| Cancer of the Middle and Inner Ear News-Medical.net Squamous cell carcinoma (SCC): Temporal bone cancer occurs in one of 5000–20,000 cases. Annually, it accounts for an incidence level of about 1–6 cases out of 1 million. Individuals may be diagnosed with temporal bone SCC when they are 50 or 60 ... |
Euphorbia hirta linn., is a species of Euphorbiaceae family. They are known as asthma plant, barokhervi. The plant E. hirta is famous for its medicinal importance among the tribal popu...
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| Newburgh Gazette | Survey finds lag in HPV vaccination rates for childhood cancer survivors News-Medical.net Persistent infection with certain high-risk strains of HPV can cause cancer of the cervix, vagina, penis, tongue, throat, anus and other sites. Previous studies from St. Jude and others found that childhood cancer survivors are at an increased risk of ... Most US teens getting HPV vaccine, CDC saysHiTechFacts all 19 news articles » |
IJMS, Vol. 18, Pages 1825: Extract of Sheng-Mai-San Ameliorates Myocardial Ischemia-Induced Heart Failure by Modulating Ca2+-Calcineurin-Mediated Drp1 Signaling Pathways
International Journal of Molecular Sciences doi: 10.3390/ijms18091825
Authors: Ye Yang Yushan Tian Siyao Hu Suxia Bi Suxia Li Yuanjia Hu Junping Kou Jin Qi Boyang Yu
Sheng-Mai-San (SMS) is a well-known traditional Chinese medicine (TCM) complex prescription used to treat heart failure (HF) and angina in clinic. However, its potential therapeutic mechanisms remain unclear. The present study evaluated the cardioprotection of extract of SMS (ESMS) on myocardial ischemia (MI)-induced HF, and explored the underlying molecular mechanisms. The results demonstrated that ESMS (728.0 mg/kg) significantly attenuated MI injury-induced HF by improving cardiac function and pathological changes, decreasing lactate dehydrogenase (LDH), creatine kinase (CK) activities, and brain natriuretic peptide (BNP) levels; increasing ATPase activity; and reducing intracellular Ca2+ levels in MI-induced HF mice model. It also significantly decreased the apoptotic index. In vitro, ESMS (400 μg/mL) inhibited mitochondrial-dependent myocardial apoptosis by modulating the expression of caspase-3 and the Bcl-2/Bax ratio, and improved mitochondrial function through increasing mitochondrial membrane potential and cellular ATP content. ESMS restored intracellular Ca2+ and downregulated the expression of Calcineurin A (CnA), thus inhibiting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and increasing phosphorylation of Drp1 at Ser637 to prevent cardiomyocyte mitochondrial fission. Above-mentioned results demonstrated ESMS suppressed mitochondrial-mediated apoptosis in oxygen glucose deprivation (OGD) injured H9c2 cardiomyocytes. These findings suggested that ESMS attenuated MI-induced HF by regulating Ca2+ homeostasis and suppressing mitochondrial mediated apoptosis through the modulation of Ca2+-calcineurin-mediated Drp1 signaling pathways. Our results provide insight into the mechanism and clinical applications of SMS and suggest a potential therapeutic strategy for HF.
Publication date: Available online 24 August 2017
Source:Asian Pacific Journal of Tropical Medicine
Author(s): Xiao-Ri Qin, Yan Tan, Xiao-Ning Sun
ObjectiveTo evaluate the effects of retrograde colonic electrical stimulation (RCES) with trains of short pulses and RCES with long pulses on colonic transit in irritable bowel syndrome (IBS) rats and to investigate whether stress-induced visceral hypersensitivity could be alleviated by RCES so as to find a valuable new approach for IBS treatment.MethodsA total of 48 male rats were randomly divided into model group and control group. Visceral hypersensitivity model was induced by a 6-day HIS protocol composed of two stressors, restraint stress for 40 min and forced swimming stress for 20 min. The extent of visceral hypersensitivity was quantified by electromyography and abdominal withdrawal reflx scores (AWRs) of colorectal distension (use a balloon) at different pressures. After the modeling, all rats were equipped with electrodes in descending colon for retrograde electrical stimulation and a PE tube for perfusing phenol red saline solution in the ileocecus. After recovering from surgery, RCES with long pulses, RCES with trains of short pulses, and sham RCES were performed in colonic serosa of rats for 40 min in six groups of 8 each, including three groups of visceral hypersensitivity rats and three groups of health rats. Colonic transit was assessed by calculating the output of phenol red from the anus every 10 min for 90 min. Finally, the extent of visceral hypersensitivity will be quantified again in model group.ResultsAfter the 6-day HIS protocol, the HIS rats displayed an increased sensitivity to colorectal distention, compared to control group at different distention pressures (P < 0.01). CRES with trains of short pulses and long pulses significantly attenuated the hypersensitive responses to colorectal distention in the HIS rats compared with sham RCES group (P < 0.01). The effects of RCES on rats colon transmission: In the IBS rats, the colonic emptying were (77.4 ± 3.4)%, (74.8 ± 2.4)% and (64.2 ± 1.6)% in the sham RCES group, long pulses group and trains of short pulses group at 90 min; In healthy rats, The colonic emptying was (65.2 ± 3.5)%, (63.5 ± 4.0)% and (54.0 ± 2.5)% in the sham RCES group, long pulses group and trains of short pulses group at 90 min.ConclusionRCES with long pulses and RCES with trains of short pulses can significantly alleviate stress-induced visceral hypersensitivity. RCES with trains of short pulses has an inhibitory effect of colonic transit, both in visceral hypersensitivity rats and healthy rats.
