Brain mechanisms of visual long-term memory retrieval in primates

Publication date: Available online 30 June 2018
Source:Neuroscience Research
Author(s): Masaki Takeda
Memorizing events or objects and retrieving them from memory are essential for daily life. Historically, memory processing was studied in neuropsychology, in which patients provided us with insights into the brain mechanisms underlying memory. Psychological hypotheses about memory processing have been further investigated using neuroscience techniques, such as functional imaging and electrophysiology. In this article, I briefly summarize recent findings on multi-scale neural circuitry for memory at the scale of single neurons and cortical layers as well as inter-area and whole-brain interactions. The key idea which connects multi-scale neural circuits is how neuronal assemblies utilize the frequency of communication between neurons, cortical layers, and brain areas. Using findings and ideas from other cognitive function studies, I discuss the plausible communication between neurons involved in memory.



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Antioxidant and antitumor activities of Cr(III), Mn(II), Fe(III), Cd(II), Zn(II) and Hg(II) complexes containing a carbohydrazone ligand ending by 4-pyridyl ring

Publication date: 5 December 2018
Source:Journal of Molecular Structure, Volume 1173
Author(s): Ahmed Fetoh, Ola A. El-Gammal, Gaber M. Abu El-Reash
Cr(III), Mn(II), Fe(III), Cd(II), Zn(II) and Hg(II) complexes derived from carbohydrazone ligand were synthesized and characterized by spectroscopic methods, DFT calculations and TGA analysis. IR spectra together with DFT optimization revealed that the ligand uses its two (CN)azomthine in coordination with either Mn(II), Fe(III) or Zn(II) ions. While, Cd(II) and Hg(II) ions coordinates via the nitrogen atoms of the two pyridyl groups. On the other hand, the coordination takes place through the two (CN)azomthine and the (CO)carbonyl groups in Cr(III) complex. On the basis of the electronic spectra and as the magnetic measurements, an octahedral coordination geometry was proposed in case of Cr(III) and Fe(III) complexes and a tetrahedral geometry in case of Mn(II) complex. Kinetic and thermodynamic parameters of the isolated complexes were estimated using Coats-Redfern and Horowitz-Metzger models. The antioxidant (DDPH and ABTS methods), anti-hemolytic and cytotoxic activities of the compounds have been screened. The DDPH and ABTS antioxidant activity was investigated and indicated that Zn(II) complex exhibited the highest antioxidant activity. While, Fe(III) complex had significantly the same percentage of hemolysis as that of the positive control. With respect to antitumor activity, H2APEC and Zn(II) complex demonstrated the potent activity followed by Fe(III) complex.

Graphical abstract

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Fluorescence lifetime measurement excited with ultraviolet surface plasmon resonance

Publication date: 15 November 2018
Source:Optics Communications, Volume 427
Author(s): Taras Hanulia, Wataru Inami, Atsushi Ono, Yoshimasa Kawata
We present an application of surface plasmon resonance in the ultraviolet region (UV-SPR) to lifetime measurement of fluorescent materials. Surface plasmon resonance (SPR) has been used to enhance fluorescence intensity and UV-SPR is important in the analysis of organic and biomolecules, including proteins and DNA, because UV light can excite many kinds of fluorescent dyes simultaneously or autofluorescence of biological specimens without any stain process. We obtained 16 times improvement of signal-to-noise ratio in lifetime measurement. We demonstrated the fluorescence lifetime of anthracene and CdSe/ZnS quantum dots using UV-SPR. The shortened fluorescence lifetime excited with UV-SPR compare to lifetime exited without SPR was analyzed.



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Structural and chemical characterization of CdSe-ZnS core-shell quantum dots

Publication date: 1 November 2018
Source:Applied Surface Science, Volume 457
Author(s): N. Fernández-Delgado, M. Herrera, A.H. Tavabi, M. Luysberg, R.E. Dunin-Borkowski, P.J. Rodriguez-Cantó, R. Abargues, J.P. Martínez-Pastor, S.I. Molina
The structural and compositional properties of CdSe-ZnS core-shell quantum dots (QDs) with a sub-nm shell thickness are analyzed at the atomic scale using electron microscopy. QDs with both wurtzite and zinc blende crystal structures, as well as intermixing of the two structures and stacking faults, are observed. High-angle annular dark-field scanning transmission electron microscopy suggests the presence of a lower atomic number epitaxial shell of irregular thickness around a CdSe core. The presence of a shell is confirmed using energy dispersive X-ray spectroscopy. Despite the thickness irregularities, the optical properties of the particles, such as photoluminescence and quantum yield, show clear enhancement after growth of the ZnS shell.

