Analytical Chemistry
DOI: 10.1021/acs.analchem.6b00082
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Παρασκευή 25 Μαρτίου 2016
Broad-Specificity Chemiluminescence Enzyme Immunoassay for (Fluoro)quinolones: Hapten Design and Molecular Modeling Study of Antibody Recognition
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Intending to forget is not easy: Behavioral and electrophysiological evidence
Source:International Journal of Psychophysiology
Author(s): Heming Gao, Bihua Cao, Qi Zhang, Mingming Qi, Fuhong Li, Hong Li
Previous researches have shown that recognition accuracy is lower for items cued to-be-forgotten (TBF) than to-be-remembered (TBR). Does directed forgetting help people forget more items than non-directed forgetting? Here, we modified the directed forgetting paradigm by adding a non-cue condition (NC). Consequently, non-directed forgetting would occur in NC. Behavioral results showed higher recognition accuracy for TBF than NC items, indicating that directed forgetting is less effective than non-directed forgetting. Electrophysiological results indicated that: (1) Remembered TBF items evoke an increased late positive component (LPC) than remembered NC items; (2) compared with remembered NC items, remembered TBF items showed a pronounced left-lateralized old/new effect and a reduced right-lateralized reversed old/new effect; (3) a right-lateralized reversed old/new effect was observed for forgotten TBF, but it was absent for forgotten NC items. These results demonstrate that the TBF items have a greater memory trace than the NC items. Forgetting cue has little effect of forgetting item from memory, and it might prompt subject to process or at least focus attention on the TBF items.
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Effectiveness of three pneumococcal conjugate vaccines (PCV) to prevent invasive pneumococcal disease in Quebec, Canada
Source:Vaccine, Volume 34, Issue 18
Author(s): Alejandro Cané, Bettina Hamelin, Raul Isturiz
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Role of microsatellite instability, immunohistochemistry and mismatch repair germline aberrations in immunosuppressed transplant patients: a phenocopy dilemma in Muir-Torre syndrome
Journal Name: Clinical Chemistry and Laboratory Medicine (CCLM)
Issue: Ahead of print
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Protein S100B: from cancer diagnostics to the evaluation of mild traumatic brain injury
Journal Name: Clinical Chemistry and Laboratory Medicine (CCLM)
Issue: Ahead of print
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Automated CH50 liposome-based immunoassay: consideration in dilution and validation of reference interval
Journal Name: Clinical Chemistry and Laboratory Medicine (CCLM)
Issue: Ahead of print
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Neutrophil Isolation and Analysis to Determine their Role in Lymphoma Cell Sensitivity to Therapeutic Agents
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A rare case of self-injection of elemental mercury
Self-injection of elemental mercury is a rare finding especially in healthy people who are mentally sound. Early detection and removal of mercury from the body by chelation and physical removal of a stored inj...
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Effectiveness of three pneumococcal conjugate vaccines to prevent invasive pneumococcal disease in Quebec, Canada
Source:Vaccine, Volume 34, Issue 18
Author(s): Philippe De Wals, Geneviève Deceuninck, Gaston De Serres
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Comparable immune responsiveness but increased reactogenicity after subcutaneous versus intramuscular administration of tick borne encephalitis (TBE) vaccine
Source:Vaccine, Volume 34, Issue 17
Author(s): Stefan Hopf, Erika Garner-Spitzer, Michael Hofer, Michael Kundi, Ursula Wiedermann
Evaluation of safety, immunogenicity and efficacy of vaccines during licensing studies is performed in relation to the selected vaccination route. For most adjuvanted vaccines, such as the TBE vaccine FSME-IMMUN, only intramuscular (i.m.) administration is licensed. Yet in certain situations, either because of medical indications, accidental application or due to a lack of sufficient muscular tissue, the vaccine might rather be applied subcutaneously (s.c.). With respect to the TBE vaccine there are currently however no data to support the use of the subcutaneous route of vaccination.In order to compare the reactogenicity and immune responsiveness upon i.m. and s.c. TBE vaccination 116 (58 females and 58 males) participants with a documented primary TBE vaccination course were randomized to receive either an i.m. or s.c. booster. Venous blood was collected before, 7 days, 1 month and 6 months after vaccination to determine antibody titer profiles. PBMC were isolated prior to and 7 days after booster to analyze lymphocyte subpopulations and cytokine production upon antigen restimulation. Subjects were monitored for the occurrence of side effects for 7 days post vaccination.Comparable levels of TBE specific neutralizing antibodies were induced after s.c. and i.m. vaccination. At the cellular level, IL-2, IFN gamma and IL-10 levels did not significantly differ using either route of vaccination and the distribution of T cell subsets was comparable along with a relative decrease of regulatory T-cells after both ways of administration.In contrast to the immunogenicity analyses, the data from safety diaries revealed a significantly higher rate of local, but not of systemic reactions after s.c. administration. In conclusion, this study demonstrates that both routes lead to comparable immune responses to the TBE antigen. The higher rate and intensity of local reactions, particularly among women, after s.c. vaccination however needs to be addressed during counseling.
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Current status of synthetic hemozoin adjuvant: A preliminary safety evaluation
Source:Vaccine, Volume 34, Issue 18
Author(s): Michelle Sue Jann Lee, Yoshikatsu Igari, Toshihiro Tsukui, Ken J. Ishii, Cevayir Coban
Although adjuvants are a "must-have" component of successful vaccines, there are very few adjuvants licensed for use in humans, there is therefore an urgent need to develop new and safer adjuvants. Synthetic hemozoin (sHZ), a chemical analog of hemozoin which is produced by the malaria parasite, exhibits a potent adjuvant effect which enhances antigen-specific immune responses to vaccines. The potency of sHZ adjuvanticity is not limited to malaria specific vaccines, it has also been demonstrated to be effective in influenza and dog allergy models. While the synthesis of uniformly sized sHZ with consistent characteristics has proven difficult, we have recently successfully optimized the manufacture of sHZ product with an optimal adjuvant effect. Here, we summarize recent developments on the adjuvant properties of optimized sHZ adjuvant, including its good laboratory practice (GLP) non-clinical safety profile in animals. These studies ensure the safety of optimized sHZ product to be readily used as vaccine adjuvant beforehand in veterinary medicine.