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Publication date: Available online 24 August 2017
Source:Asian Pacific Journal of Tropical Medicine
Author(s): Qi-qi Shi, Peng Cheng, Chong-xing Zhang, Xiu-xia Guo, Li-juan Liu, Hai-fang Wang, Jing-xuan Kou, Xiao-dan Huang, Huai-wei Wang, Mao-qing Gong
ObjectiveTo conduct an analysis of the epidemiological changes in malaria that have occurred in Shanxian county from 2002 to 2016.MethodsA retrospective study was conducted and data were collected from web-based reporting system to explore the epidemiological characteristics in Shanxian county from 2002 to 2016. All individual case information was obtained from village malaria servicers organized by the local Shandong Institute of Parasitic Diseases.ResultsA total of 133 cases were identified as malaria in Shanxian county during This period, including 124 indigenous cases (93.2%) and 9 imported cases (6.8%). The 124 indigenous malaria cases were infected with Plasmodium vivax (P. vivax), whereas 8 of the 9 confirmed imported cases were infected with Plasmodium falciparum (P. falciparum) and 1 patient was infected with P. falciparum mixed with P. vivax. The total number of malaria cases included 86 males (64.7%) and 47 females (35.3%). Age of the patients ranged from 1 to 83 years, although most (64.7%) infections occurred in the 21-to 60-year-old age group. Remarkably, 117 of the total malaria 23 cases (98.0%) were reported from 2006-2011. The epidemic season was from June to October, with the peak occurring yearly from July to September. The most common occupation of the infected patients was farmer. In total, 58.1% of the cases occurred in 3 townships, namely, Fugang, Huanggang and Caozhuang.ConclusionsIn Shanxian county, the local malaria incidence experienced an emerge-peak-control-eliminate status. However, due to the numbers of migrant labourers returning from Africa, imported cases were continuous and presented an increasing annual trend, which became a non-negligible and a significant impediment 31 for malaria elimination. Therefore, the need to eliminate instances of malaria reintroduction to receptive malaria-free areas should drive strategies to align with the epidemiological changes.
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Publication date: Available online 24 August 2017
Source:Asian Pacific Journal of Tropical Medicine
Author(s): Patel Mahipal, Rajesh Singh Pawar
ObjectiveTo evaluate the nephroprotective effect of defatted mehtanolic extract and aqueous extract of Murraya koenigii against cyclophosphamide drug.MethodsNephrotoxicity was induced by cyclophosphamide in 7 days at 150 mg/kg body weight through intraperitoneal route in rat model. Nephroprotective activity of Murraya koenigii extract (100 mg/kg and 200 mg/kg in intraperitoneal route) was measured, including nephrological source, oxidative stress parameters like superoxide dismutase, glutathione, the lipid peroxide and in vivo assay like blood urea nitrogen, creatinine were determined and analyzed by One way analysis of variance followed by Tukey's test.ResultsThe study result showed that important phytochemicals such as carbohydrates, flavonoids, tannin, alkaloids, glycosides, protein and steroids were found to be present in the extract of Murraya koenigii. The renal function markers like blood urea nitrogen and ceatinine level were found to be decreased significantly by M. koenigii extract treatment. A significant difference was found to be at P<0.01.ConclusionsThe present study reveals the protective role of Murraya koenigii extract against cyclophosphamide induced nephrotoxicity.
Publication date: Available online 24 August 2017
Source:Asian Pacific Journal of Tropical Medicine
Author(s): Omar M.E. Abdel-Salam, Eman R. Youness, Nadia A. Mohammed, Noha N. Yassen, Yasser A. Khadrawy, Safinaz Ebrahim El-Toukhy, Amany A. Sleem
ObjectiveTo investigate the effect of NG-nitro-L-arginine methyl ester (L-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, and 7-nitroindazole (7-NI), a selective neuronal NOS inhibitor, on oxidative stress and tissue damage in brain and liver and on DNA damage of peripheral blood lymphocytes in malathion intoxicated rats.MethodsMalathion (150 mg/kg) was given intraperitoneally (i.p.) along with L-NAME or 7-NI (10 or 20 mg/kg, i.p.) and rats were euthanized 4 h later. The lipid peroxidation product malondialdehyde (MDA), nitric oxide (nitrite), reduced glutathione (GSH) concentrations and paraoxonase-1 (PON-1) activity were measured in both brain and liver. Moreover, the activities of glutathione peroxidase (GPx) acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), total antioxidant capacity (TAC), glucose concentrations were determined in brain. Liver enzyme determination, Comet assay, histopathological examination of brain and liver sections and inducible nitric oxide synthase (iNOS) immunohistochemistry were also performed.Results(i) Rats treated with only malathion exhibited increased nitric oxide and lipid peroxidation (malondialdehyde) accompanied with a decrease in GSH content, and PON-1 activity in brain and liver. Glutathione peroxidase activity, TAC, glucose concentrations, AChE and BChE activities were decreased in brain. There were also raised liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and increased DNA damage of peripheral blood lymphocytes (Comet assay). Malathion caused marked histopathological changes and increased the expression of iNOS in brain and liver tissues. (ii) In brain of malathion-intoxicated rats, L-NAME or 7-NI resulted in decreased nitrite and MDA contents while increasing TAC and PON1 activity. Reduced GSH and GPx activity showed an increase by L-NAME. AChE activity increased by 20 mg/kg L-NAME and 10 mg/kg 7-NI. AChE activity decreased by the higher dose of 7-NI while either dose of 7-NI resulted in decreased BChE activity.(iii) In liver of malathion-intoxicated rats, decreased MDA content was observed after L-NAME or 7-NI. Nitrite level was unchanged by L-NAME but increased after 7-NI which also resulted in decreased GSH concentration and PON1 activity. Either inhibitor resulted in decreased liver ALT activity. (iv) DNA damage of peripheral blood lymphocytes was markedly inhibited by L-NAME or 7-NI treatment. (v) iNOS expression in brain and liver decreased by L-NAME or 7-NI. (vi) More marked improvement of the histopathological alterations induced by malathion in brain and liver was observed after 7-NI compared with L-NAME.ConclusionsIn malathion intoxication in rats, the neuronal NOS inhibitor 7-NI and to much less extent L-NAME was able to protect the brain and liver tissue integrity along with improvement in oxidative stress parameters. The decrease in DNA damage of peripheral blood lymphocytes by NOS inhibitors also suggests involvement of nitric oxide in this process.
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The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT) participates in the hypoxia-inducible factor (HIF) pathway which senses a decline in cellular oxygen tension. In hypoxia, HIF-1α a...
