen
Transdermal gene delivery holds significant advantages as it is able to minimize the problems of systemic administration such as enzymatic degradation, systemic toxicity, and poor delivery to target tissues. This technology has the potential to transform the treatment and prevention of a range of diseases. However, the skin poses a great barrier for gene delivery because of the "bricks-and-mortar" structure of the stratum corneum and the tight junctions between keratinocytes in the epidermis. This review systematically summarizes the typical physical and chemical approaches to overcome these barriers and facilitate gen delivery via skin for applications in vaccination, wound healing, skin cancers and skin diseases. Next, the advantages and disadvantages of different approaches are discussed and the insights for future development are provided.

Graphical abstract

http://ift.tt/2BMdryl

RAS and PD-L1: A Masters’ Liaison in Cancer Immune Evasion

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Nicole Glodde, Michael Hölzel
Mutant RAS is a major oncoprotein in human cancer and PD-L1 is a key driver of cancer immune evasion. In this issue of Immunity, Coelho et al. (2017) demonstrate that oncogenic RAS signaling promotes tumor immune escape by stabilizing PD-L1 mRNA.

Teaser

Mutant RAS is a major oncoprotein in human cancer and PD-L1 is a key driver of cancer immune evasion. In this issue of Immunity, Coelho et al. (2017) demonstrate that oncogenic RAS signaling promotes tumor immune escape by stabilizing PD-L1 mRNA.


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Feeling Exhausted? Tuning Irf4 Energizes Dysfunctional T Cells

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Vijaykumar Chennupati, Werner Held
The regulatory mechanisms governing T cell exhaustion remain incompletely understood. Man et al. (2017) and Wu et al. (2017) report that the T cell receptor responsive transcription factor Irf4 promotes T cell exhaustion in chronic viral infection but dampens exhaustion in response to tissue allografts.

Teaser

The regulatory mechanisms governing T cell exhaustion remain incompletely understood. Man et al. (2017) and Wu et al. (2017) report that the T cell receptor responsive transcription factor Irf4 promotes T cell exhaustion in chronic viral infection but dampens exhaustion in response to tissue allografts.


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The Skinny on Fat Trm Cells

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Stanley Cheuk, Liv Eidsmo
White adipose tissue (WAT) is exposed to pathogens that breach epithelial barriers, but the role of adipose T cells in immunity isn't clear. In this issue of Immunity, Han et al. (2017) find that WAT harbors a reservoir of memory T cells that provide antimicrobial immunity at the expense of lipid synthesis and metabolism.

Teaser

White adipose tissue (WAT) is exposed to pathogens that breach epithelial barriers, but the role of adipose T cells in immunity isn't clear. In this issue of Immunity, Han et al. (2017) find that WAT harbors a reservoir of memory T cells that provide antimicrobial immunity at the expense of lipid synthesis and metabolism.


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PTENtiating CFTR for Antimicrobial Immunity

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Kong Chen, Jay K. Kolls
Ivacaftor is a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) that reduces Pseudomonas aeruginosa culture positivity in CF patients with unclear mechanisms. Riquelme et al. (2017) propose that improved CFTR trafficking could enhance P. aeruginosa clearance through activating the tumor suppressor PTEN.

Teaser

Ivacaftor is a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) that reduces Pseudomonas aeruginosa culture positivity in CF patients with unclear mechanisms. Riquelme et al. (2017) propose that improved CFTR trafficking could enhance P. aeruginosa clearance through activating the tumor suppressor PTEN.


http://ift.tt/2oPv37z

Mdr1 Saves T Cells from Bile

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Ana Izcue, Oliver Pabst
The gut contents shape intestinal immune homeostasis, a phenomenon best documented for microbiota-immune interactions. In this issue of Immunity, Cao et al. (2017) show that bile acids trigger T cell-mediated inflammation at their site of active absorption in the ileum, unless cells are protected by the membrane transporter Mdr1.

Teaser

The gut contents shape intestinal immune homeostasis, a phenomenon best documented for microbiota-immune interactions. In this issue of Immunity, Cao et al. (2017) show that bile acids trigger T cell-mediated inflammation at their site of active absorption in the ileum, unless cells are protected by the membrane transporter Mdr1.


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Charles D. Surh 1961–2017

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Stephen Hedrick, Jonathan Sprent




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I Remember You: Epigenetic Priming in Epithelial Stem Cells

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Boris Novakovic, Hendrik G. Stunnenberg
Exposure to inflammatory stimuli can remodel immune cells in a way that alters their response to future insults. In a landmark paper in Nature, Elaine Fuchs and colleagues show that memory of inflammation is not restricted to the hematopoietic lineage (Naik et al., 2017).

Teaser

Exposure to inflammatory stimuli can remodel immune cells in a way that alters their response to future insults. In a landmark paper in Nature, Elaine Fuchs and colleagues show that memory of inflammation is not restricted to the hematopoietic lineage (Naik et al., 2017).


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LncRNA Seduction of GOT2 Goes Viral

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Y. Grace Chen, Howard Y. Chang
Mechanisms of viral infection are active areas of investigation. In a recent issue of Science, Wang et al. (2017) reveal an additional function of a host-encoded long non-coding RNA (lncRNA) in regulating viral expression by binding a host metabolic enzyme to enhance its catalytic activity.

Teaser

Mechanisms of viral infection are active areas of investigation. In a recent issue of Science, Wang et al. (2017) reveal an additional function of a host-encoded long non-coding RNA (lncRNA) in regulating viral expression by binding a host metabolic enzyme to enhance its catalytic activity.


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Recent Advances in Type-2-Cell-Mediated Immunity: Insights from Helminth Infection

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Nicola L. Harris, P'ng Loke
Type-2-cell-mediated immune responses play a critical role in mediating both host-resistance and disease-tolerance mechanisms during helminth infections. Recently, type 2 cell responses have emerged as major regulators of tissue repair and metabolic homeostasis even under steady-state conditions. In this review, we consider how studies of helminth infection have contributed toward our expanding cellular and molecular understanding of type-2-cell-mediated immunity, as well as new areas such as the microbiome. By studying how these successful parasites form chronic infections without overt pathology, we are gaining additional insights into allergic and inflammatory diseases, as well as normal physiology.

Teaser

Type-2-cell-mediated immune responses play critical roles in regulating host resistance against helminths and promoting tissue repair and metabolic homeostasis. Harris and Loke review recent advances in the field resulting from studies of helminth-host interactions and provide insight into the activation and function of type 2 immune cells.


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Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Jil Sander, Susanne V. Schmidt, Branko Cirovic, Naomi McGovern, Olympia Papantonopoulou, Anna-Lena Hardt, Anna C. Aschenbrenner, Christoph Kreer, Thomas Quast, Alexander M. Xu, Lisa M. Schmidleithner, Heidi Theis, Lan Do Thi Huong, Hermi Rizal Bin Sumatoh, Mario A.R. Lauterbach, Jonas Schulte-Schrepping, Patrick Günther, Jia Xue, Kevin Baßler, Thomas Ulas, Kathrin Klee, Natalie Katzmarski, Stefanie Herresthal, Wolfgang Krebs, Bianca Martin, Eicke Latz, Kristian Händler, Michael Kraut, Waldemar Kolanus, Marc Beyer, Christine S. Falk, Bettina Wiegmann, Sven Burgdorf, Nicholas A. Melosh, Evan W. Newell, Florent Ginhoux, Andreas Schlitzer, Joachim L. Schultze
Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time-dependent differentiation relying on NCOR2. Finally, moDCs are phenotypically heterogeneous and therefore necessitate the use of high-dimensional phenotyping to open new possibilities for better clinical tailoring of these cellular therapies.

Teaser

Monocyte-derived cellular derivatives are used clinically and are a crucial tool in basic research. Sander and colleagues now show that they transcriptionally relate to in vivo inflammatory monocytes, that they integrate differentiation cues time dependently, and that in vitro differentiated monocytes are phenotypically heterogeneous.


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Natural Killer Cells Promote Fetal Development through the Secretion of Growth-Promoting Factors

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Binqing Fu, Yonggang Zhou, Xiang Ni, Xianhong Tong, Xiuxiu Xu, Zhongjun Dong, Rui Sun, Zhigang Tian, Haiming Wei
Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy. However, the role of NK cells in fetal growth is unclear. Here, we have identified a CD49a⁺Eomes⁺ subset of NK cells that secreted growth-promoting factors (GPFs), including pleiotrophin and osteoglycin, in both humans and mice. The crosstalk between HLA-G and ILT2 served as a stimulus for GPF-secreting function of this NK cell subset. Decreases in this GPF-secreting NK cell subset impaired fetal development, resulting in fetal growth restriction. The transcription factor Nfil3, but not T-bet, affected the function and the number of this decidual NK cell subset. Adoptive transfer of induced CD49a⁺Eomes⁺ NK cells reversed impaired fetal growth and rebuilt an appropriate local microenvironment. These findings reveal properties of NK cells in promoting fetal growth. In addition, this research proposes approaches for therapeutic administration of NK cells in order to reverse restricted nourishments within the uterine microenvironment during early pregnancy.