Graphical abstract

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Interaction effects of chlorine and phosphorus on thermochemical behaviors of heavy metals during incineration of sulfur-rich textile dyeing sludge

Publication date: 1 November 2018
Source:Chemical Engineering Journal, Volume 351
Author(s): Jingyong Liu, Zhongxu Zhuo, Wuming Xie, Jiahong Kuo, Xingwen Lu, Musa Buyukada, Fatih Evrendilek
Sulfur (S)-rich textile dyeing sludge (TDSS) with different chlorine (Cl) and phosphorus (P) contents was incinerated at 900 °C to determine interaction effects of Cl and P on the distributions and transformations of the seven heavy metals (Ni, Pb, Cr, Cu, Zn, Mn, and Cd). The volatilizations of the heavy metals were adversely affected by the P addition. The Cl addition in low concentrations offset the negative effects of P on the Ni, Cr and Mn volatilizations. An interaction effect between Cl and P was found on the Pb and Cd volatilizations. Up to certain Cl and P concentrations, their synergistic effect restrained the Ni, Cu, Mn and Cr volatilizations but promoted the Zn volatilization. The addition of Cl/P in different ratios changed the distributions of Cu, Mn, Pb, and Cd. The addition of over 1% NH4Cl and NH4H2PO4 together decreased the residual fractions mainly transformed into oxidizable forms (6.5–19.7%) which in turn raised their potential toxicity and bioavailability. With the decreased Cl and S contents of the bottom ash, the volatilization rate of Cl was higher than that of S. The NH4H2PO4 addition increased the Ca content on the surface but decreased the Cl and S contents. S emissions were mainly in the forms of SO2, SO3, COS, CS2, and H2SO4, with Cl emission in the form of HCl. The increased P content was correlated with the Cl volatilization positively and the S volatilization negatively. The increased P content decreased the S volatilization by 11.2–17.0% with the addition of up to 1% Cl.



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Emerging functional markers for cancer stem cell-based therapies: Understanding signaling networks for targeting metastasis

Publication date: Available online 30 June 2018
Source:Seminars in Cancer Biology
Author(s): Stephan Marquardt, Manish Solanki, Alf Spitschak, Julio Vera, Brigitte M. Pützer
Metastasis is one of the most challenging issues in cancer patient management, and effective therapies to specifically target disease progression are missing, emphasizing the urgent need for developing novel antimetastatic therapeutics. Cancer stem cells (CSCs) gained fast attention as a minor population of highly malignant cells within liquid and solid tumors that are responsible for tumor onset, self-renewal, resistance to radio- and chemotherapies, and evasion of immune surveillance accelerating recurrence and metastasis. Recent progress in the identification of their phenotypic and molecular characteristics and interactions with the tumor microenvironment provides great potential for the development of CSC-based targeted therapies and radical improvement in metastasis prevention and cancer patient prognosis. Here, we report on newly uncovered signaling mechanisms controlling CSC's aggressiveness and treatment resistance, and CSC-specific agents and molecular therapeutics, some of which are currently under investigation in clinical trials, gearing towards decisive functional CSC intrinsic or surface markers. One special research focus rests upon subverted regulatory pathways such as insulin-like growth factor 1 receptor signaling and its interactors in metastasis-initiating cell populations directly related to the gain of stem cell- and EMT-associated properties, as well as key components of the E2F transcription factor network regulating metastatic progression, microenvironmental changes, and chemoresistance. In addition, the study provides insight into systems biology tools to establish complex molecular relationships behind the emergence of aggressive phenotypes from high-throughput data that rely on network-based analysis and their use to investigate immune escape mechanisms or predict clinical outcome-relevant CSC receptor signaling signatures. We further propose that customized vector technologies could drastically enhance systemic drug delivery to target sites, and summarize recent progress and remaining challenges. This review integrates available knowledge on CSC biology, computational modeling approaches, molecular targeting strategies, and delivery techniques to envision future clinical therapies designed to conquer metastasis-initiating cells.