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Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): B. Mehrazma, M. Robinson, S.K.A. Opare, A. Petoyan, J. Lou, F.T. Hane, A. Rauk, Z. Leonenko
By combining MD simulations and AFS experimental technique, we demonstrated a powerful approach for rational design and single molecule testing of novel inhibitor molecules which can block amyloid-amyloid binding – the first step of toxic amyloid oligomer formation. We designed and tested novel pseudo-peptide amyloid-β (Aβ) inhibitors that bind to the Aβ peptide and effectively prevent amyloid-amyloid binding. First, molecular dynamics (MD) simulations have provided information on the structures and binding characteristics of the designed pseudo-peptides targeting amyloid fragment Aβ (13−23). The binding affinities between the inhibitor and Aβ as well as the inhibitor to itself have been estimated using Umbrella Sampling calculations. Atomic Force Spectroscopy (AFS) was used to experimentally test several proposed inhibitors in their ability to block amyloid-amyloid binding – the first step of toxic amyloid oligomer formation. The experimental AFS data are in a good agreement with theoretical MD calculations and demonstrate that three proposed pseudo-peptides bind to amyloid fragment with different affinities and all effectively prevent Aβ-Aβ binding in similar way. We propose that the designed pseudo-peptides can be used as potential drug candidates to prevent Aβ toxicity in Alzheimer's disease.
Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Jin Zhang, Walter R.P. Scott, Frank Gabel, Miao Wu, Ruqaiba Desmond, JungHwan Bae, Giuseppe Zaccai, W. Russ Algar, Suzana K. Straus
Daptomycin, sold under the trade name CUBICIN, is the first lipopeptide antibiotic to be approved for use against Gram-positive organisms, including a number of highly resistant species. Over the last few decades, a number of studies have tried to pinpoint the mechanism of action of daptomycin. These proposed modes of action often have points in common (e.g. the requirement for Ca2+ and lipid membranes containing a high proportion of phosphatidylglycerol (PG) headgroups), but also points of divergence (e.g. oligomerization in solution and in membranes, membrane perturbation vs. inhibition of cell envelope synthesis). In this study, we investigate how concentration effects may have an impact on the interpretation of the biophysical data used to support a given mechanism of action. Results obtained from small angle neutron scattering (SANS) experiments and molecular dynamics (MD) simulations show that daptomycin oligomerizes at high concentrations (both with and without Ca2+) in solution, but that this oligomer readily falls apart. Photon correlation spectroscopy (PCS) experiments demonstrate that daptomycin causes fusion more readily in DMPC/PG membranes than in POPC/PG, suggesting that the latter may be a better model system. Finally, fluorescence and Förster resonance energy transfer (FRET) experiments reveal that daptomycin binds strongly to the lipid membrane and that oligomerization occurs in a concentration-dependent manner. The combined experiments provide an improved framework for more general and rigorous biophysical studies toward understanding the elusive mechanism of action of daptomycin. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman.
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Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Katy A. Doré, Anna M. Davies, Nyssa Drinkwater, Andrew J. Beavil, James M. McDonnell, Brian J. Sutton
Immunoglobulin E (IgE) is the antibody that plays a central role in the mechanisms of allergic diseases such as asthma. Interactions with its receptors, FcεRI on mast cells and CD23 on B cells, are mediated by the Fc region, a dimer of the Cε2, Cε3 and Cε4 domains. A sub-fragment lacking the Cε2 domains, Fcε3–4, also binds to both receptors, although receptor binding almost exclusively involves the Cε3 domains. This domain also contains the N-linked glycosylation site conserved in other isotypes. We report here the crystal structures of IgE-Fc and Fcε3–4 at the highest resolutions yet determined, 1.75Å and 2.0Å respectively, revealing unprecedented detail regarding the carbohydrate and its interactions with protein domains. Analysis of the crystallographic B factors of these, together with all earlier IgE-Fc and Fcε3–4 structures, shows that the Cε3 domains exhibit the greatest intrinsic flexibility and quaternary structural variation within IgE-Fc. Intriguingly, both well-ordered carbohydrate and disordered polypeptide can be seen within the same Cε3 domains. A simplified method for comparing the quaternary structures of the Cε3 domains in free and receptor-bound IgE-Fc structures is presented, which clearly delineates the FcεRI and CD23 bound states. Importantly, differential scanning fluorimetric analysis of IgE-Fc and Fcε3–4 identifies Cε3 as the domain most susceptible to thermally-induced unfolding, and responsible for the characteristically low melting temperature of IgE.
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Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Rizvan Uluisik, Elvira Romero, Giovanni Gadda
The effect of temperature on the reaction of alcohol oxidation catalyzed by choline oxidase was investigated with the S101A variant of choline oxidase. Anaerobic enzyme reduction in a stopped-flow spectrophotometer was biphasic using either choline or 1,2-[2H4]-choline as a substrate. The limiting rate constants klim1 and klim2 at saturating substrate were well separated (klim1/klim2>9), and were >15-fold slower than for wild-type choline oxidase. Solvent deuterium kinetic isotope effects (KIEs) ~4 established that klim1 probes the proton transfer from the substrate hydroxyl to a catalytic base. Primary substrate deuterium KIEs ≥7 demonstrated that klim2 reports on hydride transfer from the choline alkoxide to the flavin. Between 15°C and 39°C the klim1 and klim2 values increased with increasing temperature, allowing for the analyses of H+ and H– transfers using Eyring and Arrhenius formalisms. Temperature-independent KIE on the klim1 value (H2Oklim1/D2Oklim1) suggests that proton transfer occurs within a highly reorganized tunneling-ready-state with a narrow distribution of donor-acceptor distances. Eyring analysis of the klim2 value gave lines with the slope(choline)>slope(D-choline), suggesting kinetic complexity. Spectral evidence for the transient occurrence of a covalent flavin-substrate adduct during the first phase of the anaerobic reaction of S101A CHO with choline is presented, supporting the notion that an important role of amino acid residues in the active site of flavin-dependent enzymes is to eliminate alternative reactions of the versatile enzyme-bound flavin for the reaction that needs to be catalyzed.
Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Robert B. Freedman, Jasmine L. Desmond, Lee J. Byrne, Jack W. Heal, Mark J. Howard, Narinder Sanghera, Kelly L. Walker, A. Katrine Wallis, Stephen A. Wells, Richard A. Williamson, Rudolf A. Römer
Protein disulfide isomerase (PDI) has diverse functions in the endoplasmic reticulum as catalyst of redox transfer, disulfide isomerization and oxidative protein folding, as molecular chaperone and in multi-subunit complexes. It interacts with an extraordinarily wide range of substrate and partner proteins, but there is only limited structural information on these interactions. Extensive evidence on the flexibility of PDI in solution is not matched by any detailed picture of the scope of its motion. A new rapid method for simulating the motion of large proteins provides detailed molecular trajectories for PDI demonstrating extensive changes in the relative orientation of its four domains, great variation in the distances between key sites and internal motion within the core ligand-binding domain. The review shows that these simulations are consistent with experimental evidence and provide insight into the functional capabilities conferred by the extensive flexible motion of PDI.
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Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Silke Flindt Badino, Jeppe Kari, Stefan Jarl Christensen, Kim Borch, Peter Westh
Cellulose degrading fungi such as Hypocrea jecorina secrete several cellulases including the two cellobiohydrolases (CBHs) Cel6A and Cel7A. The two CBHs differ in catalytic mechanism, attack different ends, belong to different families, but are both processive multi-domain enzymes that are essential in the hydrolysis of cellulose. Here we present a direct kinetic comparison of these two enzymes acting on insoluble cellulose. We used both continuous- and end-point assays under either enzyme- or substrate excess, and found distinct kinetic differences between the two CBHs. Cel6A was catalytically superior with a maximal rate over four times higher than Cel7A. Conversely, the ability of Cel6A to attack diverse structures on the cellulose surface was inferior to Cel7A. This latter difference was pronounced as the density of attack sites for Cel7A was almost an order of magnitude higher compared to Cel6A. We conclude that Cel6A is a fast but selective enzyme and that Cel7A is slower, but promiscuous. One consequence of this is that Cel6A is more effective when substrate is plentiful, while Cel7A excels when substrate is limiting. These diverse kinetic properties of Cel6A and Cel7A might elucidate why both cellobiohydrolases are prominent in cellulolytic degrading fungi.
Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Andrea González, Esteban Nova, Miguel Del Campo, Augusto Manubens, Alfredo De Ioannes, Jorge Ferreira, María Inés Becker
Hemocyanins have highly conserved copper-containing active sites that bind oxygen. However, structural differences among the hemocyanins of various mollusks may affect their physicochemical properties. Here, we studied the oxygen-binding cooperativity and affinity of Concholepas concholepas hemocyanin (CCH) and its two isolated subunits over a wide range of temperatures and pH values. Considering the differences in the quaternary structures of CCH and keyhole limpet hemocyanin (KLH), we hypothesized that the heterodidecameric CCH has different oxygen-binding parameters than the homodidecameric KLH. A novel modification of the polarographic method was applied in which rat liver submitochondrial particles containing cytochrome c oxidase were introduced to totally deplete oxygen of the test solution using ascorbate as the electron donor. This method was both sensitive and reproducible. The results showed that CCH, like other hemocyanins, exhibits cooperativity, showing an inverse relationship between the oxygen-binding parameters and temperature. According to their Hill coefficients, KLH has greater cooperativity than CCH at physiological pH; however, CCH is less sensitive to pH changes than KLH. Appreciable differences in binding behavior were found between the CCH subunits: the cooperativity of CCH-A was not only almost double that of CCH-B, but it was also slightly superior to that of CCH, thus suggesting that the oxygen-binding domains of the CCH subunits are different in their primary structure. Collectively, these data suggest that CCH-A is the main oxygen-binding domain in CCH; CCH-B may play a more structural role, perhaps utilizing its surprising predisposition to form tubular polymers, unlike CCH-A, as demonstrated here using electron microscopy.
Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Leonid S. Brown, Oliver P. Ernst
Retinal-binding proteins, mainly known as rhodopsins, function as photosensors and ion transporters in a wide range of organisms. From halobacterial light-driven proton pump, bacteriorhodopsin, to bovine photoreceptor, visual rhodopsin, they have served as prototypical α-helical membrane proteins in a large number of biophysical studies and aided in the development of many cutting-edge techniques of structural biology and biospectroscopy. In the last decade, microbial and animal rhodopsin families have expanded significantly, bringing into play a number of new interesting structures and functions. In this review, we will discuss recent advances in biophysical approaches to retinal-binding proteins, primarily microbial rhodopsins, including those in optical spectroscopy, X-ray crystallography, nuclear magnetic resonance, and electron paramagnetic resonance, as applied to such fundamental biological aspects as protein oligomerization, folding, and structure.
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Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Gary C.H. Mo, Christopher M. Yip
Identifying the key structural and dynamical determinants that drive the association of biomolecules, whether in solution, or perhaps more importantly in a membrane environment, has critical implications for our understanding of cellular dynamics, processes, and signaling. With recent advances in high-resolution imaging techniques, from the development of new molecular labels to technical advances in imaging methodologies and platforms, researchers are now reaping the benefits of being able to directly characterize and quantify local dynamics, structures, and conformations in live cells and tissues. These capabilities are providing unique insights into association stoichiometries, interactions, and structures on sub-micron length scales. We previously examined the role of lipid headgroup chemistry and phase state in guiding the formation of pseudoisocyanine (PIC) dye J-aggregates on supported planar bilayers [Langmuir, 25, 10,719]. We describe here how these same J-aggregates can report on the in situ formation of organellar membrane domains in live cells. Live cell hyperspectral confocal microscopy using GFP-conjugated GTPase markers of early (Rab5) and late (Rab7) endosomes revealed that the PIC J-aggregates were confined to domains on either the limiting membrane or intralumenal vesicles (ILV) of late endosomes, known to be enriched in the anionic lipid bis(monoacylglycero)phosphate (BMP). Correlated confocal fluorescence - atomic force microscopy performed on endosomal membrane-mimetic supported planar lipid bilayers confirmed BMP-specific templating of the PIC J-aggregates. These data provide strong evidence for the formation of BMP-rich lipid domains during multivesicular body formation and portend the application of structured dye aggregates as markers of cellular membrane domain structure, size, and formation.