Graphical abstract

Teaser

Maternal nourishment of the fetus at early stage has remained undefined. Fu et al. identify CD49a⁺Eomes⁺ trNK cells in the uterus that secrete growth-promoting factors enhancing fetal growth during critical early stages of fetal development.


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CCR6 Defines Memory B Cell Precursors in Mouse and Human Germinal Centers, Revealing Light-Zone Location and Predominant Low Antigen Affinity

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Dan Suan, Nike J. Kräutler, Jesper L.V. Maag, Danyal Butt, Katherine Bourne, Jana R. Hermes, Danielle T. Avery, Clara Young, Aaron Statham, Michael Elliott, Marcel E. Dinger, Antony Basten, Stuart G. Tangye, Robert Brink
Memory B cells (MBCs) and plasma cells (PCs) constitute the two cellular outputs of germinal center (GC) responses that together facilitate long-term humoral immunity. Although expression of the transcription factor BLIMP-1 identifies cells undergoing PC differentiation, no such marker exists for cells committed to the MBC lineage. Here, we report that the chemokine receptor CCR6 uniquely marks MBC precursors in both mouse and human GCs. CCR6⁺ GC B cells were highly enriched within the GC light zone (LZ), were the most quiescent of all GC B cells, exhibited a cell-surface phenotype and gene expression signature indicative of an MBC transition, and possessed the augmented response characteristics of MBCs. MBC precursors within the GC LZ predominantly possessed a low affinity for antigen but also included cells from within the high-affinity pool. These data indicate a fundamental dichotomy between the processes that drive MBC and PC differentiation during GC responses.

Graphical abstract

Teaser

Although memory B cells sustain long-term humoral immunity, the nature of their precursors within the germinal center has remained elusive. Suan et al. demonstrate that these cells are uniquely identified by CCR6 expression in both mouse and human germinal centers, that they are the most quiescent B cells in these structures, and that they are generated within the light zone. Memory B cell precursors have a primarily low affinity for antigen but also include cells emerging from the high-affinity compartment.


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The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Wei Cao, Hisako Kayama, Mei Lan Chen, Amber Delmas, Amy Sun, Sang Yong Kim, Erumbi S. Rangarajan, Kelly McKevitt, Amanda P. Beck, Cody B. Jackson, Gogce Crynen, Angelos Oikonomopoulos, Precious N. Lacey, Gustavo J. Martinez, Tina Izard, Robin G. Lorenz, Alex Rodriguez-Palacios, Fabio Cominelli, Maria T. Abreu, Daniel W. Hommes, Sergei B. Koralov, Kiyoshi Takeda, Mark S. Sundrud
CD4⁺ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4⁺ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1^−/− hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1^−/− mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.

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Teaser

The role of host-derived intestinal metabolites in mucosal immune regulation is poorly understood. Here, Cao et al. show that effector CD4⁺ T cells upregulate expression of the xenobiotic transporter, Mdr1, in the ileum to safeguard immune homeostasis, revealing an important immunologic consequence of ileal bile acid reabsorption.


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Swell, or Not Too Swell: Cytokines Regulate Arterial Aneurysm Formation

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Peter Libby, Amélie Vromman




http://ift.tt/2D9CB7V

Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Saskia F. Erttmann, Anetta Härtlova, Marta Sloniecka, Faizal A.M. Raffi, Ava Hosseinzadeh, Tomas Edgren, Reza Rofougaran, Ulrike Resch, Maria Fällman, Torben Ek, Nelson O. Gekara




http://ift.tt/2oSOgFm

Detecting white matter activity using conventional 3 Tesla fMRI: An evaluation of standard field strength and hemodynamic response function

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Matthew J. Courtemanche, Carolyn J. Sparrey, Xiaowei Song, Alex MacKay, Ryan C.N. D'Arcy
Detection of functional magnetic resonance imaging (fMRI) activation in white matter has been increasingly reported despite historically being controversial. Much of the development work to-date has used high-field 4 T MRI and specialized pulse sequences. In the current study, we utilized conventional 3 T MRI and a commonly applied gradient-echo-planar imaging sequence to evaluate white matter (WM) fMRI sensitivity within a common framework. Functional WM activity was replicated in target regions of interest within the corpus callosum, at the group and individual levels. As expected there was a reduction in overall WM activation sensitivity. Individual analyses revealed that 8 of the 13 individuals showed white matter activation, showing a lower percentage of individuals with WM activation detected. Importantly, WM activation results were sensitive to analyses that applied alternate hemodynamic response functions, with an increase in the group level cluster when hemodynamic response function (HRF) onset slope was reduced. The findings supported the growing evidence that WM activation is detectable, with activation levels are closer to thresholds used for routine 3T MRI studies. Optimization factors, such as the HRF model, appear to be important to further enhance the characterization of WM activity in fMRI.



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The neural network for face recognition: Insights from an fMRI study on developmental prosopagnosia

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Yuanfang Zhao, Zonglei Zhen, Xiqin Liu, Yiying Song, Jia Liu
Face recognition is supported by collaborative work of multiple face-responsive regions in the brain. Based on findings from individuals with normal face recognition ability, a neural model has been proposed with the occipital face area (OFA), fusiform face area (FFA), and face-selective posterior superior temporal sulcus (pSTS) as the core face network (CFN) and the rest of the face-responsive regions as the extended face network (EFN). However, little is known about how these regions work collaboratively for face recognition in our daily life. Here we focused on individuals suffering developmental prosopagnosia (DP), a neurodevelopmental disorder specifically impairing face recognition, to shed light on the infrastructure of the neural model of face recognition. Specifically, we used a variant of global brain connectivity method to comprehensively explore resting-state functional connectivity (FC) among face-responsive regions in a large sample of DPs (N = 64). We found that both the FCs within the CFN and those between the CFN and EFN were largely reduced in DP. Importantly, the right OFA and FFA served as the dysconnectivity hubs within the CFN, i.e., FCs concerning these two regions within the CFN were largely disrupted. In addition, DPs' right FFA also showed reduced FCs with the EFN. Moreover, these disrupted FCs were related to DP's behavioral deficit in face recognition, with the FCs from the FFA to the anterior temporal lobe (ATL) and pSTS the most predictive. Based on these findings, we proposed a revised neural model of face recognition demonstrating the relatedness of interactions among face-responsive regions to face recognition.



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Affective and non-affective touch evoke differential brain responses in 2-month-old infants

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Emma H. Jönsson, Kalle Kotilahti, Juha Heiskala, Helena Backlund Wasling, Håkan Olausson, Ilona Croy, Hanna Mustaniemi, Petri Hiltunen, Jetro J. Tuulari, Noora M. Scheinin, Linnea Karlsson, Hasse Karlsson, Ilkka Nissilä
Caressing touch is an effective way to communicate emotions and to create social bonds. It is also one of the key mediators of early parental bonding. The caresses are generally thought to represent a social form of touching and indeed, slow, gentle brushing is encoded in specialized peripheral nerve fibers, the C-tactile (CT) afferents. In adults, areas such as the posterior insula and superior temporal sulcus are activated by affective, slow stroking touch but not by fast stroking stimulation. However, whether these areas are activated in infants, after social tactile stimulation, is unknown.In this study, we compared the total hemoglobin responses measured with diffuse optical tomography (DOT) in the left hemisphere following slow and fast stroking touch stimulation in 16 2-month-old infants. We compared slow stroking (optimal CT afferent stimulation) to fast stroking (non-optimal CT stimulation). Activated regions were delineated using two methods: one based on contrast between the two conditions, and the other based on voxel-based statistical significance of the difference between the two conditions. The first method showed a single activation cluster in the temporal cortex with center of gravity in the middle temporal gyrus where the total hemoglobin increased after the slow stroking relative to the fast stroking (p = 0.04 uncorrected). The second method revealed a cluster in the insula with an increase in total hemoglobin in the insular cortex in response to slow stroking relative to fast stroking (p = 0.0005 uncorrected; p = 0.04 corrected for multiple comparisons).These activation clusters encompass areas that are involved in processing of affective, slow stroking touch in the adult brain. We conclude that the infant brain shows a pronounced and adult-like response to slow stroking touch compared to fast stroking touch in the insular cortex but the expected response in the primary somatosensory cortex was not found at this age. The results imply that emotionally valent touch is encoded in the brain in adult-like manner already soon after birth and this suggests a potential for involvement of touch in bonding with the caretaker.