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Editorial Board/Aims and Scope
Source:Vaccine, Volume 34, Issue 18
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Hepatitis B vaccination uptake and correlates of serologic response among HIV-infected and uninfected men who have sex with men (MSM) in Bangkok, Thailand
Source:Vaccine, Volume 34, Issue 17
Author(s): Wannee Chonwattana, Boonyos Raengsakulrach, Timothy H. Holtz, Punneeporn Wasinrapee, Jaray Tongtoyai, Supaporn Chaikummao, Sarika Pattanasin, Janet M. McNicholl, Frits van Griensven, Marcel E. Curlin
BackgroundVaccination against hepatitis B virus (HBV) is recommended for all HBV-susceptible men who have sex with men (MSM). There is limited information on correlates of immunity to HBV vaccination in this group. We present serologic response rates to hepatitis B vaccine and identify factors associated with impaired response among HIV-uninfected and HIV-infected Thai MSM.MethodologyHBV-susceptible volunteers were offered hepatitis B vaccination at months zero, one, and six. We measured baseline (pre-vaccination) total serum IgG and IgG subclasses (all participants), baseline CD4 count, and plasma HIV-1 viral load (PVL) (HIV+ participants). HBV serologies were retested at 12 months. Serologic responses were compared between all groups in men receiving three vaccine doses.Results511/651 HIV-negative and 64/84 HIV-positive participants completed the three-dose series. Response rates in HIV-uninfected and -infected participants were 90.1% vs. 50.0% (p<0.0001). Median pre-vaccination IgG was higher among non-responders than responders overall (1238.9.0 vs. 1057.0mg/dL, p=0.003) and among HIV-infected participants (1534.0 vs. 1244.5mg/dL, p=0.005), but not significantly among HIV-uninfected participants (1105.5 vs. 1054.3mg/dL, p=0.96). Pre-vaccination IgG1 and IgG3 levels were higher among HIV-positive than HIV-negative participants (median 866.0 vs. 520.3, and 105.8 vs. 83.1mg/dL, respectively, p<0.0001). Among HIV-infected participants, median CD4 count in non-responders was 378 cells/μL vs. 431 cells/μL in responders (p=0.20). Median PVL in non-responders was 64,800 copies/mL vs. 15500 copies/mL in responders (p=0.04). Participants with pre-vaccination plasma IgG >1550mg/dL and PVL >10,000 copies/mL were almost always non-responsive (p<0.01).ConclusionsHIV infection was associated with poor vaccine responses. High plasma viral load, elevated pre-vaccination total serum IgG and elevated pre-vaccination IgG1 are associated with poorer response to vaccination among HIV-infected MSM. In this group, the combination of high PVL and pre-vaccination total IgG is highly predictive of vaccine failure.
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Monitoring the process of measles elimination by serosurveillance data: The Apulian 2012 study
Source:Vaccine, Volume 34, Issue 18
Author(s): S. Tafuri, M.S. Gallone, M.F. Gallone, M.T. Pappagallo, A. Larocca, C. Germinario
In 2003 Italy adopted the National Plan for Measles and Congenital Rubella Elimination, but some outbreaks of measles are still occurring, as the target coverage rate (≥95%) for new-borns has currently not been achieved.In order to support the monitoring of the measles elimination programme, the authors carried out a survey about the seroprevalence of measles among Apulia young adults.The study was carried out from May 2011 to June 2012 among blood donors of the Department of Transfusion Medicine of Policlinico General Hospital in Bari. Subjects were enrolled by a convenience sampling. For each enrolled patient we collected a 5mL serum sample. Collected sera were tested by chemiluminescence (CLIA) for anti-Measles IgG.We enrolled 1764 subjects; 1362 (77.2%) were male with a mean age of 38.4±11.7 years. Anti-Measles IgG titre was >16.5UA/mL in 95.1% (95% CI=94.1–96.1) of enrolled subjects with a Geometric Mean Titre (GMT) of 2.3±0.4, which did not differ dividing the enrolled subjects into age groups.As our data showed, the universal routine vaccination changed the epidemiological pattern among adults, in particular young adults (18–24 years), who showed lowest seropositivity rates; in these groups of population there is a risk of the onset of outbreaks due to the presence of susceptible population. This is a paradox linked to the vaccination strategy: when coverage rates keep sub-optimal, measles is more likely to affect young adults and a higher percentage of complications is expected. According to our data, health authorities have to plan a mop-up strategy to actively offer measles vaccination to susceptible young adults.
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Safety of classical swine fever virus vaccine strain LOM in pregnant sows and their offspring
Source:Vaccine, Volume 34, Issue 17
Author(s): Seong-In Lim, Jae-Young Song, Jaejo Kim, Bang-Hun Hyun, Ha-Young Kim, In-Soo Cho, Byounghan Kim, Gye-Hyeong Woo, Jung-Bok Lee, Dong-Jun An
The present study aimed to evaluate the safety of the classical swine fever virus (CSFV) vaccine strain LOM in pregnant sows. Pregnant sows with free CSFV antibody were inoculated with a commercial LOM vaccine during early pregnancy (day 38; n=3) or mid-pregnancy (days 49–59; n=11). In pregnant sows vaccinated during the early stages of gestation, abortion (day 109) was observed in one case, with two stillbirths and seven mummified fetuses. The viability of live-born piglets was 34.9% in sows vaccinated during mid-pregnancy compared with 81.8% in the control group. Post-mortem examination of the organs of the sows and piglets did not reveal any pathological lesions caused by CSFV; however, CSFV RNA was detected in the organs of several vaccinated sows and their litters. The LOM strain was transmitted from sows with free CSFV antibody to their fetus, but did not appear to induce immune tolerance in the offspring from vaccinated pregnant sows. Side effects were not observed in pregnant sows with antibody to the LOM strain: transmission from sow to their litters and stillbirth or mummified fetuses. The LOM strain may induce sterile immunity and provide rapid, long-lasting, and complete protection against CSFV; however, it should be contraindicated in pregnant sows due to potential adverse effects in pregnant sows with free CSFV antibody.