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Regenerative endodontic procedures (REPs) have been shown to promote the resolution of signs and symptoms of disease and increase survival compared with traditional treatment procedures. However, there is still variable predictability of continued root development and evidence that the tissues formed do not recapitulate the native pulp-dentin complex. There is growing evidence that the apical papilla is capable of surviving prolonged endodontic infection and apical periodontitis and that it represents a rich source of undifferentiated mesenchymal stem cells in REPs.
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Clinicians face many challenges when treating immature permanent teeth in young patients. Immediate blood clot induction can be a successful option as described by some case reports. No experimental studies or clinical trials have addressed this question. We have designed a clinical trial in which we hypothesized that there is no difference in success between immediate or delayed induction protocols. After confirmation of pulpal necrosis, patients were randomized. In the delayed group, 15 teeth were treated following the American Association of Endodontists guidelines, and calcium hydroxide was used as the intracanal medication.
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The goal of endodontics is to save teeth. Since inception, endodontic treatments are performed to obturate disinfected root canals with inert materials such as gutta-percha. Although teeth can be saved after successful endodontic treatments, they are devitalized and therefore susceptible to reinfections and fractures. The American Association of Endodontists (AAE) has made a tremendous effort to revitalize disinfected immature permanent teeth in children and adolescents with diagnoses including pulp necrosis or apical periodontitis.
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The balance between the immune/inflammatory and regenerative responses in the diseased pulp is central to the clinical outcome, and this response is unique within the body because of its tissue site. Cariogenic bacteria invade the dentin and pulp tissues, triggering molecular and cellular events dependent on the disease stage. At the early onset, odontoblasts respond to bacterial components in an attempt to protect the tooth's hard and soft tissues and limit disease progression. However, as disease advances, the odontoblasts die, and cells central to the pulp core, including resident immune cells, pulpal fibroblasts, endothelial cells, and stem cells, respond to the bacterial challenge via their expression of a range of pattern recognition receptors that identify pathogen-associated molecular patterns.
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Signaling molecules play an essential role in tissue engineering because they regulate regenerative processes. Evidence exists from animal studies that single molecules such as members of the transforming growth factor beta superfamily and factors that induce the growth of blood vessels (vascular endothelial growth factor), nerves (brain-derived neurotrophic factor), or fibroblasts (fibroblast growth factor) may induce reparative dentin formation. Mainly the formation of atubular dentin (osteodentin) has been described after the application of single molecules or combinations of recombinant growth factors on healthy exposed pulps or in pulp regeneration.
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Studies have indicated a pervasive pattern of decreasing healthcare costs during elderly patients' last year of life. The aim of this study was to explore the predictors of high healthcare costs (HC) in elderl...
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This study aimed to evaluate the long-term outcome and toxicities in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated by concurrent chemoradiotherapy (CCRT) with/without adding cetu...
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Accessibility to essential cancer medications in low- and middle-income countries is threatened by insufficient availability and affordability. The objective of this study is to characterize variation in trans...
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Many epidemiological studies have confirmed the relationship of obesity and psoriasis, and it is believed that obesity is an independent risk factor for its development and is associated with a worse prognosis. Furthermore, the reduction of body weight, using low-calorie diet combined with exercise, reduces the severity of psoriasis. Visceral adipose tissue is the largest endocrine organ, producing proinflammatory cytokines (TNF-α, IL-6, IL-17) and adipokines (adiponectin, omentin, chemerin). They participate in the development of dyslipidemia, insulin resistance, diabetes, and consequently of the cardiovascular diseases. Macrophages of visceral adipose tissue have a special role and they increase significantly in obesity. They are responsible for the development of inflammation in adipose tissue and produce inflammatory cytokines (TNF alpha, IL-6, Il-8, Il-17, Il-18, MCP-1) and other adipokines: resistin, visfatin, retinol-binding protein 4. This explains the concept of «psoriatic march «and observations of the frequent coexistence of psoriasis with obesity. Inflammation associated with systemic disease, fanned by pro-inflammatory cytokines and adipokines produced by the visceral adipose tissue lead to the development of insulin resistance, endothelial cell damage. Endothelial dysfunction predisposes to the formation of atherosclerotic plaques and faster development of cardiovascular events. Complication of obesity is the development of non-alcoholic fatty liver disease (NAFLD), which states twice as likely in patients with plaque psoriasis and is associated with the severity of the disease. Another consequence is the development of depression. Probably the proinflammatory cytokines can interact with metabolism of neurotransmitters. Obesity also has a significant impact on the treatment of psoriasis, increasing the risk of adverse effects of systemic drugs, reducing the efficacy of biological agents which dose should be adjusted to the weight of the patient. It is a factor responsible for the increased volume of distribution and it causes low titter of drug concentration.
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Metformin, currently recommended as the drug of first choice in type 2 diabetes mellitus (T2DM), is one of the few antihiperglycemic drugs to reduce cardiovascular risk. Nonetheless, due to the risk of lactic acidosis during metformin therapy, its usage in patients with diabetes and heart failure (HF) is still a matter of debate. The aim of this review is to present data supporting the possibility of using metformin in the treatment of diabetic patients with concomitant heart failure. In the failing heart, metformin through the mechanism related to AMP-activated protein kinase (AMPK) activity, improves free fatty acids (FFA) and glucose metabolism, mitochondrial biogenesis, as well as nitric oxide (NO)-NO synthase pathway. Metformin can also inhibit the generation and accumulation of advanced glycation end products (AGEs) and thereby prevents the development of the adverse structural and functional changes in myocardium. In summary, experimental and clinical data indicate the ability of metformin to prevent the development of the structural and functional changes in myocardium, although further basic research and clinical studies assessing benefits and safety of metformin therapy in patients with HF are required.