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Extracts of Cordyceps sinensis inhibit breast cancer cell metastasis via down-regulation of metastasis-related cytokines expression

Publication date: 25 March 2018
Source:Journal of Ethnopharmacology, Volume 214
Author(s): Hongwei Cai, Jing Li, Baohua Gu, Ying Xiao, Rongsheng Chen, Xiaoyu Liu, Xiaomin Xie, Li Cao
Ethnopharmacological relevanceCordyceps sinensis is a traditional Chinese medicine and has been used as adjuvant treatments for cancer and it has been also demonstrated to be effective in cancer patients.Aim of the studyThe objective of the present study is to investigate the anti-metastasis effects of water extracts of Cordyceps sinensis (WECS) in breast cancer and the potential mechanisms.Materials and methodsThe cytotoxicity of WECS on 4T1 breast cancer cells was evaluated in vitro using cell counting kit-8 (CCK8) assay. The in vivo anti-metastatic activity of intraperitoneally administered WECS and its effect on animal survival were measured in a mouse breast cancer metastasis model. To explore the molecular mechanisms of the anti-metastasis effect of WECS, the expression of matrix metalloprotein-9 (MMP-9) in serum was determined by enzyme-linked immunosorbent assay (ELISA). In addition, a protein array was used to examine the cytokine expression profiles in lung homogenates.ResultsTreatment with WECS (0.10–0.40mg/ml) significantly inhibited 4T1 cell viability in vitro. In animal studies, 50mg/kg WECS significantly reduced the number of metastatic lung nodules and the weight of lung, without affecting body weight of mice. Furthermore, WECS increased the survival rate of 4T1 tumor bearing mice in a dose dependent manner, and at high dose, WECS (50mg/kg) significantly increased the life span of the mice compared to untreated control group. The expression level of MMP-9 in serum was decreased about 50% in 50mg/kg WECS treated group compared to control group. The results of protein array showed that the expression of CC chemokine ligand 17 (CCL17), MMP-9, osteopontin (OPN), interleukin-33 (IL-33), CC chemokine ligand 12 (CCL12) and CC chemokine ligand 6 (CCL6) in the lungs of 4T1 tumor bearing mice was increased more than two fold compared with normal mice. Among them, the expression of CCL17, MMP-9, OPN, IL-33 was significantly reduced by treatment of 50mg/kg WECS.ConclusionOur results demonstrated that WECS has potent anti-metastasis activity in a mouse breast cancer metastasis model possibly by down-regulation the expression of several metastasis-related cytokines.

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The hidden mechanism beyond ginger (Zingiber officinale Rosc.) potent in vivo and in vitro anti-inflammatory activity

Publication date: 25 March 2018
Source:Journal of Ethnopharmacology, Volume 214
Author(s): Shahira M. Ezzat, Marwa I. Ezzat, Mona M. Okba, Esther T. Menze, Ashraf B. Abdel-Naim
Ethnopharmacological relevanceGinger (Zingiber officinale Roscoe) is a well known anti-inflammatory drug in the Egyptian, Indian and Chinese folk medicines, yet its mechanism of action is unclear.Aim of the studyTo explore its mechanism of action and to correlate it to its biophytochemicals.Materials and methodsVarious extracts viz. water, 50%, 70%, 80%, and 90% ethanol were prepared from ginger rhizomes. Fractionation of the aqueous extract (AE) was accomplished using Diaion HP-20. In vitro anti-inflammatory activity of the different extracts and isolated compounds was evaluated using protein denaturation inhibition, membrane stabilization, protease inhibition, and anti-lipoxygenase assays. In vivo anti-inflammatory activity of AE was estimated using carrageenan-induced rat paw edema in rats at doses 25, 50, 100 and 200mg/kg b.wt.ResultsAll the tested extracts showed significant (p< 0.1) in vitro anti-inflammatory activities. The strongest anti-lipoxygenase activity was observed for AE that was more significant than that of diclofenac (58% and 52%, respectively) at the same concentration (125μg/ml). Purification of AE led to the isolation of 6-poradol (G1), 6-shogaol (G2); methyl 6- gingerol (G3), 5-gingerol (G4), 6-gingerol (G5), 8-gingerol (G6), 10-gingerol (G7), and 1-dehydro-6-gingerol (G8). G1, G2 and G8 exhibited potent activity in all the studied assays, while G4 and G5 exhibited moderate activity. In vivo administration of AE ameliorated rat paw edema in a dose-dependent manner. AE (at 200mg/kg) showed significant reduction in production of PGE2, TNF-α, IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated upon activation, normal T-cell expressed and secreted (RANTES), myeloperoxidase (MPO) activity by 60%, 57%, 60%, 41%, 32% and 67%, respectively. AE at 100 and 200mg/kg was equipotent to indomethacin in reduction of NOx level and in increasing the total antioxidant capacity (TAC). Histopathological examination revealed very few inflammatory cells infiltration and edema after administration of AE (200mg/kg) prior to carrageenan.ConclusionsGinger anti-inflammatory activity is mediated by inhibiting macrophage and neutrophils activation as well as negatively affecting monocyte and leukocyte migration. This was evidenced by the dose-dependent decrease in pro-inflammatory cytokines and chemokines and replenishment the total antioxidant capacity.

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Metabolic profiles revealed anti-ischemia-reperfusion injury of Yangxinshi tablet in Rats

Publication date: 25 March 2018
Source:Journal of Ethnopharmacology, Volume 214
Author(s): Hai Zhang, Yahong Zhao, Zhengxiang Xia, Hongli Du, Yue Gao, Dan Xue, Zhenyu Zhu, Yifeng Chai
Ethnopharmacological relevanceMyocardial ischemia-reperfusion (I/R) injury is a serious injury that is resulted from the recovery of blood supply after myocardial ischemia. Yangxinshi tablet is a compound Chinese herbal preparation and often used to alleviate the myocardial ischemia in clinical, but its protective mechanism of anti-myocardial ischemia reperfusion injury remains unclear. The objective of this study was to evaluate the anti-I/R injury effect of Yangxinshi tablet on a myocardial I/R rat model and to identify serum biomarker metabolites associated with I/R based on ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF/MS) metabolomic method, and explore the metabolic mechanism of anti-I/R injury of Yangxinshi tablet.Materials and methodsUnsupervised principle component analysis highlighted significant differences in the metabolome of the myocardial I/R, healthy control and drug-treated rats. Partial least squares-discriminant analysis revealed 25 metabolites as the most potential biomarker metabolites discriminating the myocardial I/R rats and control rats. Most of the metabolites were primarily involved in oxidative stress, energy metabolism, fatty acid metabolism, amino acid metabolism. These metabolites were validated by assessing the efficacy after intragastric administration of Yangxinshit ablet to the myocardial I/R rat model.ResultsBased on metabolomic results, the action mechanism of anti-I/R injury of Yangxinshi tablet was concluded as follows: (1) enhance the ability of scavenging free radicals and reactive oxygen species in vivo; (2) provide energy for myocardium via accelerating the intracellular carnitine transportion to accelerate the oxidation of fatty acid and (3) attenuate ceramide to reduce cardiomyocyte apoptosis.ConclusionsYangxinshi tablet has cardio-protection effects on I/R rats via regulation of multiple metabolic pathways involving in oxidative stress, energy metabolism, fatty acid, and amino acid metabolisms. This study will be meaningful for its clinical application and valuable for further exploring the action mechanism of Yangxinshi tablet.

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Immunomodulatory effects of Sceletium tortuosum (Trimesemine™) elucidated in vitro: Implications for chronic disease

Publication date: 25 March 2018
Source:Journal of Ethnopharmacology, Volume 214
Author(s): Amber C. Bennett, Carine Smith
Ethnopharmacological relevanceSceletium tortuosum, among other Sceletium species, was traditionally used by the Khoisan people of Southern Africa for relief of pain-related ailments. However, the commercial availability of this supplement has greatly expanded due to anecdotal claims of its mood-elevating and anxiolytic properties. Unrelated research has elucidated a significant link between cytokines and the mediation of depression. Therefore, the effect of Sceletium supplementation on immune cell functionality is of interest, since the efficacy of potential depression treatments could, at least in part, rely on downregulation of pro-inflammatory signalling.Aim of the studyThe current study evaluated the immunomodulatory effects of a Sceletium extract, both basally and in the context of acute endotoxin stimulation.Materials and methodsPrimary human monocytes were supplemented with either a 0.01mg/ml or 1mg/ml Sceletium extract dose, with or without E. coli LPS stimulation in vitro, for 24h. Mitochondrial viability, as an indirect measure of cytotoxicity, and cytokine release in response to the treatment intervention were assessed.ResultsSceletium extract treatment was associated with increased mitochondrial viability, as well as up-regulated IL-10 release under basal conditions. LPS exposure significantly decreased mitochondrial viability, but this was prevented completely under Sceletium-treated conditions. The acute inflammatory response to LPS stimulation was not negatively affected. Sceletium treatment conferred most significant effects at a dose of 0.01mg/ml.ConclusionsSceletium exerts significant cytoprotective effects in the setting of endotoxin stimulation. Cytokine assessment indicated that Sceletium possesses mild anti-inflammatory properties, but does not hinder the mounting of an adequate immune response to acute immune challenge. These findings indicate that Sceletium may be beneficial for the attenuation of cytokine-induced depression, as well as in systemic low-grade inflammation.