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Effect of different detoxification procedures on the residual pertussis toxin activities in vaccines
Source:Vaccine, Volume 34, Issue 18
Author(s): Chun-Ting Yuen, Catpagavalli Asokanathan, Sarah Cook, Naomi Lin, Dorothy Xing
Pertussis toxin (PTx) is a major virulence factor produced by Bordetella pertussis and its detoxified form is one of the major protective antigens in vaccines against whooping cough. Ideally, PTx in the vaccine should be completely detoxified while still preserving immunogenicity. However, this may not always be the case. Due to multilevel reaction mechanisms of chemical detoxification that act on different molecular sites and with different production processes, it is difficult to define a molecular characteristic of a pertussis toxoid. PTx has two functional distinctive domains: the ADP-ribosyltransferase enzymatic subunit S1 (A-protomer) and the host cell binding carbohydrate-binding subunits S2–5 (B-oligomer); and in this study, we investigated the effect of different detoxification processes on these two functional activities of the residual PTx in toxoids and vaccines currently marketed worldwide using a recently developed in vitro biochemical assay system. The patho-physiological activities in these samples were also estimated using the in vivo official histamine sensitisation tests. Different types of vaccines, detoxified by formaldehyde, glutaraldehyde or by both, have different residual functional and individual baseline activities. Of the vaccines tested, PT toxoid detoxified by formaldehyde had the lowest residual PTx ADP-ribosyltransferase activity. The carbohydrate binding results detected by anti-PTx polyclonal (pAb) and anti-PTx subunits monoclonal antibodies (mAb) showed specific binding profiles for toxoids and vaccines produced from different detoxification methods. In addition, we also demonstrated that using pAb or mAb S2/3 as detection antibodies would give a better differential difference between these vaccine lots than using mAbs S1 or S4. In summary, we showed for the first time that by measuring the activities of the two functional domains of PTx, we could characterise pertussis toxoids prepared from different chemical detoxification methods and this study also highlights the potential use of this in vitro biochemical assay system for in-process control.
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An adenoviral cancer vaccine co-encoding a tumor associated antigen together with secreted 4-1BBL leads to delayed tumor progression
Source:Vaccine, Volume 34, Issue 18
Author(s): Emeline Ragonnaud, Anne-Marie C. Andersson, Anders Elm Pedersen, Henriette Laursen, Peter J. Holst
Previous studies have shown promising results when using an agonistic anti-4-1BB antibody treatment against established tumors. While this is promising, this type of treatment can induce severe side effects. Therefore, we decided to incorporate the membrane form of 4-1BB ligand (4-1BBL) in a replicative deficient adenovirus vaccine expressing the invariant chain (Ii) adjuvant fused to a tumor associated antigen (TAA). The Ii adjuvant increases and prolongs TAA specific CD8+ T cells as previously shown and local expression of 4-1BBL was chosen to avoid the toxicity associated with systemic antibody administration. Furthermore, adenovirus encoded 4-1BBL expression has previously been successfully used to enhance responses toward Plasmodium falciparum and Influenza A antigens. We showed that the incorporation of 4-1BBL in the adenovirus vector led to surface expression of 4-1BBL on antigen presenting cells, but it did not enhance T cell responses in mice towards the Ii linked antigen. In tumor-bearing mice, our vaccine was found to decrease the frequency of TAA specific CD8+ T cells, but this difference did not alter the therapeutic efficacy. In order to reconcile our findings with the previous reports of increased anti-cancer efficacy using systemically delivered 4-1BB agonists, we incorporated a secreted version of 4-1BBL (Fc-4-1BBL) in our vaccine and co-expressed it with the Ii linked to TAA. In tumor bearing mice, this vaccine initially delayed tumor growth and slightly increased survival compared to the vaccine expressing the membrane form of 4-1BBL. Accordingly, secreted 4-1BBL co-encoded with the Ii linked antigen may offer a simplification compared to administration of drug and vaccine separately.
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Editorial Board/Aims and Scope
Source:Vaccine, Volume 34, Issue 17
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Response to Bogaert
Source:Vaccine, Volume 34, Issue 17
Author(s): G. Dennis Shanks, John F. Brundage
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Reply to Brundage and Shanks
Source:Vaccine, Volume 34, Issue 17
Author(s): Kandace L. Bogaert
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Use of allicin as feed additive to enhance vaccination capacity of Clostridium perfringens toxoid in rabbits
Publication date: 12 April 2016
Source:Vaccine, Volume 34, Issue 17
Author(s): Waleed Abu El Hammed, Hamdy Soufy, Ahmed El-Shemy, Soad M. Nasr, Mohamed I. Dessouky
The present study assessed the efficacy of Clostridium perfringens (C. perfringens) toxoid and/or allicin – as feed additive – in rabbits for preventing or minimizing the severity of infection with locally isolated strain of C. perfringens type A. Serum biochemical, immunological and pathological investigations were also done. One hundred rabbits of 6 weeks of age were divided into five equal groups (G1–G5). G1 were kept as normal control. G2 was allocated for C. perfringens type A infection. G3 was vaccinated with C. perfringens toxoid at zero time and then with a booster dose at the 3rd week of the experimental period. G4 was treated with allicin 20% added to the ration (200mg/kg ration) all over the experimental period. G5 was vaccinated with C. perfringens toxoid at the zero time then with a booster dose at the 3rd week of the experiment period, and treated with allicin 20% from the zero time till the end of the experiment. At the 4th week, G2, G3, G4 and G5 were challenged orally (5ml) and subcutaneously (2ml) with 24h cooked meat broth containing 1×107colony-forming units/ml of C. perfringens type A strain. Blood and tissue samples were collected from all groups post-vaccination then post-challenge for biochemical analysis, serum neutralization test and histopathological examinations. Results revealed that rabbits treated with both allicin and toxoid vaccine demonstrated high level of antitoxin titre post-challenge, improved liver and kidney functions, and reduced morbidity and mortality rates and the severity of histopathological changes associated with challenge of rabbits with C. perfringens type A strain. In conclusion, vaccination of rabbits with C. perfringens toxoid combined with allicin 20% gave better protection, enhanced immune response and had no adverse effects on the general health conditions against C. perfringens type A infection compared to rabbits vaccinated with C. perfringens toxoid only.