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| West Central Tribune | A postal worker faked cancer and got paid to miss two years of work. Here's how a judge punished her. West Central Tribune The tale that Caroline Boyle started spinning in 2015 was grim. She told colleagues that cancer attacked her white blood cells and ravaged her immune system, leaving Doyle too weak to come into work at the U.S. Postal Service office in Aurora, Colorado. and more » |
Male exposure to cigarette smoke is associated with seminal defects and with congenital anomalies and childhood cancers in offspring. In mice, paternal exposure to cigarette smoke condensate (CSC) causes molecular defects in germ cells and phenotypic effects in their offspring. Here we used an ex vivo testicular explant model and in vivo exposure to determine the concentration at which CSC impairs spermatogenesis and offspring development. We explanted testis tissue at postnatal day (P)5.5 and cultured it until P11.5. Assessment of growth parameters by analyzing expression of cell-specific markers revealed that the explant system maintained structural and functional integrity. We exposed the P5.5 to -11.5 explants to various concentrations (40–160 µg/ml) of CSC and confirmed that nicotine in the CSC was metabolized to cotinine. We assessed various growth and differentiation parameters, as well as testosterone production, and observed that many spermatogenesis features were impaired at 160 µg/ml CSC. The same parameters were impaired by a similar CSC concentration in vivo. Finally, females mated to males that were exposed to 160 µg/ml CSC neonatally had increased rates of pup resorption. We conclude that male exposure to CSC impairs offspring development and that the concentration at which CSC impairs spermatogenesis is similar in vivo and ex vivo. Given that the concentrations of CSC we used contained similar doses of nicotine as human smokers are exposed to, we argue that our model mimics human male reproductive effects of smoking.—Esakky, P., Hansen, D. A., Drury, A. M., Felder, P., Cusumano, A., Moley, K. H. Testicular cells exhibit similar molecular responses to cigarette smoke condensate ex vivo and in vivo.
The protein tyrosine phosphatase N (PTPN)-12 is a multifunctional protein and has elicited much research attention because its decreased protein level has been associated with poor prognosis of several types of cancers. Recently, we have solved the crystal structure of the phosphatase domain of PTPN12, which disclosed a specific PTPN12–insert–loop harboring a cyclin-dependent kinase (CDK)-2 phosphorylation site. However, the functional significance of this phosphorylation is undefined. In the present study, we found that S19 site phosphorylation of PTPN12 by CDK2 discharged its antitumor activity by down-regulation of its inhibitory role in cell migration, but not affecting its other regulatory functions. Phosphorylation of PTPN12 at the S19 site changed its substrate interface, and by doing so, selectively decreased its activity toward the human epidermal growth factor receptor (HER)-2 pY1196 site, but not other HER2 phosphorylation sites or other known PTPN12 substrates. A further in-depth mechanism study revealed that the phosphorylation of PTPN12 by CDK2 impaired recruitment of the serine/threonine-protein kinase (PAK)-1 to HER2, resulted in the blockade of the HER2-pY1196–PAK1-T423 signaling pathway, thus increased tumor cell motility. Taken together, our results identified a new phosphorylation-based substrate recognition mechanism of PTPN12 by CDK2, which orchestrated signaling crosstalk between the oncogenic CDK2 and HER2 pathways. The newly identified governing mechanism of the substrate selectivity of a particular phosphatase was previously unappreciated and exemplifies how a phospho-network is precisely controlled in different cellular contexts.—Li, H., Yang, D., Ning, S., Xu, Y., Yang, F., Yin, R., Feng, T., Han, S., Guo, L., Zhang, P., Qu, W., Guo, R., Song, C., Xiao, P., Zhou, C., Xu, Z., Sun, J.-P., Yu, X. Switching of the substrate specificity of protein tyrosine phosphatase N12 by cyclin-dependent kinase 2 phosphorylation orchestrating 2 oncogenic pathways.
Angiopoietin-like 4 (Angptl4) is a circulating protein secreted by white and brown adipose tissues and the liver. Structurally, Angptl4 contains an N-terminal coiled-coil domain (CCD) connected to a C-terminal fibrinogen-like domain (FLD) via a cleavable linker, and both full-length Angptl4 and its individual domains circulate in the bloodstream. Angptl4 inhibits extracellular lipoprotein lipase (LPL) activity and stimulates the lipolysis of triacylglycerol stored by adipocytes in the white adipose tissue (WAT). The former activity is furnished by the CCD, but the Angptl4 domain responsible for stimulating adipocyte lipolysis is unknown. We show here that the purified FLD of Angptl4 is sufficient to stimulate lipolysis in mouse primary adipocytes and that increasing circulating FLD levels in mice through adenovirus-mediated overexpression (Ad-FLD) not only induces WAT lipolysis in vivo, but also reduces diet-induced obesity without affecting LPL activity. Intriguingly, reduced adiposity in Ad-FLD mice was associated with increased oxygen consumption, fat utilization, and the expression of thermogenic genes (Ucp1 and Ppargc1a) in subcutaneous WAT. Moreover, Ad-FLD mice exhibited increased glucose tolerance. Chronically enhancing WAT lipolysis could produce ectopic steatosis, due to an overflow of lipids from the WAT to peripheral tissues; however, this did not occur when Ad-FLD mice were fed a high-fat diet. Rather, these mice had reductions in both circulating triacylglycerol levels and the mRNA levels of lipogenic genes in the liver and skeletal muscle. We conclude that separating the FLD from the CCD-mediated LPL-inhibitory activity of full-length Angptl4 reveals lipolytic and thermogenic properties with therapeutic relevance to obesity and diabetes.