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Pathway analysis of global gene expression change in dendritic cells induced by the polysaccharide from the roots of Actinidia eriantha

Publication date: 25 March 2018
Source:Journal of Ethnopharmacology, Volume 214
Author(s): Jing Du, Xiangfeng Chen, Chenying Wang, Hongxiang Sun
Ethnopharmacological relevanceThe roots of Actinidia eriantha Benth have been used clinically to treat a variety of cancers in traditional Chinese medicine. The polysaccharide from this drug (AEPS) was previously reported to be a potential antitumor agent with immunomodulatory activity. However, the mechanisms of its antitumor action in immunomodulation have not yet been well-defined.Aim of the studyTo investigate the effects of AEPS on the phenotypic and functional maturation of dendritic cells and to explore the intracellular signaling mechanisms of its antitumor action in the immunomodulation.Materials and methodsThe effects of AEPS on the phagocytic activity, expression of surface molecules, mRNA and protein expression levels of cytokines and chemokines in mouse bone-marrow derived dendritic cells (BMDCs) were determined by flow cytometry, qRT-PCR and ELISA, respectively. The transcriptional profile induced by AEPS was established using oligonucleotide microarray, and Ingenuity Pathway Analysis (IPA) was used to identify potential signaling pathways. Western blotting, neutralization experiments and inhibition assay were performed to confirm signaling pathway involved in maturation of DCs induced by AEPS. Furthermore, we discussed the downstream effects of the action of AEPS using clustering, network and pathway mapping approaches.ResultsAEPS could significantly reduced phagocytic activity, promoted expression of accessory and co-stimulatory molecules, and up-regulated the mRNA and protein expression levels of cytokines and chemokines in BMDCs. Microarray assay revealed that AEPS induced significantly differential expression of 452 genes including up-regulated cytokines (IL-6, IL-1β, TNF-α, IL-10, IL-12p40, IFN-β and IFN-γ), chemokines (MIP-1α, MIP-1β, CCL5, MDC and MCP-1), transcription factors (STAT1, STAT2, STAT5b, IRF1 and IRF7) and pattern recognition receptors (TLR3, DDX58, DHX58 and IFIH1) in the BMDCs. AEPS-induced production of TNF-α and IL-12p40 from BMDCs was inhibited by antibodies against TLR2 and TLR4. Furthermore, AEPS induced the phosphorylation of NF-κB p65 in a time-dependent manner, and BAY 11-7082, an inhibitor of NF-κB, remarkably suppressed the production of cytokines induced by AEPS.ConclusionAEPS triggers the phenotypic and functional maturation of DCs via TLR2/4 and NF-κB signaling pathway, resulting in augmented antitumor immune responses. Our results suggested that AEPS might be helpful in potentiating the efficiency of DC-based cancer immunotherapy. This study further expanded current knowledge on the mechanisms of antitumor action of AEPS.

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Interactions between crude drug extracts used in Japanese traditional Kampo medicines and organic anion-transporting polypeptide 2B1

Publication date: 25 March 2018
Source:Journal of Ethnopharmacology, Volume 214
Author(s): Rie Iijima, Tomoki Watanabe, Kan'ichiro Ishiuchi, Takashi Matsumoto, Junko Watanabe, Toshiaki Makino
Ethnopharmacological relevanceThe use of herbal medicines has become popular worldwide, and the information on drug interactions between herbal medicines and chemical drugs is needed.Aim of the studyWe screened the inhibitory effects of crude drugs used in Kampo medicines used in Japan on organic anion-transporting polypeptide (OATP) 2B1 to predict potential interactions between Kampo medicines and chemical drugs used together.Materials and methodsWe chose 98 kinds of crude drugs frequently used as ingredients of Kampo formulations in Japan and prepared their boiling water extracts. We then screened their inhibitory effects on OATP2B1 by measuring the uptake of estrone 3-sulphate (E3S) by HEK293 cells stably expressing OATP2B1.ResultsAt the concentration of 100µg/ml, the extracts prepared from 12 kinds of crude drugs, Scuteralliae Radix, Arecae Semen, Aurantii Fructus Immaturus, Perillae Herba, Panacis Japonici Rhizoma, Moutan Cortex, Polygalae Radix, Rhei Rhizoma, Cannabis Fructus, Chrysanthemi Flos, Eriobotryae Folium, and Querci Cortex, suppressed the function of OATP2B1 by less than 20%. The extract of bofutsushosan, a representative Kampo formulation, inhibited OATP2B1 function with sufficient levels to suppress absorption of OATP2B1 substrates in clinics. We further evaluated the inhibitory effects of several ingredients containing Rhei Rhizoma, Perillae Herba, and Moutan Cortex on OATP2B1.ConclusionsBecause of crude drugs used in Kampo medicines might suppress absorption of OATP2B1 substrates, these results may contribute to the safe and effective use of Kampo medicine in clinics.A list of abbreviations: EC, (−)-epicatechin; ECG, epicatechin gallate; EGC, epigallocatechin; EGCG, Epigallocatechin gallate; FBS, fetal bovine serum; grapefruit juice; HEK293, Human embryonic kidney; IC50, The half inhibitory concentration; OATP, organic anion-transporting polypeptide; β-PGG, penta-O-galloyl-β-D-glucose; t.i.d, 3 times a day

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Ameliorative effects of Juniperus rigida fruit on oxazolone- and 2,4-dinitrochlorobenzene-induced atopic dermatitis in mice

Publication date: 25 March 2018
Source:Journal of Ethnopharmacology, Volume 214
Author(s): Sullim Lee, No-June Park, Sim-Kyu Bong, Jonghwan Jegal, Sang-a Park, Su-Nam Kim, Min Hye Yang
Ethnopharmacological relevanceThe fruits of Juniperus rigida have been used in Korean traditional medicine for the treatment of inflammatory diseases in humans such as rheumatoid arthritis.Aim of the studyThis study aimed to investigate the anti-atopic properties of J. rigida fruit in in vivo murine atopic dermatitis (AD) models.Methods and resultsBALB/c mouse ears ad SKH-1 hairless mice stimulated with oxazolone (4 weeks) and DNCB (3 weeks), respectively, were treated with the 1% Juniperus rigida fruit EtOH extract (JFE). The JFE improved AD symptoms in both oxazolone- and DNCB-induced AD mice by accelerating skin barrier recovery function and suppressing the overproduction of serum immunoglobulin E (IgE) and interleukin 4 (IL-4). The JFE was found to contain isoscutellarein-7-O-β-xylopyranoside, cupressuflavone, podocarpusflavone A, and hinokiflavone as major components based on phytochemical analysis. Eight flavonoids were isolated from JFE, and of those, cupressuflavone and isoscutellarein-7-O-β-xylopyranoside strongly down-regulated IL-4 expression and β-hexosaminidase release in RBL-2H3 cells.ConclusionTherapeutic attempts with J. rigida fruit and its active components might be useful in treating AD and related skin inflammatory diseases.