Graphical abstract
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Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection
Source:Vaccine, Volume 34, Issue 17
Author(s): Oi-Wing Ng, Adeline Chia, Anthony T. Tan, Ramesh S. Jadi, Hoe Nam Leong, Antonio Bertoletti, Yee-Joo Tan
Severe acute respiratory syndrome (SARS) is a highly contagious infectious disease which first emerged in late 2002, caused by a then novel human coronavirus, SARS coronavirus (SARS-CoV). The virus is believed to have originated from bats and transmitted to human through intermediate animals such as civet cats. The re-emergence of SARS-CoV remains a valid concern due to the continual persistence of zoonotic SARS-CoVs and SARS-like CoVs (SL-CoVs) in bat reservoirs. In this study, the screening for the presence of SARS-specific T cells in a cohort of three SARS-recovered individuals at 9 and 11 years post-infection was carried out, and all memory T cell responses detected target the SARS-CoV structural proteins. Two CD8+ T cell responses targeting the SARS-CoV membrane (M) and nucleocapsid (N) proteins were characterized by determining their HLA restriction and minimal T cell epitope regions. Furthermore, these responses were found to persist up to 11 years post-infection. An absence of cross-reactivity of these CD8+ T cell responses against the newly-emerged Middle East respiratory syndrome coronavirus (MERS-CoV) was also demonstrated. The knowledge of the persistence of SARS-specific celullar immunity targeting the viral structural proteins in SARS-recovered individuals is important in the design and development of SARS vaccines, which are currently unavailable.
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Dementia and Physical Activity (DAPA) - an exercise intervention to improve cognition in people with mild to moderate dementia: study protocol for a randomized controlled trial
Dementia is more common in older than in younger people, and as a result of the ageing of the population in developed countries, it is becoming more prevalent. Drug treatments for dementia are limited, and the...
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The use of paclitaxel coated balloon (PCB) in acute coronary syndrome of small vessel de novo lesions: an analysis of a prospective ‘real world’ registry
Paclitaxel-coated balloon (PCB) angioplasty in small vessel de novo lesions has favourable outcome and appears to be an alternative to stent implantation. However there is limitted data on its use specifically...
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A Karnaugh map based approach towards systemic reviews and meta-analysis
Studying meta-analysis and systemic reviews since long had helped us conclude numerous parallel or conflicting studies. Existing studies are presented in tabulated forms which contain appropriate information f...
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The administration of high-dose propofol sedation with manual and target-controlled infusion in children undergoing radiation therapy: a 7-year clinical investigation
Radiation therapy requires the patient to remain immobile for a long time, which is challenging in children. This study therefore aimed to determine the adequate target concentration and dosage of propofol in ...
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Field homogeneity improvement of maglev NdFeB magnetic rails from joints
An ideal magnetic rail should provide a homogeneous magnetic field along the longitudinal direction to guarantee the reliable friction-free operation of high temperature superconducting (HTS) maglev vehicles. ...
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Differential inequalities imposed by the extended hypergeometric function
Recently, the generalized hypergeometric function is extended by utilizing the Beta function. Based on this type of function, we introduce a new operator in the open unit disk. The present article investigates...
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Supramolecular Affinity Chromatography for Methylation-Targeted Proteomics
Analytical Chemistry
DOI: 10.1021/acs.analchem.5b04508
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Promising effects of treatment with flotation-REST (restricted environmental stimulation technique) as an intervention for generalized anxiety disorder (GAD): a randomized controlled pilot trial
During Flotation-REST a person is floating inside a quiet and dark tank, filled with heated salt saturated water. Deep relaxation and beneficial effects on e.g. stress, sleep difficulties, anxiety and depressi...
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Immune thrombocytopenia after bee venom therapy: a case report
Immune thrombocytopenia (ITP) is a hematological disorder with an isolated decrease in number of circulating platelets. Bee venom therapy (BVT) is a form of alternative medicine. It is still being practiced in...
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Imaging CD4 T Cell Interstitial Migration in the Inflamed Dermis
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Induction of Maternal Immune Activation in Mice at Mid-gestation Stage with Viral Mimic Poly(I:C)
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Synthesis, and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids
Publication date: 15 April 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8
Author(s): Jolanta Obniska, Anna Rapacz, Sabina Rybka, Małgorzata Góra, Krzysztof Kamiński, Kinga Sałat, Paweł Żmudzki
This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50=32.08mg/kg, MES test) and 9 (ED50=40.34mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action.
Graphical abstract
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1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists
Publication date: 15 April 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8
Author(s): Fabrizio Micheli, Andrea Bernardelli, Federica Bianchi, Simone Braggio, Laura Castelletti, Palmina Cavallini, Paolo Cavanni, Susanna Cremonesi, Michele Dal Cin, Aldo Feriani, Beatrice Oliosi, Teresa Semeraro, Luca Tarsi, Silvia Tomelleri, Andrea Wong, Filippo Visentini, Laura Zonzini, Christian Heidbreder
A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.