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CAPA peptides such as periviscerokinin (PVK) are insect neuropeptides involved in many signaling pathways controlling, for example, metabolism, behavior, and reproduction. They are present in a large number of insects and together with their cognate receptors, are important for research into approaches for improving insect control. However, the CAPA receptors in the silkworm (Bombyx mori) insect model are unknown. Here, we cloned cDNAs of two putative CAPA peptide receptor genes, BNGR-A27 and -A25, from the brain of B. mori larvae. We found that the predicted BNGR-A27 ORF encodes 450 amino acids and that one BNGR-A25 splice variant encodes a full-length isoform (BNGR-A25L) of 418 amino acid residues and another a short isoform (BNGR-A25S) of 341 amino acids with a truncated C-terminal tail. Functional assays indicated that both BNGR-A25L and -A27 are activated by the PVK neuropeptides Bom-CAPA-PVK1 and -PVK2, leading to a significant increase in cAMP response element controlled luciferase activity and Ca2+ mobilization in a Gq inhibitor-sensitive manner. In contrast, BNGR-A25S was not significantly activated in response to the PVK peptides. Moreover, Bom-CAPA-PVK1 directly bound to BNGR-A25L and -A27, but not BNGR-A25S. Of note, CAPA-PVKs-mediated ERK1/2 phosphorylation and receptor internalization confirmed that BNGR-A25L and -A27 are two canonical receptors for Bombyx CAPA-PVKs. However, BNGR-A25S alone is a nonfunctional receptor, but serve as a dominant-negative protein for BNGR-A25L. These results provide evidence that BNGR-A25L and -A27 are two functional Gq-coupled receptors for Bombyx CAPA-PVKs, enabling the further elucidation of the endocrinological roles of Bom-CAPA-PVKs and their receptors in insect biology.
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Upon activation by the Gq family of Gα subunits, Gβγ subunits and some Rho family GTPases, phospholipase C-β (PLC-β) isoforms hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) to the second messengers inositol 1,4,5-trisphosphate and diacylglycerol. PLC-β isoforms also function as GTPase-activating proteins (GAPs), potentiating Gq deactivation. To elucidate the mechanism of this mutual regulation, we measured the thermodynamics and kinetics of PLC-β3 binding to Gαq. Fluorescence resonance energy transfer (FRET) and fluorescence correlation spectroscopy, two physically distinct methods, both yielded Kd values of about 200 nM for PLC-β3-Gαq binding. This Kd is 50-100 times greater than the EC50 for Gαq-mediated PLC-β3 activation and for the Gαq GAP activity of PLC-β. The measured Kd was not altered either by the presence of phospholipid vesicles, PIP2 and Ca2+, or by the identity of the fluorescent labels. FRET-based kinetic measurements were also consistent with a Kd of 200 nM. We determined that PLC-β3 hysteresis, whereby PLC-β3 remains active for some time following either Gαq-PLC-β3 dissociation or PLC-β3-potentiated Gαq deactivation, is not sufficient to explain the observed discrepancy between EC50 and Kd. These results indicate that the mechanism by which Gαq and PLC-β3 mutually regulate each other is far more complex than a simple, two-state allosteric model, and instead is probably kinetically determined..
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Transcription factor Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses the induction of pro-inflammatory cytokine genes. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase. Keap1 regulates the activity of Nrf2 and acts as a sensor for oxidative and electrophilic stresses. In this review, we discuss the molecular mechanisms by which the Keap1-Nrf2 system senses and regulates the cellular response to environmental stresses. In particular, we focus on the multiple stress-sensing mechanisms of Keap1 and novel regulatory functions of Nrf2.
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Hypoxia and dysregulated metabolism are defining features of solid tumors. How cancer cells adapt to low O2 has been illuminated by numerous studies, with "reprogrammed" metabolism being one of the most important mechanisms. This metabolic reprogramming not only promotes cancer cell plasticity, but also provides novel insights for treatment strategies. As the most studied O2 "sensor", hypoxia-inducible factor (HIF) is regarded as an important regulator of hypoxia-induced transcriptional responses. This review will summarize our current understanding of hypoxia-induced changes in cancer cell metabolism, with an initial focus on HIF-mediated effects, and highlight how these metabolic alterations affect malignant phenotypes.
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Brown and beige adipose tissues can catabolize stored energy to generate heat. This unique capacity for thermogenesis could be leveraged as a therapy for metabolic disease. Uncoupling protein 1 (UCP1) is the principal effector of adipose tissue thermogenesis, uncoupling protonmotive force from ATP synthesis to increase the rate of mitochondrial substrate oxidation and heat production. Evidence from numerous genetic models and pharmacological interventions have now demonstrated a clear signaling role for mitochondrial reactive oxygen species (ROS) in driving adipose tissue thermogenesis. Herein, we summarize the redox processes that have been shown to support thermogenic identity and function in animal and cellular models of thermogenesis. Additionally, we contextualize these findings within established principles of redox signaling, and fundamental mechanistic studies of UCP1- dependent uncoupling using in vitro models. We provide a framework for understanding the role of mitochondrial ROS signaling in thermogenesis together with testable hypotheses and new directions for understanding mechanisms and developing therapies.
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ATP7B is a copper-transporting P1B-type ATPase (Cu-ATPase) with an essential role in human physiology. Mutations in ATP7B cause a potentially fatal Wilson disease, and changes in ATP7B expression are observed in several cancers. Despite its physiologic importance, the biochemical information about ATP7B remains limited owing to a complex multi-domain organization of the protein. By analogy with the better characterized prokaryotic Cu-ATPases, ATP7B is assumed to be a single-chain monomer. We show that in eukaryotic cells, human ATP7B forms dimers that can be purified following solubilization. Deletion of the four N-terminal metal-binding domains, characteristic for human ATP7B, does not disrupt dimerization, i.e. the dimer interface is formed by the domains that are conserved among Cu-ATPases. Unlike the full-length ATP7B, which is targeted to the trans-Golgi network, 1-4ΔMBD-7B is targeted primarily to vesicles. This result and the analysis of differentially tagged ATP7B variants indicate that the dimeric structure is retained during ATP7B trafficking between the intracellular compartments. Purified dimeric species of 1-4ΔMBD-7B were characterized by a negative stain electron microscopy in the presence of ADP/MgCl2. Single particle analysis yielded a low resolution 3D model, which provides the first insight into an overall architecture of a human Cu-ATPase, positions of the main domains, and a dimer interface.