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http://ift.tt/2D8LuP6

Cardioprotective effect of Asphodelus tenuifolius Cav. on blood pressure and metabolic alterations in glucose-induced metabolic syndrome rats–An ethnopharmacological approach

Publication date: 25 March 2018
Source:Journal of Ethnopharmacology, Volume 214
Author(s): Waqas Younis, Alamgeer, V.B. Schini-Kerth, Arquimedes Gasparotto Junior, Muhammad Majid

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http://ift.tt/2D8Lr5S

Neuroprotective effect of He-Ying-Qing-Re formula on retinal ganglion cell in diabetic retinopathy

Publication date: 25 March 2018
Source:Journal of Ethnopharmacology, Volume 214
Author(s): Cheng Zhang, Yu Xu, Hor-Yue Tan, Sha Li, Ning Wang, Yinjian Zhang, Yibin Feng
Ethnopharmacology relevanceHe-Ying-Qing-Re Formula (HF) was empirically modified from Si-Miao-Yong-An Decoction (SD), which was recorded in the literature of Divine Doctor's Secret Transmission, and has been utilized for centuries to treat vasculopathy through clearing heat and accelerating bloodstream. HF has been used as an effective holistic treatment of diabetic retinopathy (DR) for decades and experimentally reported to ameliorate retinal condition in diabetic mice.Aim of the studyOur study aims to investigate the effect of HF in preventing sustained hyperglycemia and hyperlipidemia-associated retinal ganglion cell (RGC) cell death and its possible mechanism.Materials and methodsChromatographic fingerprint of HF was obtained upon the UPLC-based analytic system; Diabetic retinopathy was established in streptozotocin (STZ) injection-induced hyperglycemic mice; Alterations of retinal structure was assayed by H&E staining. Expression of PSD-95 and CHOP in retinae was assessed by immunofluorescence; RGC cell line (mRGC) was used for in vitro study. Cell death was analyzed by flow cytometry; Intracellular reactive oxygen species (ROS) was measured by 2′,7′-dichlorofluorescin diacetate (DCFDA); Apoptosis-related proteins and signaling were monitored with immunoblotting and colorimetric assay.ResultsChlorogenic acid, ferulic acid, and rutin were identified in HF. HF attenuates the loss of RGCs, thinning of inner retinal layers in diabetic mice. Furthermore, expressions of Brn3a and PSD-95 were restored while CHOP level was downregulated upon HF treatment. In vitro study, HF alleviates H2O2-induced apoptosis of mRGCs and loss of postsynaptic protein via scavenging ROS and suppressing ATF4/CHOP-mediated endoplasmic reticulum stress and mitochondria-related pro-apoptotic factors, probably as cleaved-caspase-3, and phospho-p38 mitogen-activated protein kinase (MARK). Meanwhile, both pro-survival protein levels like Bcl-2/Bcl-xL and postsynaptic protein of PSD-95 were upregulated upon HF treatment.ConclusionHF administration was a valid therapeutic approach for DR treatment, oriented at the blockade of endoplasmic reticulum- and mitochondria-dependent oxidative stress-induced retinal neurodegeneration including RGC apoptosis.



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Brain activity-induced neuronal glucose uptake/glycolysis: Is the lactate shuttle not required?

Publication date: Available online 19 December 2017
Source:Brain Research Bulletin
Author(s): Bor Luen Tang
The astrocyte-neuron lactate shuttle (ANLS) hypothesis posits that during neuronal activation, astrocytic glycolysis consumes glucose and generates lactate, with the latter then imported by neurons as a preferred fuel. The hypothesis has been controversial, with multiple theoretical postulates for and against, and with empirical evidence that were either supportive or otherwise. Recent findings using direct in vivo imaging of lactate and glucose uptake as well as associated metabolic changes in neurons have now placed important constraints on the hypothesis. Here, I review these recent findings and discuss their implications on neuronal energetics.



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Amino-Si-rhodamines: A new class of two-photon fluorescent dyes with intrinsic targeting ability for lysosomes

Publication date: March 2018
Source:Biomaterials, Volume 158
Author(s): Hongxing Zhang, Jing Liu, Linfang Wang, Minjia Sun, Xiaohan Yan, Juanjuan Wang, Jian-Ping Guo, Wei Guo
Noninvasive and specific visualization of lysosomes by fluorescence technology is critical for studying lysosomal trafficking in health and disease and for evaluating new cancer therapeutics that target tumor cell lysosomes. To date, there are two basic types of lysosomal probes whose lysosomal localization correlates with lysosomal acidity and endocytosis pathway, respectively. However, the former may suffer from pH-sensitive lysosomal localization and alkalization-induced lysosomal enzyme inactivation, and the latter need long incubation time to penetrate cell membrane due to the energy-dependency of endocytosis process. In this work, a new class of two-photon fluorescent dyes, termed amino-Si-rhodamines (ASiRs), were developed, which possess the intrinsic lysosome-targeted ability that is independent of lysosomal acidity and endocytosis pathway. As a result, ASiRs show not only the stable lysosomal localization against lysosomal pH changes and negligible interference to lysosomal function, but also excellent cell-membrane-permeability due to the energy-independent passive diffusion pathway. These merits, coupled with their excellent two-photon photophysical properties, long-term retention ability in lysosomes, and negligible cytotoxicity, make ASiRs very suitable for real-time and long-term tracking of lysosomes in living cells or tissues without interference to normal cellular processes. Moreover, the easy functionalization via amino linker further allows the construction of various fluorescent probes for biological targets of interest based on ASiR skeleton, as indicated by the cancer-targeted fluorescent probe ASiR6 as well as a fluorescent peroxynitrite probe ASiR-P.

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Noninvasive small-animal imaging of galectin-1 upregulation for predicting tumor resistance to radiotherapy

Publication date: March 2018
Source:Biomaterials, Volume 158
Author(s): Jianhao Lai, Dehua Lu, Chenran Zhang, Hua Zhu, Liquan Gao, Yanpu Wang, Rui Bao, Yang Zhao, Bing Jia, Fan Wang, Zhi Yang, Zhaofei Liu
Increasing evidence indicates that the overexpression of galectin-1, a member of the galectin family, is related to tumor progression and invasion, as well as tumor resistance to therapies (e.g., radiotherapy). Herein, we investigated whether near-infrared fluorescence (NIRF) imaging and positron-emission tomography (PET) were sensitive approaches for detecting and quantitating galectin-1 upregulation in vivo. An anti-galectin-1 antibody was labeled with either an NIRF dye or ⁶⁴Cu, and NIRF and PET imaging using the resulting probes (Dye-αGal-1 and ⁶⁴Cu- 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA]-αGal-1) were performed in 4T1 breast cancer-bearing mice treated with several rounds of sorafenib. Radiotherapy was performed in vitro and in vivo to identify the role of galectin-1 in radioresistance. NIRF and PET imaging both revealed significantly increased upregulation of galectin-1 in the hypoxic tumors after sorafenib treatment, which was verified by ex vivo biodistribution, western blotting, and enzyme-linked immunosorbent assays. Galectin-1 specific inhibition by thiodigalactoside dramatically improved the efficacy of radiotherapy, and overcame sorafenib-induced radiotherapy resistance. Taken together, galectin-1 is a key mediator of tumor resistance to radiotherapy. Targeted molecular imaging allows for real-time, noninvasive, and quantitative detection of the dynamic changes in galectin-1 levels in vivo; this introduces the possibility of early detection of tumor resistance to therapies.

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Zwitterionic starch-based hydrogel for the expansion and “stemness” maintenance of brown adipose derived stem cells

Publication date: March 2018
Source:Biomaterials, Volume 157
Author(s): Dianyu Dong, Tong Hao, Changyong Wang, Ying Zhang, Zhihui Qin, Boguang Yang, Wancai Fang, Lei Ye, Fanglian Yao, Junjie Li
Brown adipose derived stem cells (BADSCs) have become a promising stem cell treatment candidate for myocardial infarction because of their efficiently spontaneous differentiation capacity towards cardiomyocytes. The lack of existing cell passage protocols motivates us to develop a neotype 3D cell expansion technique for BADSCs. In this study, "clickable" zwitterionic starch based hydrogels are developed using methacrylate modified sulfobetaine derived starch with dithiol-functionalized poly (ethylene glycol) as crosslinker via the "thiol-ene" Michael addition reaction. Moreover, CGRGDS peptide is immobilized into the hydrogel via a similar "clickable" approach. Their Young's moduli range from 22.28 to 74.81 kPa depending on the concentration of precursor solutions. Excellent anti-fouling property is also presented owing to the introduction of zwitterionic moieties. BADSCs are homogeneously encapsulated in the hydrogels and then routinely cultured for 10 days. Results suggest a capacious cell proliferation and the extent increases with either the decrease of mechanical strength or the introduction of CGRGDS. More excitingly, the cell "stemness" is well maintained during this period and the expanded cells released from the hydrogels well keep the efficiently spontaneous cardiomyogenic differentiation capacity. Therefore, it is suggested that zwitterionic starch based hydrogel is able for the expansion and "stemness " maintenance of BADSCs.

Graphical abstract

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The implant effect after intracranial electrode placement: is transient clinical improvement explained by post-implantation electrophysiological changes?