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Patient-derived tumor organoids for prediction of cancer treatment response

Publication date: Available online 30 June 2018
Source:Seminars in Cancer Biology
Author(s): Peter W. Nagle, John Th. M. Plukker, Christina T. Muijs, Peter van Luijk, Robert P. Coppes
Cancer treatment, in particular radiotherapy and chemotherapy, is often hindered by an inherent resistance of cancer cells. Cancer stem cells in particular have previously been shown to be more resistant than other cells within a tumor and are thought repopulate the tumour after therapies. Therefore, it is of utmost importance to develop tools and techniques that can be used to study mechanisms of resistance of cancer stem cells as potential treatment targets. Organoids (and cancer-derived organoids), are three-dimensional tissue-resembling cellular clusters derived from tissue or tumor specific stem cells that mimic the in vivo (tumor) characteristics, as well as (tumor) cell heterogeneity. Cancer organoids may further enhance the in vitro and in vivo models that are currently available, improve our understanding of cancer stem cell resistance and can be used to develop novel cancer treatments by improved targeting of cancer stem cells. In this review, we compare organoids with the more traditional laboratory models, such as cell lines and xenografts, and review the literature of the current role of cancer organoids in determining treatment responses.



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Social Competence Treatment after Traumatic Brain Injury: A Multicenter, Randomized, Controlled Trial of Interactive Group Treatment versus Non-Interactive Treatment

Publication date: Available online 30 June 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Cynthia Harrison-Felix, Jody K. Newman, Lenore Hawley, Clare Morey, Jessica M. Ketchum, William C. Walker, Kathleen R. Bell, Scott R. Millis, Cynthia Braden, James Malec, Flora M. Hammond, C.B. Eagye, Laura Howe
ObjectiveTo evaluate the effectiveness of a replicable group treatment program for improving social competence after traumatic brain injury (TBI).DesignMulticenter randomized controlled trial comparing two methods of conducting a social competency skills program, an interactive group format versus a classroom lecture.SettingCommunity and Veteran rehabilitation centers.Participants179 civilian, military, and veteran adults with TBI and social competence difficulties, at least 6 months post-injury.Experimental InterventionThirteen weekly group interactive sessions (1.5 hours) with structured and facilitated group interactions to improve social competence.Alternative (Control) InterventionThirteen traditional classroom sessions using the same curriculum with brief supplemental individual sessions but without structured group interaction.Primary Outcome MeasureProfile of Pragmatic Impairment in Communication (PPIC), an objective behavioral rating of social communication impairments following TBI.Secondary OutcomesLaTrobe Communication Questionnaire (LCQ), Goal Attainment Scale (GAS), Satisfaction with Life Scale (SWLS), Post-Traumatic Stress Disorder Checklist – (PCL-C), Brief Symptom Inventory 18 (BSI-18), Scale of Perceived Social Self Efficacy (PSSE).ResultsSocial competence goals (GAS) were achieved and maintained for most participants regardless of treatment method. Significant improvements in the primary outcome (PPIC) and two of the secondary outcomes (LCQ and BSI) were seen immediately post-treatment and at 3 months post-treatment in the AT arm only, however these improvements were not significantly different between the GIST and AT arms. Similar trends were observed for PSSE and PCL-C.ConclusionsSocial competence skills improved for persons with TBI in both treatment conditions. The group interactive format was not found to be a superior method of treatment delivery in this study.



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A systematic critical appraisal of evidence-based clinical practice guidelines for the rehabilitation of children with moderate or severe acquired brain injury

Publication date: Available online 30 June 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Sarah Knight, Michael Takagi, Elizabeth Fisher, Vicki Anderson, Natasha A. Lannin, Emma Tavender, Adam Scheinberg
ObjectiveThe aim of this review was to critically appraise the quality of evidence-based clinical practice guidelines (CPGs) for the rehabilitation of children with moderate or severe acquired brain injury (ABI).Data SourcesA systematic search of MEDLINE, PsycINFO, Embase, CINAHL, and the Cochrane Library was conducted and an extensive website search of prominent professional rehabilitation society websites.Study SelectionCPGs were eligible for inclusion if they incorporated recommendation statements for inpatient and/or community rehabilitation for children with ABI and they were based on a systematic evidence search.Data ExtractionMethodological quality of eligible CPGs were appraised by three independent reviewers using the AGREE II instrument. Characteristics of eligible CPGs and strength of supporting evidence for included recommendations were extracted.Data Synthesis Of the nine included guidelines, two covered all ABIs, five focused specifically on traumatic brain injury (TBI) and two on stroke. Five of the CPGs were classified as High quality and four were of Average quality. In general, CPGs scored better for scope and purpose, rigor of development, and clarity of presentation. They scored most poorly in applicability, involvement of target users, and procedures for updating the guidelines. Inter-rater reliability for the AGREE II was generally high across domains. Very few of the 445 recommendations included across the nine CPGs were evidence-based.ConclusionsDespite variability in quality of the guideline development process, the included CPGs generally provided clear descriptions of their overall objectives, scope and purpose, employed systematic methods for searching, selecting and appraising research evidence, and produced unambiguous, clearly identifiable recommendations for children with ABI. Overall, existing CPGs focusing on rehabilitation for children with ABI are based on low quality evidence or expert consensus. Future work should focus on addressing the limitations of most of the current CPGs, particularly related to supporting implementation and integrating stakeholder involvement.