Graphical abstract
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Novel nicotine analogues with potential anti-mycobacterial activity
Publication date: 15 April 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8
Author(s): Paresh T. Gandhi, Thimmasandra Narayanappa Athmaram, Gundaiah Ramesh Arunkumar
Tuberculosis (TB) is the second leading lethal infectious disease in the world after acquired immuno deficiency (AIDs). We have developed a series of twenty-five novel nicotine analogues with de-addiction property and tested them for their activity against Mycobacterium tuberculosis (MTB). In an effort to increase the specificity of action and directing nicotine analogues to target MTB, four promising compounds were further optimized via molecular docking studies against the Dihydrofolate reductase of MTB. After lead optimization, one nicotine analogue [3-(5-(3fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one] exhibited minimum inhibitory concentration of 1μg/mL (2.86nM) against M. tuberculosis (H37Rv strain), a human pathogenic strain of clinically significant importance. Pharmacokinetic analysis of [3-(5-(3fluorophenyl)nicotinoyl)-1methylpyrrolidin-2-one] with lowest MIC value via oral route in Wistar rats revealed that at a dosage of 5mg/kg body weight gave a maximum serum drug concentration (Cmax) of 2.86μg/mL, Tmax of one hour and a half-life (T1/2) of more than 24h and Volume of distribution (Vd) of 27.36L. Whereas the parenteral (intra venous) route showed a Cmax of 3.37μg/mL, Tmax of 0.05h, T1/2 of 24h and Vd equivalent to 23.18L. The acute oral toxicity and repeated oral toxicity studies in female Wistar rats had an LD50>2000mg/kg body weight. Our data suggests that nicotine derivatives developed in the present study has good metabolic stability with tunable pharmacokinetics (PK) with therapeutic potential to combat MTB. However, further in vivo studies for anti-tuberculosis activity and elucidation of mode of action could result in more promising novel drug for treating MTB. To the best of our knowledge this is the first report revealing the anti-mycobacterial potential of nicotine analogue at potential therapeutic concentrations.
Graphical abstract
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Editorial board
Publication date: 15 April 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8
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Isatin analogs as novel inhibitors of Candida spp. β-carbonic anhydrase enzymes
Publication date: 15 April 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8
Author(s): Atilla Akdemir, Özlen Güzel-Akdemir, Nilgün Karalı, Claudiu T. Supuran
Enzyme inhibition data of structurally novel isatin-containing sulfonamides were determined for two carbonic anhydrases (CAs, EC 4.2.1.1) from pathogenic Candida species (CaNce103 from C. albicans and CgNce103 from C. glabrata). The compounds show KI values in the low nanomolar range for the fungal CAs, while they have significantly higher KI values for the human CAs. Homology models were constructed for the CaNce103 and CgNce103 and subsequently the ligands were docked into these models to rationalize their enzyme inhibitory properties.
Graphical abstract
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Antiretroviral (HIV-1) activity of azulene derivatives
Publication date: 15 April 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8
Author(s): Julia Peet, Anastasia Selyutina, Aleksei Bredihhin
The antiretroviral activity of azulene derivatives was detected for the first time. A series of eighteen diversely substituted azulenes was synthesized and tested in vitro using HIV-1 based virus-like particles (VLPs) and infectious HIV-1 virus in U2OS and TZM-bl cell lines. Among the compounds tested, the 2-hydroxyazulenes demonstrated the most significant activity by inhibiting HIV-1 replication with IC50 of 2–10 and 8–20μM for the VLPs and the infectious virus, respectively. These results indicate that azulene derivatives may be potentially useful candidates for the development of antiretroviral agents.
Graphical abstract
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3D microwave tomography of the breast using prior anatomical information
Purpose:
The authors have developed a new 3D breast image reconstruction technique that utilizes the soft tissue spatial resolution of magnetic resonance imaging(MRI) and integrates the dielectric property differentiation from microwaveimaging to produce a dual modality approach with the goal of augmenting the specificity of MR imaging, possibly without the need for nonspecific contrast agents. The integration is performed through the application of a soft prior regularization which imports segmented geometric meshes generated from MR exams and uses it to constrain the microwave tomography algorithm to recover nearly uniform property distributions within segmented regions with sharp delineation between these internal subzones.
Methods:
Previous investigations have demonstrated that this approach is effective in 2D simulation and phantom experiments and also in clinical exams. The current study extends the algorithm to 3D and provides a thorough analysis of the sensitivity and robustness to misalignment errors in size and location between the spatial prior information and the actual data.
Results:
Image results in 3D were not strongly dependent on reconstruction mesh density, and the changes of less than 30% in recovered property values arose from variations of more than 125% in target region size—an outcome which was more robust than in 2D. Similarly, changes of less than 13% occurred in the 3Dimage results from variations in target location of nearly 90% of the inclusion size. Permittivity and conductivity errors were about 5 times and 2 times smaller, respectively, with the 3D spatial prior algorithm in actual phantom experiments than those which occurred without priors.
Conclusions:
The presented study confirms that the incorporation of structural information in the form of a soft constraint can considerably improve the accuracy of the property estimates in predefined regions of interest. These findings are encouraging and establish a strong foundation for using the soft prior technique in clinical studies, where their microwaveimaging system and MRI can simultaneously collect breast exam data in patients.