Publication date: Available online 19 December 2017
Source:Clinical Neurophysiology
Author(s): Bassel Abou-Khalil, Antonio Valentin




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Spatial versus temporal inhibition in dystonia

Publication date: Available online 19 December 2017
Source:Clinical Neurophysiology
Author(s): Robert Chen




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Novel BICD2 mutation in a Japanese family with autosomal dominant lower extremity-predominant spinal muscular atrophy-2

Publication date: Available online 19 December 2017
Source:Brain and Development
Author(s): Mieko Yoshioka, Naoya Morisada, Daisaku Toyoshima, Hajime Yoshimura, Hisahide Nishio, Kazumoto Iijima, Yasuhiro Takeshima, Tomoko Uehara, Kenjiro Kosaki
IntroductionThe most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogenous and largely remain to be elucidated. We present a father and son with atrophy and weakness of the lower leg muscles since infancy. Genetic studies in this family revealed a novel BICD2 mutation causing autosomal dominant lower extremity-predominant SMA type 2.PatientsThe proband was the father, aged 30, and the son was aged 3. Both of them were born uneventfully to nonconsanguineous parents. While the father first walked at the age of 19 months, the son was unable to walk at age 3 years. In both, knee and ankle reflexes were absent and sensation was intact. Serum creatine kinase levels were normal. The son showed congenital arthrogryposis and underwent orthopedic corrections for talipes calcaneovalgus. Investigation of the father at the age of 5 years revealed normal results on nerve conduction studies and sural nerve biopsy. Electromyography showed chronic neurogenic change, and muscle biopsy showed features suggestive of denervation. The father was diagnosed clinically with a sporadic distal SMA. Follow-up studies showed very slow progression.Investigations and resultsNext-generation and Sanger sequencing revealed a deleterious mutation in BICD2: c.1667A>G, p.Tyr556Cys, in this family.DiscussionBICD2 is a cytoplasmic conserved motor-adaptor protein involved in anterograde and retrograde transport along the microtubules. Next-generation sequencing will further clarify the genetic basis of non-5q SMA.



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First report of a cross-kingdom pathogenic bacterium, Achromobacter xylosoxidans isolated from stipe-rot Coprinus comatus

Publication date: Available online 19 December 2017
Source:Microbiological Research
Author(s): Luona Ye, Mengpei Guo, Pengfei Ren, Gangzheng Wang, Yinbing Bian, Yang Xiao, Yan Zhou
Coprinus comatus is an edible mushroom widely cultivated in China as a delicious food. Various diseases have occurred on C. comatus with the cultivated area increasing. In this study, the pathogenic bacterium JTG-B1, identified as Achromobacter xylosoxidans by 16S rDNA and nrdA gene sequencing, was isolated from edible mushroom Coprinus comatus with serious rot disease on its stipe. A. xylosoxidans has been confirmed as an important opportunistic human pathogenic bacterium and has been isolated from respiratory samples from cystic fibrosis. It is widely distributed in the environment. Here, we first report that fungi can also serve as a host for A. xylosoxidans. We confirmed that it can cross-kingdom infect between animals (mice) and fungi (C. comatus). The results of pathogenicity tests, physiological, biochemical and genotyping analysis of A. xylosoxidans from different hosts suggested that different strain of A. xylosoxidans may have pathogenicity differentiation. A. xylosoxidans not only is pathogenic to C. comatus but also may threaten human health.



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Could FlhF be a key element that controls Campylobacter jejuni flagella biosynthesis in the initial assembly stage?

Publication date: Available online 19 December 2017
Source:Microbiological Research
Author(s): Fangzhe Ren, Tianyao Lei, Zhaojun Song, Ting Yu, Qiuchun Li, Jinlin Huang, Xin-an Jiao
The disordered arrangement of flagella biosynthetic genes, combined with a simplified regulatory mechanism, has made elucidating the process of Campylobacter jejuni flagellation difficult. FlhF is a recently identified element that controls the assembly of the flagella, although its function mechanism and regulatory preference are not well defined at present. In this study, we found that inactivation of FlhF caused the transcription of most flagella genes down-regulated. The importance of FlhF was systematically evaluated by analyzing changes in the transcription profiles between wild-type and flhF mutant strains, which showed that FlhF affects late flagella genes obviously. FlhF is constitutively expressed during C. jejuni growth, demonstrating that it is a class I flagella element that participates in early flagella assembly. In addition, the early flagella component FlhB was not localized to the cell pole in the flhF mutant. Thus, flagella assembly was impeded at the initial stage. We propose a model in which FlhF helps target the early flagella components to the cell pole, functioning prior to the formation of the flagella export apparatus, and thus places FlhF at the top of the flagella regulatory cascade hierarchy. Inactivation of FlhF impeded flagella assembly at the initial stage and decreased transcription of flagella genes through a feed-back control mechanism, leading to FlhF having a significant influence on the expression of late flagella components and resulting in the aflagellate C. jejuni phenotype. Our present study has uncovered how FlhF influences C. jejuni flagella biosynthesis, which will be helpful in understanding the C. jejuni flagella biosynthetic pathway and bacterial flagellation in general.



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Scoping the polymer genome: A roadmap for rational polymer dielectrics design and beyond

Publication date: Available online 19 December 2017
Source:Materials Today
Author(s): Arun Mannodi-Kanakkithodi, Anand Chandrasekaran, Chiho Kim, Tran Doan Huan, Ghanshyam Pilania, Venkatesh Botu, Rampi Ramprasad
The Materials Genome Initiative (MGI) has heralded a sea change in the philosophy of materials design. In an increasing number of applications, the successful deployment of novel materials has benefited from the use of computational methodologies, data descriptors, and machine learning. Polymers have long suffered from a lack of data on electronic, mechanical, and dielectric properties across large chemical spaces, causing a stagnation in the set of suitable candidates for various applications. Extensive efforts over the last few years have seen the fruitful application of MGI principles toward the accelerated discovery of attractive polymer dielectrics for capacitive energy storage. Here, we review these efforts, highlighting the importance of computational data generation and screening, targeted synthesis and characterization, polymer fingerprinting and machine-learning prediction models, and the creation of an online knowledgebase to guide ongoing and future polymer discovery and design. We lay special emphasis on the fingerprinting of polymers in terms of their genome or constituent atomic and molecular fragments, an idea that pays homage to the pioneers of the human genome project who identified the basic building blocks of the human DNA. By scoping the polymer genome, we present an essential roadmap for the design of polymer dielectrics, and provide future perspectives and directions for expansions to other polymer subclasses and properties.

Graphical abstract

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Study of applying naturally occurring mineral sorbents of Poland (dolomite halloysite, chalcedonite) for aided phytostabilization of soil polluted with heavy metals

Publication date: April 2018
Source:CATENA, Volume 163
Author(s): Maja Radziemska
A greenhouse experiment was carried out for evaluating the effects of mineral sorbents, i.e.: dolomite, halloysite, and chalcedonite on the chemical characteristics of soil contaminated with heavy metals and the uptake of metals by plants. The contents of trace elements in the plants and soil were determined using the method of spectrophotometry. All of the investigated element contents in the tested parts of F. rubra differed significantly in the case of applying mineral sorbents to the soil, as well as increasing concentrations of Pb, Cd and Zn. The greatest average above-ground biomass was observed when chalcedonite and halloysite were amended into the soil. Halloysite and chalcedonite also caused significant increases in Pb, Cd and Zn concentrations in the roots. The addition of dolomite significantly increased soil pH. Halloysite and chalcedonite were shown to be the most effective and decreased the average Pb, Cd and Zn contents in soil.

Graphical abstract

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Changes in the element concentration of the dorsal hippocampus CA1 region during memory consolidation and reconsolidation

Publication date: July 2018
Source:Journal of Chemical Neuroanatomy, Volume 90
Author(s): Paulo Fernandes Costa Jobim, Carla Eliete Iochims dos Santos, Luka Jeromel, Primoz Pellicon, Livio Amaral, Johnny Ferraz Dias
The concentration and distribution of Mg, P, Cl, K, Cu and Zn in the dorsal hippocampus CA1 region of rat brains were studied during memory consolidation and reconsolidation processes stimulated with inhibitory avoidance (IA) tests. Experimental rats were divided into four groups: i) group not submitted to inhibitory avoidance task (IA-N); ii) group submitted to inhibitory avoidance training session (IA-Y); iii) group submitted to inhibitory avoidance reactivation session but did not step down from the platform (IAR-N); and iv) group submitted to avoidance reactivation session and stepped down from the platform (IAR-Y). Elemental concentration and distribution in the CA1 hippocampus region were obtained through the Particle-Induced X-ray Emission (PIXE) technique. The results indicate that the concentration of Mg, P, Cl, K and Cu increased during memory consolidation. During the memory reconsolidation process, the concentrations of Mg, P, Cl and K increased, while Cu and Zn had no significant changes with respect to their basal condition. These results show that the major part of these elements may be engaged in memory consolidation could be also participating in memory reconsolidation. For all elements, the general trend related to their concentration did not change during reconsolidation regardless the presence of a novelty event, i.e. stepping down from the platform.



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Does extensive agriculture influence the concentration of trace elements in the aquatic plant Veronica anagallis-aquatica?