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Understanding health-related quality of life in caregivers of civilians and service members/veterans with traumatic brain injury: Reliability and validity data for the TBI-CareQOL measurement system

Publication date: Available online 30 June 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Noelle E. Carlozzi, Rael T. Lange, Louis M. French, Angelle M. Sander, Phillip A. Ianni, David S. Tulsky, Jennifer A. Miner, Michael A. Kallen, Tracey A. Brickell
ObjectivesTo establish the reliability and validity of the newly developed TBI-CareQOL patient reported outcomes measures in caregivers of civilians and service members/veterans (SMVs) with traumatic brain injury (TBI) so that they can be used with confidence in clinical research and practice.DesignComputer-based surveys delivered through an on-line data capture platform.Setting: Three TBI Model Systems rehabilitation hospitals, an academic medical center, and a military medical treatment facility.ParticipantsFive hundred and sixty caregivers of individuals with TBI; this included two different study samples: 344 caregivers of civilians with TBI and 216 caregivers of SMVs with TBI.InterventionNot ApplicableMain Outcome Measures5 TBI-CareQOL item banksResultsReliabilities for the TBI-CareQOL measures were excellent (all Cronbach's α > .88); three-week test-retest reliability ranged from .75 to .90 across the two samples. Convergent validity was supported by moderate to high associations among the TBI-CareQOL measures and moderate correlations between the TBI-CareQOL measures and other measures of health-related quality of life (HRQOL) and caregiver burden. Discriminant validity was supported by low correlations between the TBI-CareQOL measures and less-related constructs (e.g., caregiver satisfaction). Known groups validity was supported: caregivers of individuals that were low functioning had worse HRQOL than caregivers of high functioning individuals.ConclusionsResults provide psychometric support for the new TBI-CareQOL item banks. As such, these measures fill a significant gap in the caregiver literature where sensitive patient-reported outcomes (PRO) measures that capture changes in HRQOL are needed to detect improvements for interventions designed to assist family caregivers.



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Diagnostic and clinical utility of the GAD-2 for screening anxiety symptoms in individuals with multiple sclerosis

Publication date: Available online 30 June 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Abbey J. Hughes, Katherine M. Dunn, Trisha Chaffee, Jagriti (Jackie) Bhattarai, Meghan Beier
ObjectiveTo assess the diagnostic and clinical utility of the two-item Generalized Anxiety Disorder Scale (GAD-2) for screening anxiety symptoms in individuals with multiple sclerosis (MS).DesignCross-sectional.SettingUniversity-affiliated MS neurology and rehabilitation center.ParticipantsThe sample was comprised of 99 adults (ages 19 to 72; M = 46.2; SD = 13.0; 75% female) with a physician-confirmed MS diagnosis who were receiving care in a university-affiliated MS center. Disease durations ranged from 1 to 37 years (M = 10.7; SD = 8.4).InterventionsNot applicable.Main Outcome MeasuresParticipants completed the GAD-7 and GAD-2. Internal consistency was calculated for both measures. Area under the receiver operating characteristics curve (AUC), the 95% confidence interval for the AUC, and Youden's J were calculated to determine the optimal GAD-2 cut-off score for identifying clinically significant anxiety symptoms, as defined by the previously validated GAD-7 cut-off score of ≥ 8.ResultsInternal consistency was excellent for the GAD-7 (Cronbach α = .91) and acceptable for the GAD-2 (α = .77), and the measures were highly correlated (r = .94). The GAD-2 had excellent overall accuracy for identifying clinically significant anxiety symptoms (AUC = 0.97, 95% CI 0.94 – 1.00). A GAD-2 cut-off score of ≥ 3 provided an optimal balance of good sensitivity (0.87) and excellent specificity (0.92) for detecting clinically significant anxiety symptoms. Alternatively, a cut-off score of ≥ 2 provided excellent sensitivity (1.00) and fair specificity (0.76).ConclusionsThe GAD-2 is a clinically useful and psychometrically valid tool for screening anxiety symptoms in MS rehabilitation and neurology care settings. Importantly, this tool has the potential to identify individuals with MS who are at risk for anxiety disorders and who may benefit from rehabilitation psychology interventions to ultimately improve functioning and quality of life.