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Design, synthesis, topoisomerase I & II inhibitory activity, antiproliferative activity, and structure–activity relationship study of pyrazoline derivatives: An ATP-competitive human topoisomerase IIα catalytic inhibitor
Publication date: 15 April 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8
Author(s): Pervez Ahmad, Hyunjung Woo, Kyu-Yeon Jun, Adnan A. Kadi, Hatem A. Abdel-Aziz, Youngjoo Kwon, A.F.M. Motiur Rahman
A series of pyrazoline derivatives (5) were synthesized in 92–96% yields from chalcones (3) and hydrazides (4). Subsequently, topo-I and IIα-mediated relaxation and antiproliferative activity assays were evaluated for 5. Among the tested compounds, 5h had a very strong topo-I activity of 97% (Camptothecin, 74%) at concentration of 100μM. Nevertheless, all the compounds 5a–5i showed significant topo II inhibitory activity in the range of 90–94% (Etoposide, 96%) at the same concentration. Cytotoxic potential of these compounds was tested in a panel of three human tumor cell lines, HCT15, BT474 and T47D. All the compounds showed strong activity against HCT15 cell line with IC50 at the range of 1.9–10.4μM (Adriamycin, 23.0; Etoposide, 6.9; and Camptothecin, 7.1μM). Moreover, compounds 5c, 5f and 5i were observed to have strong antiproliferative activity against BT474 cell lines. Since, compound 5d showed antiproliferative activity at a very low IC50 thus 5d was then selected to study on their mode of action with diverse methods of ATP competition assay, ATPase assay and DNA-topo IIα cleavable complex assay and the results revealed that it functioned as a ATP-competitive human topoisomerase IIα catalytic inhibitor. Further evaluation of endogenous topo-mediated DNA relaxation in cells has been conducted to find that, 5d inhibited endogenous topo-mediated pBR322 plasmid relaxation is more efficient (78.0±4.7% at 50μM) than Etoposide (36.0±1.7% at 50μM).
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Technical Note: Cortical thickness and density estimation from clinical CT using a prior thickness-density relationship
Purpose:
Cortical thickness and density are critical components in determining the strength of bony structures. Computed tomography(CT) is one possible modality for analyzing the cortex in 3D. In this paper, a model-based approach for measuring the cortical bone thickness and density from clinical CTimages is proposed.
Methods:
Density variations across the cortex were modeled as a function of the cortical thickness and density, location of the cortex, density of surrounding tissues, and imaging blur. High resolution micro-CT data of cadaver proximal femurs were analyzed to determine a relationship between cortical thickness and density. This thickness-density relationship was used as prior information to be incorporated in the model to obtain accurate measurements of cortical thickness and density from clinical CT volumes. The method was validated using micro-CT scans of 23 cadaver proximal femurs. Simulated clinical CTimages with different voxel sizes were generated from the micro-CT data. Cortical thickness and density were estimated from the simulated images using the proposed method and compared with measurements obtained using the micro-CT images to evaluate the effect of voxel size on the accuracy of the method. Then, 19 of the 23 specimens were imaged using a clinical CT scanner. Cortical thickness and density were estimated from the clinical CTimages using the proposed method and compared with the micro-CT measurements. Finally, a case-control study including 20 patients with osteoporosis and 20 age-matched controls with normal bone density was performed to evaluate the proposed method in a clinical context.
Results:
Cortical thickness (density) estimation errors were 0.07 ± 0.19 mm (−18 ± 92 mg/cm3) using the simulated clinical CT volumes with the smallest voxel size (0.33 × 0.33 × 0.5 mm3), and 0.10 ± 0.24 mm (−10 ± 115 mg/cm3) using the volumes with the largest voxel size (1.0 × 1.0 × 3.0 mm3). A trend for the cortical thickness and density estimation errors to increase with voxel size was observed and was more pronounced for thin cortices. Using clinical CT data for 19 of the 23 samples, mean errors of 0.18 ± 0.24 mm for the cortical thickness and 15 ± 106 mg/cm3 for the density were found. The case-control study showed that osteoporotic patients had a thinner cortex and a lower cortical density, with average differences of −0.8 mm and −58.6 mg/cm3 at the proximal femur in comparison with age-matched controls (p-value
Conclusions:
This method might be a promising approach for the quantification of cortical bone thickness and density using clinical routine imaging techniques. Future work will concentrate on investigating how this approach can improve the estimation of mechanical strength of bony structures, the prevention of fracture, and the management of osteoporosis.
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Calibration of coronary calcium scores determined using iterative image reconstruction (AIDR 3D) at 120, 100, and 80 kVp
Purpose:
Computed tomography(CT)radiation dose reduction is frequently achieved by applying lower tube voltages and using iterative reconstruction (IR). For calcium scoring, the reference protocol at 120 kVp with filtered back projection (FBP) is still used, because kVp and IR may influence the Agatston score (AS) and volume score (VS). The authors present a two-step method to optimize dose: first, to determine the lowest feasible exposure and highest noise thresholds; second, to define a calibration method that ensures that the AS and VS are similar to the reference protocol.
Methods:
AS and VS were measured for an anthropomorphic thoracic phantom that includes a calciumcalibration module. The phantom was scanned on a 320-row CT scanner, at tube voltages of 120 kVp using FBP, and 120, 100, and 80 kVp using adaptive iterative dose reduction (AIDR 3D)reconstruction. The minimum CTDIs were determined based on three objective quality criteria. Calibration was performed to estimate adjusted CT number thresholds for the lower kVp acquisitions. Finally, the accuracies of the total and individual insert scores at dose level close to the minimum CTDI level were investigated and compared to low (FBPLD − 120) and high (FBPHD − 120) dose reference protocols (based on ten repeated acquisitions for each group).