Publication date: 15 April 2018
Source:Ecotoxicology and Environmental Safety, Volume 150
Author(s): Ana Kroflič, Mateja Germ, Aleksandra Golob, Vekoslava Stibilj
The present study describes the influence of extensive agriculture on the concentrations of As, Cr, Cu, Cd, Se, Pb and Zn in sediments and in the aquatic plant Veronica anagallis-aquatica. The investigation, spanning 4 years, was conducted on three watercourses in Slovenia (Pšata, Lipsenjščica and Žerovniščica) flowing through agricultural areas. The different sampling sites were chosen on the basis of the presence of different activities in these regions: dairy farming, stock raising and extensive agriculture. The concentrations of the selected elements in sediments and V. anagallis-aquatica were below the literature background values. The distribution of the selected elements among different plant parts (roots, stems and leaves) were also investigated. The majority of the studied elements, with the exception of Zn and Cu, were accumulated mainly in root tissues.



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Synthesis, characterization, and functional properties of chlorophylls, pheophytins, and Zn-pheophytins

Publication date: 15 April 2018
Source:Food Chemistry, Volume 245
Author(s): Yu-Ra Kang, Joon Park, Sung Keun Jung, Yoon Hyuk Chang
The aims of this study were to synthesize chlorophyll derivatives, pheophytins and Zn-pheophytins, from chlorophylls extracted from spinach, characterize them, and evaluate their antioxidant and anti-inflammatory activities. The chlorophylls isolated from spinach were identified by means of FT-IR and NMR spectroscopies. The synthesis of pheophytins and Zn-pheophytins was confirmed by UV–Vis spectral analyses. The antioxidant activity of chlorophylls, pheophytins, and Zn-pheophytins was studied. The results revealed that the Zn-pheophytins showed the highest 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and β-carotene bleaching activities, followed by chlorophylls and pheophytins. Additionally, Zn-pheophytins showed substantial inhibitory activity against lipopolysaccharide (LPS)-induced NO production in RAW 264.7 cells. Furthermore, Zn-pheophytins remarkably suppressed LPS-induced expression of inducible nitric oxide synthase (iNOS) in RAW 264.7 cells and showed no cytotoxicity. Our findings indicated that Zn-pheophytins have strong antioxidant and anti-inflammatory properties and can therefore be a potential source of bioactive compounds for nutraceutical, cosmetic, and pharmaceutical applications.

Graphical abstract

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Testosterone deficiency prevents left ventricular contractility dysfunction after myocardial infarction

Publication date: 15 January 2018
Source:Molecular and Cellular Endocrinology, Volume 460
Author(s): R.F. Ribeiro Júnior, K.S. Ronconi, I.C.G. Jesus, P.W.M. Almeida, L. Forechi, D.V. Vassallo, S. Guatimosim, I. Stefanon, A.A. Fernandes
Testosterone may affect myocardial contractility since its deficiency decreases the contraction and relaxation of the heart. Meanwhile, testosterone replacement therapy has raised concerns because it may worsen cardiac dysfunction and remodeling after myocardial infarction (MI). In this study, we evaluate cardiac contractility 60 days after MI in rats with suppressed testosterone. Male Wistar rats underwent bilateral orchidectomy one week before the ligation of the anterior descending left coronary artery. The animals were divided into orchidectomized (OCT); MI; orchidectomized + MI (OCT + MI); orchidectomized + MI + testosterone (OCT + MI + T) and control (Sham) groups. Eight weeks after MI, papillary muscle contractility was analyzed under increasing calcium (0.62, 1.25, 2.5 and 3.75 mM) and isoproterenol (10⁻⁸ to 10⁻² M) concentrations. Ventricular myocytes were isolated for intracellular calcium measurements and assessment of Ca²⁺ handling proteins. Contractility was preserved in the orchidectomized animals after myocardial infarction and was reduced when testosterone was replaced (Ca²⁺ 3.75 mM: Sham: 608 ± 70 (n = 11); OCT: 590 ± 37 (n = 16); MI: 311 ± 33* (n = 9); OCT + MI: 594 ± 76 (n = 7); OCT + MI + T: 433 ± 38* (n=4), g/g *p < 0.05 vs Sham). Orchidectomy also increased the Ca²⁺ transient amplitude of the ventricular myocytes and SERCA-2a protein expression levels. PLB phosphorylation levels at Thr¹⁷ were not different in the orchidectomized animals compared to the Sham animals but were reduced after testosterone replacement. CAMKII phosphorylation and protein nitrosylation increased in the orchidectomized animals. Our results support the view that testosterone deficiency prevents MI contractility dysfunction by altering the key proteins involved in Ca²⁺ handling.



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Editorial Board

Publication date: 15 January 2018
Source:Molecular and Cellular Endocrinology, Volume 460





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Corrigendum to “Biglycan is a novel binding partner of fibroblast growth factor receptor 3c (FGFR3c) in the human testis” [Mol. Cell Endocrinol.] 399 (2015) 235-243

Publication date: 15 January 2018
Source:Molecular and Cellular Endocrinology, Volume 460
Author(s): S.B. Winge, J. Nielsen, A. Jorgensen, S. Owczarek, K.A. Ewen, J.E. Nielsen, A. Juul, V. Berezin, E. Rajpert-De Meyts




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Successful treatment of giant invasive cutaneous squamous cell carcinoma by plum-blossom needle assisted photodynamic therapy sequential with imiquimod: case experience

Publication date: Available online 19 December 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Peiru Wang, Linglin Zhang, Guolong Zhang, Zhongxia Zhou, Haiyan Zhang, Zijun Zhao, Lei Shi Xiuli Wang
Giant cutaneous squamous cell carcinoma (cSCC) in elderly people is difficult to treat. Herein, we report a case of 96-year-old male who was diagnosed to have giant facial invasive SCC (4cm*4.5cm*2 cm). He was successfully treated with plum-blossom needle assisted photodynamic therapy (PDT) sequential with imiquimod. The patient achieved complete remission after 9 sessions of PDT and 3 months of imiquimod but developed residual vitiligo-like hypopigmentation. There was no recurrence at 18 months of follow-up. This case suggests that plum-blossom needle pretreated PDT sequential by topical imiquimod is a viable treatment option for refractory and giant thick SCC.



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Point-of-Care Ultrasound Diagnosis of Proximal Hamstring Rupture

Publication date: Available online 18 December 2017
Source:The Journal of Emergency Medicine
Author(s): Rachel R. Bengtzen, O. John Ma, Andrea Herzka
BackgroundAcute proximal hamstring ruptures can be a diagnostic challenge in the emergency department. The revealing sign of large posterior thigh ecchymosis is typically not yet present; the physical examination is limited due to pain, radiographs can be unremarkable, and definitive testing with magnetic resonance imaging is not practical. These avulsions are often misdiagnosed as hamstring strains and treated conservatively. The diagnosis is made after failed treatment, often months after the injury. Surgical repair at that time can be technically challenging and higher risk due to tendon retraction and adhesion of the tendon stump to the sciatic nerve.Case ReportsThe first case illustrates an example of how delay in diagnosis can occur in both emergency medicine and outpatient primary care settings. It also shows complications and morbidity potential for patients who warrant and do not receive timely surgical repair. The second case illustrates physical examination findings obtainable during the acute setting, and the use of point-of-care ultrasound (POCUS) in facilitating an expedited diagnosis and treatment plan.Why Should an Emergency Physician Be Aware of This?Timely diagnosis of hamstring rupture is paramount to optimize patient outcomes for this serious injury. The best results are obtained with surgical repair within 3–6 weeks of injury. POCUS evaluation can aid significantly in the timely diagnosis of this injury. If the POCUS examination raises clinical concern for a proximal hamstring rupture, this may allow for earlier diagnosis and definitive treatment of proximal hamstring rupture.



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Hypovolemic Shock Caused by Angiotensin-Converting Enzyme Inhibitor-Induced Visceral Angioedema: A Case Series and A Simple Method to Diagnose this Complication in the Emergency Department

Publication date: Available online 18 December 2017
Source:The Journal of Emergency Medicine
Author(s): Joseph Myslinski, Andrew Heiser, Ashley Kinney
BackgroundVisceral angioedema is a rarely reported side effect of angiotensin-converting-enzyme inhibitors (ACEI). Because signs and symptoms tend to be nonspecific, the diagnosis is difficult to make, especially in the emergency department (ED).Case ReportWe describe 2 patients presenting with signs of hypovolemic shock, in which the diagnosis of ACEI-induced visceral angioedema was made in the ED. We surmise that patients with abdominal pain, who present with hypovolemic shock and are taking medications that can predispose to angioedema, may have this complication if their hemoglobin level is elevated compared with their previous levels. An abdominal computed tomography scan, if it does not identify any other significant etiology, will increase the probability that ACEI-induced visceral angioedema is the diagnosis when there is nonspecific bowel wall thickening or edema.Why Should an Emergency Physician Be Aware of This?Identification of ACEI-induced visceral angioedema in the ED will avoid prolonged admissions, unnecessary procedures, and future recurrences.