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Formation and nucleolytic processing of Cas9-induced DNA breaks in human cells quantified by droplet digital PCR

Publication date: Available online 30 June 2018
Source:DNA Repair
Author(s): Diego Dibitetto, Mattia La Monica, Matteo Ferrari, Federica Marini, Achille Pellicioli
Cas9 endonuclease from S. pyogenes is widely used to induce controlled double strand breaks (DSB) at desired genomic loci for gene editing. Here, we describe a droplet digital PCR (ddPCR) method to precisely quantify the kinetic of formation and 5′-end nucleolytic processing of Cas9-induced DSB in different human cells lines. Notably, DSB processing is a finely regulated process, which dictates the choice between non-homologous end joining (NHEJ) and homology directed repair (HDR). This step of DSB repair is also a relevant point to be taken into consideration to improve Cas9-mediated technology. Indeed, by this protocol, we show that processing of Cas9-induced DSB is impaired by CTIP or BRCA1 depletion, while it is accelerated after down-regulation of DNA-PKcs and 53BP1, two DSB repair key factors. In conclusion, the method we describe here can be used to study DSB repair mechanisms, with direct utility for molecularly optimising the knock-out/in outcomes in genome manipulation.

Graphical abstract

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Effect of Age on Biomaterial-mediated in situ Bone Tissue Regeneration

Publication date: Available online 30 June 2018
Source:Acta Biomaterialia
Author(s): Mengqian Liu, Manando Nakasaki, Yu-Ru Vernon Shih, Shyni Varghese
Emerging studies show the potential application of synthetic biomaterials that are intrinsically osteoconductive and osteoinductive as bone grafts to treat critical bone defects. Here, the biomaterial not only assists recruitment of endogenous cells, but also supports cellular activities relevant to bone tissue formation and function. While such biomaterial-mediated in situ tissue engineering is highly attractive, success of such an approach relies largely on the regenerative potential of the recruited cells, which is anticipated to vary with age. In this study, we investigated the effect of the age of the host on mineralized biomaterial-mediated bone tissue repair using critical-sized cranial defects as a model system. Mice of varying ages, 1-month-old (juvenile), 2-month-old (young-adult), 6-month-old (middle-aged), and 14-month-old (elderly), were used as recipients. Our results show that the bio-mineralized scaffolds support bone tissue formation by recruiting endogenous cells for all groups albeit with differences in an age-related manner. Analyses of bone tissue formation after 2 and 8 weeks post-treatment show low mineral deposition and reduced number of osteocalcin and tartrate-resistant acid phosphatase (TRAP)-expressing cells in elderly mice.Statement of signifcanceTissue engineering strategies that promote tissue repair through recruitment of endogenous cells will have a significant impact in regenerative medicine. Previous studies from our group has shown that biomineralized materials containing calcium phosphate minerals can contribute to neo-bone tissue through recruitment and activation of endogenous cells. In this study, we investigated the effect of age of the recipient on these biomaterial-mediated bone tissue repair. Our results show that the age of the recipient mouse had a significant impact on the quality and quantity of the engineered neo-bone tissues, in which delayed/compromised bone tissue formation was observed in older mice. These findings are in agreement with the clinical findings that the age of the patient is a key factor in bone repair.