Results:
IR allows the exposure to be reduced by 69% at 120 kVp, with no significant effect on the total scores when averaged over all included dose steps and compared to FBP-120 (AS: 693 vs 699, p = 0.182; VS: 588 vs 587 mm3, p = 0.569). Also when averaged over ten repeated scans and compared to FBPHD − 120 (AS: 709 vs 704, p = 0.435; VS: 604 vs 601 mm3, p = 0.479), there is no statistical significant effect. Reducing the peak tube voltage allows even greater dose reductions: 73% at 100 kVp and 76% at 80 kVp. The calibrated CT number thresholds for analysis at 120, 100, and 80 kVp were, respectively, 130, 133, and 160 HU for the Agatston score, and 130, 132, and 140 HU for the volume score. Following the calibration, the mean scores of the four groups with dose variation were not significantly different from the reference protocol, at 100 kVp (AS: 698 vs 699, p = 0.818; VS: 584 vs 587 mm3, p = 0.365) or at 80 kVp (AS: 698 vs 699, p = 0.996; VS: 586 vs 587 mm3, p = 0.827). Similarly, there was no significant score difference with FBPLD − 120 during repeated scanning: 100 kVp (AS: 690 vs 694, p = 0.394; VS: 579 vs 585 mm3, p = 0.168) and 80 kVp (AS: 703 vs 694, p = 0.115; VS: 588 vs 585 mm3, p = 0.613). Compared to FBPHD − 120 group, the relative score deviation for the accuracy of the 400 and 800 mg/cm3 HA inserts with 3 and 5 mm diameter is less than 7%. However, the relative deviation of the smaller 1 mm inserts is poorer (up to 41% deviations for scores
Conclusions:
With iterative reconstruction using AIDR 3D, deviations of the total Agatston and volume scores remain within 4% of the reference protocol. The 1 mm inserts were detected as calcification, but scores less than ten tend to be underestimated. Following the calibration process, the application of IR in combination with reduced tube voltages allows up to 76% lower radiation dose.
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Simulation of pseudo-CT images based on deformable image registration of ultrasound images: A proof of concept for transabdominal ultrasound imaging of the prostate during radiotherapy
Purpose:
Imaging of patient anatomy during treatment is a necessity for position verification and for adaptive radiotherapy based on daily dose recalculation. Ultrasound(US)image guided radiotherapy systems are currently available to collect USimages at the simulation stage (USsim), coregistered with the simulation computed tomography(CT), and during all treatment fractions. The authors hypothesize that a deformation field derived from US-based deformable image registration can be used to create a daily pseudo-CT (CTps) image that is more representative of the patients' geometry during treatment than the CT acquired at simulation stage (CTsim).
Methods:
The three prostate patients, considered to evaluate this hypothesis, had coregistered CT and US scans on various days. In particular, two patients had two US–CT datasets each and the third one had five US–CT datasets. Deformation fields were computed between pairs of USimages of the same patient and then applied to the corresponding USsim scan to yield a new deformed CTps scan. The original treatment plans were used to recalculate dose distributions in the simulation, deformed and ground truth CT(CTgt) images to compare dice similarity coefficients, maximum absolute distance, and mean absolute distance on CT delineations and gamma index (γ) evaluations on both the Hounsfield units (HUs) and the dose.
Results:
In the majority, deformation did improve the results for all three evaluation methods. The change in gamma failure for dose (γDose, 3%, 3 mm) ranged from an improvement of 11.2% in the prostate volume to a deterioration of 1.3% in the prostate and bladder. The change in gamma failure for the CTimages (γCT, 50 HU, 3 mm) ranged from an improvement of 20.5% in the anus and rectum to a deterioration of 3.2% in the prostate.
Conclusions:
This new technique may generate CTpsimages that are more representative of the actual patient anatomy than the CTsim scan.
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Personal exposure to ultrafine particles from PVC welding and concrete work during tunnel rehabilitation
Objectives
To investigate the exposure to number concentration of ultrafine particles and the size distribution in the breathing zone of workers during rehabilitation of a subsea tunnel.
MethodsPersonal exposure was measured using a TSI 3091 Fast Mobility Particle Sizer (FMPS), measuring the number concentration of submicrometre particles (including ultrafine particles) and the particle size distribution in the size range 5.6–560 nm. The measurements were performed in the breathing zone of the operators by the use of a conductive silicone tubing. Working tasks studied were operation of the slipforming machine, operations related to finishing the verge, and welding the PVC membrane. In addition, background levels were measured.
ResultsArithmetic mean values of ultrafine particles were in the range 6.26x105–3.34x106. Vertical PVC welding gave the highest exposure. Horizontal welding was the work task with the highest maximum peak exposure, 8.1x107 particles/cm3. Background concentrations of 4.0x104–3.1x105 were found in the tunnel. The mobility diameter at peak particle concentration varied between 10.8 nm during horizontal PVC welding and during breaks and 60.4 nm while finishing the verge.
ConclusionsPVC welding in a vertical position resulted in very high exposure of the worker to ultrafine particles compared to other types of work tasks. In evaluations of worker exposure to ultrafine particles, it seems important to distinguish between personal samples taken in the breathing zone of the worker and more stationary work area measurements. There is a need for a portable particle-sizing instrument for measurements of ultrafine particles in working environments.
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Caveolin-1protects against hepatic ischemia/reperfusion injury through ameliorating peroxynitrite-mediated cell death
Publication date: Available online 25 March 2016
Source:Free Radical Biology and Medicine
Author(s): Lei Gao, Xingmiao Chen, Tao Peng, Dan Yang, Qi Wang, Zhiping Lv, Jiangang Shen
Nitrative stress is considered as an important pathological process of hepatic ischemia and reperfusion injury but its regulating mechanisms are largely unknown. In this study, we tested the hypothesis that caveolin-1 (Cav-1), a plasma membrane scaffolding protein, could be an important cellular signaling against hepatic I/R injury through inhibiting peroxynitrite (ONOO−)-induced cellular damage. Male wild-type miceand Cav-1 knockout (Cav-1-/-) were subjected to 1hour hepatic ischemia following 1, 6 and 12hours of reperfusion by clipping and releasing portal vessels respectively. Immortalized human hepatocyte cell line (L02) was subjected to 1hour hypoxia and 6hour reoxygenation and treated with Cav-1 scaffolding domain peptide. The major discoveries included: (1) the expression of Cav-1 in serum and liver tissues of wild-type mice was time-dependently elevated during hepatic ischemia-reperfusion injury. (2) Cav-1 scaffolding domain peptide treatment inhibited cleaved caspase-3 expression in the hypoxia-reoxygenated L02 cells; (3) Cav-1 knockout (Cav-1-/-) mice had significantly higher levels of serum transaminases (ALT&AST) and TNF-α, and higher rates of apoptotic cell death in liver tissues than wild-type mice after subjected to 1hour hepatic ischemia and 6hour reperfusion; (4) Cav-1-/-mice revealed higher expression levels of iNOS, ONOO−and 3-nitrotyrosine (3-NT) in the liver than wild-type mice, and Fe-TMPyP, a representative peroxynitrite decomposition catalyst (PDC), remarkably reduced level of ONOO−and 3-NT and ameliorated the serum ALT, AST and TNF-α levels in both wild-typeand Cav-1-/-mice. Taken together, we conclude that Cav-1 could play a critical role in preventing nitrative stress-induced liver damage during hepatic ischemia-reperfusion injury.