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Normal Anal Examination After Penetration: A Case Report

Publication date: Available online 18 December 2017
Source:The Journal of Emergency Medicine
Author(s): Brett Slingsby, Amy Goldberg
BackgroundPhysical findings are rare after anal penetration. Furthermore, children delay in disclosing or are reticent to discuss penetration.Case ReportA 12-year-old boy presented to medical care multiple times over a several-week period complaining of abdominal pain, bloody diarrhea, and poor appetite. On colonoscopy, he was found to have a cylindrical foreign body (measuring 7 cm tall and 7 cm in diameter) in his rectum, which had been present for at least 2 weeks. He initially denied knowing how the object got into his rectum and later stated that he inserted it himself out of curiosity. One week after the object was removed, follow-up examination using video colposcopy revealed a completely normal anal examination; the patient had a normal anal examination despite known anal penetration and removal of the object.Why Should an Emergency Physician Be Aware of This?Children can have a normal anal examination despite anal penetration, and do not always disclose anal penetration. The aforementioned concepts can be applied to situations related to child sexual abuse in the emergency department, where physical examinations are frequently normal and children delay in disclosing the abuse. When there is concern for sexual abuse, even in the absence of a disclosure or examination findings, patients should be referred for a child abuse pediatrics evaluation if available.



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Intravenous Flecainide for Emergency Department Management of Acute Atrial Fibrillation

Publication date: Available online 18 December 2017
Source:The Journal of Emergency Medicine
Author(s): Gerard C. Markey, Nigel Salter, John Ryan
BackgroundAtrial fibrillation (AF) is the most commonly encountered dysrhythmia in the emergency department, and its prevalence is increasing. A substantial proportion of these patients have recent-onset AF (<48 h). The poor prognosis associated with AF is being increasingly recognized, and there is some evidence for better outcomes in younger patients with recent-onset AF when sinus rhythm is restored. Flecainide is recommended in the latest international guidelines for cardioversion of recent-onset AF, but its safety and efficacy relative to other recommended agents are unclear.ObjectiveOur aim was to clarify the Level 1 evidence for the use of i.v. flecainide in acute AF.MethodsWe performed a systematic review and meta-analysis of the literature. Medline, Ovid, Embase, and Cochrane Central databases were searched for relevant studies. Only randomized controlled trials (RCTs) of i.v. flecainide for acute conversion of recent-onset AF were selected for meta-analysis.ResultsFour hundred and three studies were screened, of which 11 RCTs were eligible for meta-analysis. Flecainide had high efficacy for cardioversion within 2 h (number needed to treat [NNT] = 1.8). Efficacy was superior to propafenone, amiodarone, procainamide, ibutilide, and sotalol (NNT = 4.3). There was no statistically significant difference in pro-dysrhythmia compared to these anti-dysrhythmics or placebo.ConclusionsIntravenous flecainide cardioversion could be a safe and effective option for emergency physicians to restore sinus rhythm in selected patients with acute AF.



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Evolution of Survival in Cardiac Arrest with Age in Elderly Patients: Is Resuscitation a Dead End?

Publication date: Available online 19 December 2017
Source:The Journal of Emergency Medicine
Author(s): Nicolas Segal, Christophe di Pompéo, Joséphine Escutnaire, Eric Wiel, Cyrielle Dumont, Laurent Castra, Karim Tazarourte, Carlos El Khoury, Pierre-Yves Gueugniaud, Hervé Hubert
BackgroundEven if age is not considered the key prognostic factor for survival in cardiac arrest (CA), some studies question whether cardiopulmonary resuscitation (CPR) in the elderly could be futile.ObjectiveThe aim of this study was to describe differences in out-of-hospital CA survival rates according to age stratification based on the French National CA registry (RéAC). The second objective was to analyze the differences in resuscitation interventions according to age.MethodsWe performed a retrospective cohort study based on data extracted from the RéAC. All 18,249 elderly patients (>65 years old) with non-traumatic CA recorded between July 2011 and March 2015 were included. Patients' ages were stratified into 5-year increments.ResultsCardiopulmonary resuscitation (CPR) was started significantly more often in younger patients (p = 0.019). Ventilation and automated external defibrillation by bystanders were started without any difference between age subgroups (p = 0.147 and p = 0.123, respectively). No difference in terms of rate of external chest compressions or ventilation initiation was found between the subgroups (p = 0.357 and p = 0.131, respectively). Advanced cardiac life support was started significantly more often in younger patients (p = 0.023). Total CPR duration, return of spontaneous circulation, and survival at hospital admission and at 30 days or hospital discharge decreased significantly with age (p < 10⁻³). The survival decrease was linear, with a loss of 3% survival chances each 5-year interval.ConclusionsThis study found that survival in older persons decreased linearly by 3% every 5 years. However, this diminished rate of survival could be the consequence of a shorter duration and less advanced life support.



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Diagnosis of Simultaneous Acute Ruptures of the Anterior Cruciate Ligament and Posterior Cruciate Ligament Using Point-Of-Care Ultrasound in the Emergency Department

Publication date: Available online 18 December 2017
Source:The Journal of Emergency Medicine
Author(s): Sun Hwa Lee, Seong Jong Yun
BackgroundPatients with acute anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) injuries from sport-related activities are frequently seen in the emergency department (ED). However, knee instability tests are known to show variable sensitivity and specificity. These tests would also have limited functionality in patients with severe pain and swelling in the knee.Case ReportA 19-year-old female judo player presented to the ED with severe left knee pain. She had abruptly twisted her left knee while she was shoulder-throwing her opponent. She complained of severe pain and refused physical examination of the knee injury; as a result, evaluation of knee instability could not be performed. However, a point-of-care ultrasound helped in making a prompt and accurate diagnosis of simultaneous, complete rupture and partial ruptures of the ACL and PCL, respectively. The ultrasound findings correlated well with the magnetic resonance imaging images in the assessment of the combined ACL-PCL ruptures. The patient underwent simultaneous arthroscopic ACL and PCL reconstruction with a hamstring tendon autograft and was discharged.Why Should an Emergency Physician Be Aware of This?Point-of-care ultrasound imaging of the knee in trauma patients may be helpful for diagnosis of ACL and PCL injuries by augmenting findings of physical examinations in patients with severe pain and swelling in the knee. Ultimately, it may lead to more accurate diagnosis and treatment plans in knee trauma patients.



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Emphysematous Esophagitis and Gastritis Due to Ingestion of Concentrated Hydrogen Peroxide

Publication date: Available online 18 December 2017
Source:The Journal of Emergency Medicine
Author(s): Kai Li, Daniel Shepherd, Craig G. Smollin




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Excessive fetal movements are a sign of fetal compromise which merits further examination

Publication date: February 2018
Source:Medical Hypotheses, Volume 111
Author(s): Alexander E.P. Heazell, Tomasina Stacey, Louise M. O'Brien, Edwin A. Mitchell, Jane Warland
Changes in fetal movement are associated with increased risk of stillbirth after 28 weeks of pregnancy. The majority of studies have focussed on maternal perception of reduced fetal movements, which is associated with stillbirth via placental dysfunction. Recent studies have also described an association between a single episode of excessive fetal movements and late stillbirth. We present a hypothesis that a sudden episode of excessive fetal activity indicates fetal compromise relating to underlying disturbance of the in utero environment, which if it persists can lead to fetal death. The origin of the excessive fetal movements is unknown; they may represent fetal seizures induced by asphyxia or infection, an attempt to release cord entanglement or a change in fetal behaviour (inducing signs of distress) in response to a noxious stimulus. It is also possible that an increase in maternal anxiety may lead to increased perception of fetal activity.Current evidence regarding excessive fetal movements is sparse; there is no clinical guidance regarding how reporting of this symptom might relate to a fetus at risk and which management might reduce the risk of subsequent stillbirth. This could be addressed by prospective observational studies of mothers presenting with excessive fetal movements which could both explore the underlying pathophysiology and determine which investigations could identify fetal compromise in this population. The presence of fetal seizures or umbilical cord entanglement could be evaluated at the time of presentation by cardiotocography and ultrasonography of the fetus and cord. Exposure to infection or noxious stimuli could be evaluated by maternal history and measurement of maternal blood for inflammatory markers or toxins. Maternal anxiety could be assessed by validated anxiety scores. Fetal outcome following excessive fetal movements can be recorded after birth. In addition, the presence of perinatal asphyxia can be assessed using Apgar scores, assessment of fetal acidaemia or measurement of stress-related factors in umbilical cord blood. The placenta and cord can be systematically examined for signs of hypoxia, infection or umbilical cord compression. Such studies would provide evidence regarding the underlying cause of excessive fetal movement and how this symptom might relate to in utero compromise and stillbirth. Ultimately, this approach will determine whether excessive fetal movements can be used alongside reduced fetal movements as a tool to reduce the perinatal mortality rate.



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