Graphical abstract

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The response of pre-osteoblasts and osteoclasts to gallium containing mesoporous bioactive glasses

Publication date: Available online 30 June 2018
Source:Acta Biomaterialia
Author(s): N. Gómez-Cerezo, E. Verron, V. Montouillout, F. Fayon, P. Lagadec, J.M. Bouler, B. Bujoli, D. Arcos, M. Vallet-Regí
Mesoporous bioactive glasses (MBGs) in the system SiO2-CaO-P2O5-Ga2O3 have been synthesized by the evaporation induced self-assembly method and subsequent impregnation with Ga cations. Two different compositions have been prepared and the local environment of Ga(III) has been characterized using ²⁹Si, ⁷¹Ga and ³¹P NMR analysis, demonstrating that Ga(III) is efficiently incorporated as both, network former (GaO4 units) and network modifier (GaO6 units). In vitro bioactivity tests evidenced that Ga-containing MBGs retain their capability for nucleation and growth of an apatite-like layer in contact with a simulated body fluid with ion concentrations nearly equal to those of human blood plasma. Finally, in vitro cell culture tests evidenced that Ga incorporation results in a selective effect on osteoblasts and osteoclasts. Indeed, the presence of this element enhances the early differentiation towards osteoblast phenotype while disturbing osteoclastogenesis. Considering these results, Ga-doped MBGs might be proposed as bone substitutes, especially in osteoporosis scenarios.Statement of signifcanceOsteoporosis is the most prevalent bone disease affecting millions of patients every year. However, there is a lack of bone grafts specifically designed for the treatment of bone defects occurred because of osteoporotic fractures. The consequence is that osteoporotic bone defects are commonly treated with the same biomaterials intended for high quality bone tissue. In this work we have prepared mesoporous bioactive glasses doped with gallium, demonstrating osteoinductive capability by promoting the differentiation of pre-osteoblast toward osteoblasts and partial inhibition of osteoclastogenesis. Through a deep study of the local environment of gallium within the mesoporous matrix, this work shows that gallium release is not required to produce this effect on osteoblasts and osteoclasts. In this sense, the presence of this element at the surface of the mesoporous bioactive glasses would be enough to locally promote bone formation while reducing bone resorption.

Graphical abstract

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Mutation goals in the vitamin D receptor predicted by computational methods

Publication date: Available online 30 June 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Wanda Sicinska, Dominik Gront, Kamil Sicinski
The mechanism through which nuclear receptors respond differentially to structurally distinct agonists is a poorly understood process. We present a computational method that identifies nuclear receptor amino acids that are likely involved in biological responses triggered by ligand binding. The method involves tracing how structural changes spread from the ligand binding pocket to the sites on the receptor surface, which makes it a good tool for studying allosteric effects. We employ the method to the vitamin D receptor and verify that the identified amino acids are biologically relevant using a broad range of experimental data and a genome browser. We infer that surface vitamin D receptor residues K141, R252, I260, T280, T287 and L417 are likely involved in cell differentiation and antiproliferation, whereas P122, D149, K321, E353 and Q385 are linked to carcinogenesis.

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Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways

Publication date: Available online 30 June 2018
Source:Free Radical Biology and Medicine
Author(s): Xiangsheng Zhang, Qi Wu, Yue Lu, Jieru Wan, Haibin Dai, Xiaoming Zhou, Shengyin Lv, Xuemei Chen, Xin Zhang, Chunhua Hang, Jian Wang
Salvianolic acid B (SalB), a natural polyphenolic compound extracted from the herb of Salvia miltiorrhiza, possesses antioxidant and neuroprotective properties and has been shown to be beneficial for diseases that affect vasculature and cognitive function. Here we investigated the protective effects of SalB against subarachnoid hemorrhage (SAH)-induced oxidative damage, and the involvement of underlying molecular mechanisms. In a rat model of SAH, SalB inhibited SAH-induced oxidative damage. The reduction in oxidative damage was associated with suppressed reactive oxygen species generation; decreased lipid peroxidation; and increased glutathione peroxidase, glutathione, and superoxide dismutase activities. Concomitant with the suppressed oxidative stress, SalB significantly reduced neurologic impairment, brain edema, and neural cell apoptosis after SAH. Moreover, SalB dramatically induced nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and increased expression of heme oxygenase-1 and NADPH: quinine oxidoreductase-1. In a mouse model of SAH, Nrf2 knockout significantly reversed the antioxidant effects of SalB against SAH. Additionally, SalB activated sirtuin 1 (SIRT1) expression, whereas SIRT1-specific inhibitor sirtinol pretreatment significantly suppressed SalB-induced SIRT1 activation and Nrf2 expression. Sirtinol pretreatment also reversed the antioxidant and neuroprotective effects of SalB. In primary cultured cortical neurons, SalB suppressed oxidative damage, alleviated neuronal degeneration, and improved cell viability. These beneficial effects were associated with activation of the SIRT1 and Nrf2 signaling pathway and were reversed by sirtinol treatment. Taken together, these in vivo and in vitro findings suggest that SalB provides protection against SAH-triggered oxidative damage by upregulating the Nrf2 antioxidant signaling pathway, which may be modulated by SIRT1 activation.