Graphical abstract
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Exercise training as a drug to treat age associated frailty
Publication date: Available online 25 March 2016
Source:Free Radical Biology and Medicine
Author(s): Jose Viña, Andrea Salvador-Pascual, Francisco Jose Tarazona-Santabalbina, Leocadio Rodriguez-Mañas, Mari Carmen Gomez-Cabrera
Exercise causes an increase in the production of free radicals [1]. As a result of a hormetic mechanism antioxidant enzymes are synthesized and the cells are protected against further oxidative stress. Thus, exercise can be considered as an antioxidant [2]. Age-associated frailty is a major medical and social concern as it can easily lead to dependency.In this review we describe that oxidative stress is associated with frailty and the mechanism by which exercise prevents age-associated frailty. We propose that individually tailored multicomponent exercise programmes are one of the best ways to prevent and to treat age-associated frailty.
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Synthesis, Evaluation, and Metabolism of Novel [6]-Shogaol Derivatives as Potent Nrf2 Activators
Publication date: Available online 25 March 2016
Source:Free Radical Biology and Medicine
Author(s): Yingdong Zhu, Pei Wang, Yantao Zhao, Chun Yang, Anderson Clark, TinChung Leung, Xiaoxin Chen, Shengmin Sang
Oxidative stress is a central component of many chronic diseases. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 p45-related factor 2 (Nrf2) system is a major regulatory pathway of cytoprotective genes against oxidative and electrophilic stress. Activation of the Nrf2 pathway plays crucial roles in the chemopreventive effects of various inducers. In this study, we developed a novel class of potent Nrf2 activators derived from ginger compound, [6]-shogaol (6S), using the Tg[glutathione S-transferase pi 1 (gstp1):green fluorescent protein (GFP)] transgenic zebrafish model. Investigation of structure-activity relationships of 6S derivatives indicates that the combination of an α,β-unsaturated carbonyl entity and a catechol moiety in one compound enhances the Tg(gstp1:GFP) fluorescence signal in zebrafish embryos. Chemical reaction and in vivo metabolism studies of the four most potent 6S derivatives showed that both α,β-unsaturated carbonyl entity and catechol moiety act as major active groups for conjugation with the sulfhydryl groups of the cysteine residues. In addition, we further demonstrated that 6S derivatives increased the expression of Nrf2 downstream target, heme oxygenase-1, in both a dose- and time-dependent manner. These results suggest that α,β-unsaturated carbonyl entity and catechol moiety of 6S derivatives may react with the cysteine residues of Keap1, disrupting the Keap1-Nrf2 complex, thereby liberating and activating Nrf2. Our findings of natural product-derived Nrf2 activators lead to design options of potent Nrf2 activators for further optimization.
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A SIRT3/AMPK/autophagy network orchestrates the protective effects of trans-resveratrol in stressed peritoneal macrophages and RAW 264.7 macrophages
Publication date: Available online 25 March 2016
Source:Free Radical Biology and Medicine
Author(s): Wen-Jun Duan, Yi-Fang Li, Fang-Lan Liu, Jie Deng, Yan-Ping Wu, Wei-Lin Yuan, Bun Tsoi, Jun-Li Chen, Qi Wang, Shao-Hui Cai, Hiroshi Kurihara, Rong-Rong He
Resveratrol gains a great interest for its strong antioxidant properties, while the molecular mechanisms underlie the beneficial effects on psychosocial stress remain controversial. In this study, we demonstrated that resveratrol protected peritoneal macrophages and RAW 264.7 cells from stress-induced decrease in the total cell count, phagocytic capability, reactive oxygen species generation, monodansylcadaverine and mitochondrial membrane potential in stressed mice. Resveratrol promoted stress-induced autophagy in both models. Modulation of autophagy by rapamycin or 3-methyladenine regulated the protective effect of resveratrol, suggesting a role of autophagy in the protective mechanisms of resveratrol. The comparison studies revealed that distinct mechanisms were implicated in the protective effect of resveratrol and other antioxidants (vitamin C and edaravone). Resveratrol promoted autophagy via upregulating SIRT3 expression and phosphorylation of AMP-activated protein kinase (AMPK). Knockdown of SIRT3 resulted in decreased autophagy and abolished protective effect of resveratrol. SIRT1 was also involved in the protective mechanism of resveratrol, although its effect on autophagy was unnoticeable. Pharmacological manipulation of autophagy modulated the effects of resveratrol on SIRT3 and AMPK, revealing the engagement of a positive feedback loop. In sharp contrast, vitamin C and edaravone effectively protected macrophages from stress-induced cytotoxicity, accompanied by downregulated SIRT3 expression and AMPK phosphorylation, and decreased level of autophagy response. Taken together, we conclude that a SIRT3/AMPK/autophagy network orchestrates in the protective effect of resveratrol in macrophages.
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Bayesian Integration and Classification of Composition C-4 Plastic Explosives Based on Time-of-Flight-Secondary Ion Mass Spectrometry and Laser Ablation-Inductively Coupled Plasma Mass Spectrometry
Analytical Chemistry
DOI: 10.1021/acs.analchem.5b04151
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