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Sodium butyrate attenuates diabetes-induced aortic endothelial dysfunction via P300-mediated transcriptional activation of Nrf2

Publication date: Available online 30 June 2018
Source:Free Radical Biology and Medicine
Author(s): Junduo Wu, Ziping Jiang, Haina Zhang, Wenzhao Liang, Wenlin Huang, Huan Zhang, Ying Li, Zhaohui Wang, Junnan Wang, Ye Jia, Bin Liu, Hao Wu
Oxidative stress and inflammation are major contributors to diabetes-induced endothelial dysfunction which is the critical first step to the development of diabetic macrovascular complications. Nuclear factor erythroid 2-related factor 2 (NRF2) plays a key role in combating diabetes-induced oxidative stress and inflammation. Sodium butyrate (NaB) is an inhibitor of histone deacetylase (HDAC) and an activator of NRF2. However, NaB's effect on diabetes-induced aortic injury was unknown. It was also not known whether or to what extent NRF2 is required for both self-defense and NaB's protection in the diabetic aorta. Additionally, the mechanism by which NaB activates NRF2 was unclear. Therefore, C57BL/6 Nrf2 knockout (KO) and wild type (WT) mice were induced to diabetes by streptozotocin, and were treated in the presence or absence of NaB, for 20 weeks. The KO diabetic mice developed more severe aortic endothelial oxidative stress, inflammation and dysfunction, as compared with the WT diabetic mice. NaB significantly attenuated these effects in the WT, but not the KO, mice. In high glucose-treated aortic endothelial cells, NaB elevated Nrf2 mRNA and protein without facilitating NRF2 nuclear translocation, an effect distinct from that of sulforaphane. NaB inhibited HDAC activity, and increased occupancy of the transcription factor aryl hydrocarbon receptor and the co-activator P300 at the Nrf2 gene promoter. Further, the P300 inhibitor C646 completely abolished NaB's efficacies. Thus, NRF2 is required for both self-defense and NaB's protection against diabetes-induced aortic endothelial dysfunction. Other findings suggest that P300 mediates the transcriptional activation of Nrf2 by NaB.

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Impaired glutathione-related antioxidant defenses in the arterial tissue of diabetic patients

Publication date: Available online 30 June 2018
Source:Free Radical Biology and Medicine
Author(s): Domenico Lapenna, Giuliano Ciofani, Antonio Maria Calafiore, Francesco Cipollone, Ettore Porreca
We studied the specific enzymatic activities of selenium-dependent (GSH-Px) and -independent (GST-Px) glutathione peroxidase, glutathione reductase (GSSG-Red), and glutathione S-transferase (GST) in internal mammary arteries (IMArt) specimens obtained during coronary artery bypass surgery in 18 patients with type 2 diabetes mellitus as compared to 18 non-diabetic controls; vascular lipid peroxidation, namely fluorescent damage products of lipid peroxidation (FDPL) as 4-hydroxynonenal-related oxidative stress indicators, was also studied. Moreover, in other 16 diabetic patients and 16 controls, total glutathione (TGlut) was determined in IMArt specimens specifically homogenized in sulfosalycilic acid to prevent vascular GSH depletion. The activities of GSH-Px, GSSG-Red, and GST were significantly lower, and FDPL levels higher, in the arterial tissue of diabetic patients than in that of controls; GST-Px was undetectable. Such enzymatic activities were inversely correlated with vascular lipid peroxidation, highlighting their antioxidant role in the arterial tissue, as were HbA1c and FDPL levels with the enzymatic activities, suggesting that glycation, oxidant species and lipoperoxidation aldehydes may be involved in glutathione-related enzyme inactivation. Further, in the diabetic patients HbA1c was correlated directly with lipid peroxidation but inversely with TGlut of the arterial tissue. In the patients considered for vascular enzymatic activities and FDPL assay, 3/4-vessel coronary artery disease (CAD) as expression of atherosclerosis severity was present in 9 diabetic patients and in 3 controls. Notably, vascular glutathione-related enzymatic activities were significantly lower, and FDPL levels higher, in the 9 diabetic patients with 3/4-vessel CAD than in the 9 without, as well as in the total of 12 patients with 3/4-vessel CAD than in the total of 24 patients without. Moreover, vascular TGlut content was significantly lower in the diabetic than in the control patients. Three/4-vessel CAD was present in 6 diabetic patients and in 2 controls considered for determination of vascular Tglut content, which was significantly lower in the diabetic patients with 3/4-vessel CAD than in those without, as well in the total of 8 patients with 3/4-vessel CAD than in the total of 24 patients without. Thus, weakened glutathione-related antioxidant capacity and oxidative stress of the arterial tissue are associated with the severity of atherosclerosis. In conclusion, impaired glutathione-related antioxidant defenses of the arterial tissue occur in diabetic patients, eventually favoring vascular oxidative stress and the severity of atherosclerosis.

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OXIDIZED PHOSPHOLIPID SIGNALING IN TRAUMATIC BRAIN INJURY

Publication date: Available online 30 June 2018
Source:Free Radical Biology and Medicine
Author(s): Tamil S. Anthonymuthu, Elizabeth M. Kenny, Andrew M. Lamade, Valerian E. Kagan, Hülya Bayır
Oxidative stress is a major contributor to secondary injury signaling cascades following traumatic brain injury (TBI). The role of lipid peroxidation in the pathophysiology of a traumatic insult to neural tissue is increasingly recognized. As the methods to quantify lipid peroxidation have gradually improved, so has the understanding of mechanistic details of lipid peroxidation and related signaling events in the injury pathogenesis. While free-radical mediated, non-enzymatic lipid peroxidation has long been studied, recent advances in redox lipidomics have demonstrated the significant contribution of enzymatic lipid peroxidation to TBI pathogenesis. Complex interactions between inflammation, phospholipid peroxidation, and hydrolysis define the engagement of different cell death programs and the severity of injury and outcome. This review focuses on enzymatic phospholipid peroxidation after TBI, including the mechanism of production, signaling roles in secondary injury pathology, and temporal course of production with respect to inflammatory response. In light of the newly identified phospholipid oxidation mechanisms, we also discuss possible therapeutic targets to improve neurocognitive outcome after TBI. Finally, we discuss current limitations in identifying oxidized phospholipids and possible methodologic improvements that can offer a deeper insight into the region-specific distribution and subcellular localization of phospholipid oxidation after TBI.

Graphical abstract

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Predictors of functional improvement in people with chronic low back pain following a graded Pilates-based exercise programme

Publication date: Available online 30 June 2018
Source:Journal of Bodywork and Movement Therapies
Author(s): Leyla Baillie, Catherine J. Bacon, Claire M. Hewitt, Robert W. Moran
BackgroundSeveral studies have investigated subgroups of patients with low back pain (LBP) most likely to benefit from Pilates or movement control exercises, but none have determined prognostic factors specifically for chronic LBP. This prospective cohort study aimed to determine predictors of change in disability in people with chronic LBP following a Pilates-based exercise programme and reports summarised integrated prediction statistics to aid clinical utility for determination of subgroups likely to benefit or not benefit from treatment.MethodsHealthy adults (n = 55) with non-specific chronic LBP undertook a graded 6-week programme involving two 1-hour Pilates sessions/week (1 mat and 1 equipment-based) led in small groups by a trained Pilates instructor. Predictors of change in Patient-Specific Functional Scale (PSFS) were identified through regression analysis and used to develop clinical prediction statistics.ResultsClinically important improvement (n = 14 of 48 analysed) was predicted by four variables: gradual rather than sudden onset of LBP, PSFS <3.7 points, absence of aberrant motions on forward bending, and body mass index >24.5 kg/m². Presence of ≥3 improved probability of success from 29% to 73%. Failure to improve (n = 18) was predicted by three variables: sudden onset of low back pain, patient-specific functional score ≥3.7, and difference between left and right active straight leg raise >7°. Presence of all three increased probability of failure from 38% to 80%.ConclusionsA combination of five, easily measured variables were able to predict disability outcome following a graded programme of Pilates-based exercises in people with chronic LBP. Two common movement deficits were inversely related to positive changes in function which may call into question the structural mechanism of improvements observed.Trial Registration[redacted for anonymous review]



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