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Nischarin (Nisch) is a key protein functioning as a molecular scaffold and thereby hosting interactions with several protein partners. To explore the physiological importance of Nisch, here we generated Nisch loss-of-function mutant mice and analyzed their metabolic phenotype. Nisch mutant embryos exhibited delayed development, characterized by small size and attenuated weight gain. We uncovered the reason for this phenotype by showing that Nisch binds to and inhibits the activity of AMP-activated protein kinase (AMPK), which regulates energy homeostasis by suppressing anabolic and activating catabolic processes. The Nisch mutations enhanced AMPK activation and inhibited mechanistic target of rapamycin (mTOR) signaling in mouse embryonic fibroblasts (MEFs) as well as in muscle and liver tissues of mutant mice. Nisch-mutant mice also exhibited increased rates of glucose oxidation with increased energy expenditure, despite reduced overall food intake. Moreover, the Nisch-mutant mice had reduced expression of liver markers of gluconeogenesis associated with increased glucose tolerance. As a result, these mice displayed decreased growth and body weight. Taken together, our results indicate that Nisch is an important AMPK inhibitor and a critical regulator of energy homeostasis, including lipid and glucose metabolism.
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Mitochondrial production of superoxide and hydrogen peroxide is potentially important in cell signaling and disease. Eleven distinct mitochondrial sites that differ markedly in capacity are known to leak electrons to oxygen to produce O2.- and/or H2O2. We discuss their contributions to O2.-/H2O2 production under native conditions in mitochondria oxidizing different substrates and in conditions mimicking physical exercise, and the changes in their capacities after caloric restriction. We review the use of S1QELs and S3QELs, suppressors of mitochondrial O2.-/H2O2 generation that do not inhibit oxidative phosphorylation, as tools to characterize the contributions of specific sites in situ and in vivo.
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Life on oxygen predisposes cells to reactive oxygen species (ROS) generation by electron slippage in the electron transfer chain. Aerobic metabolism also generates as bonafide products, superoxide (O2-) and hydrogen peroxide (H2O2), in reactions involving one- or two-electron reduction of O2. Though often viewed as dangerous, ROS are now recognized as important messengers in redox signaling pathways. A delicate balance between needed versus excessive ROS production distinguishes health from an array of disease states. A collection of provocative reviews in this thematic series, discusses the relative importance of mitochondrial sites for ROS production, ROS signaling-mediated regulation of cellular stress responses and thermogenesis, and how O2 deficiency leads to metabolic reprograming in cancer.
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Abstract The hurdles in realizing immunotherapy success for cure stem from the fact that cancer patients are either refractory to immune response and/or develop resistance. Here, we propose that these phenomena are due, in part, to the deployment of a 'decoy flare' i.e., release or secretion of anomalous cancer-associated antigens. The cancer secretome, that resembles the parent cell make up, is composed of soluble macromolecules (proteins, glycans, lipids, DNAs, RNAs etc.) and insoluble vesicles (exosomes), thus hindering cancer detection/recognition by immunotherapeutic agents resulting in a 'cancer-stealth' effect. A clinical evaluation of tumor-derived secretome and specific autoantibodies may change the therapeutic landscape
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Planta Med
DOI: 10.1055/s-0043-118034
At least three Leonurus species, Leonurus cardiaca, Leonurus japonicus, and Leonurus sibiricus, are used in various traditional medicinal systems for different therapeutic purposes. The plant names "L. sibiricus" and "L. japonicus" are often used as synonyms, which causes confusion in literature and implies that several studies may be based on improperly identified plant material. To avoid further confusion, the current status of the identification of these three species is illustrated. Characteristics for their unequivocal identification are presented using stereo and light microscopy as well as HPTLC.The establishment of the species-specific anatomical, morphological, and phytochemical characters was based on reference specimens in comparison with wild collected or commercially obtained material. Morphologically, the species differed in shape and length ratio of the upper and lower lip of the corolla. Differentiating anatomical characters involve the presence, density, and dimension of trichomes on different organs. Detailed anatomical descriptions of the leaves and corollae of L. japonicus and L. sibiricus are given and compared to L. cardiaca. These three sets of characters facilitate fast and reliable identification. Complementary HPTLC fingerprints show type-specific patterns that allow the differentiation of L. japonicus from the other two species. For the distinction of L. cardiaca and L. sibiricus, flower morphology has to be considered.The presented data contribute to the quality control of the three Leonurus species and additionally meet a definite and timely need regarding the introduction of L. japonicus to the European Pharmacopoeia in addition to the already existing monograph of L. cardiaca.
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Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
The acute respiratory distress syndrome (ARDS) is a common and devastating disorder. Alcohol use disorders (AUDs) increase ARDS risk, and worsen outcomes, through mechanisms that may include enhancing pulmonary oxidative stress. Alcohol consumption increases activity of the enzyme xanthine oxidoreductase (XOR) that contributes to production of both reactive oxygen species (ROS) and uric acid, a damage-associated molecular pattern. These by-products have the potential to modulate pro-inflammatory pathways such as those involving cyclooxygenase (COX)-2, and to activate the nucleotide-binding domain, leucine-rich-containing family, pyrin-domain containing-3 (NLRP3) inflammasome. We sought to determine if pulmonary and systemic XOR activity were altered by AUDs. Bronchoscopy with bronchoalveolar lavage (BAL) and blood sampling were performed in otherwise healthy human subjects with AUDs and controls. Uric acid in epithelial lining fluid derived from BAL was substantially higher among individuals with AUDs, and did not normalize after 7 days of abstinence; serum uric acid did not differ across groups. XOR enzyme activity in fresh BAL cells and serum was significantly increased in subjects with AUDs. XOR protein in BAL cells from AUD subjects was increased in parallel with COX-2 expression, and further, mRNA expression of NLRP3 inflammasome components was sustained in LPS-stimulated BAL cells from AUD subjects in conjunction with increased IL-1β. Our data suggest that AUDs augment pulmonary and systemic XOR activity that may contribute to ROS and uric acid generation, promoting inflammation. Further investigations will be necessary to determine if XOR inhibition can mitigate alcohol-associated pulmonary oxidative stress, diminish inflammation, and improve ARDS outcomes.
DNA methylation of cytosine residues is a well-studied epigenetic change, which regulates gene transcription by altering accessibility for transcription factors. Hypoxia is a pervasive stimulus that affects many physiological processes. The circulatory and respiratory systems adapt to chronic sustained hypoxia, such as that encountered during a high altitude sojourn. Many people living at sea level experience chronic intermittent hypoxia (IH) due to sleep apnea, which leads to cardiovascular and respiratory maladaptation. This article presents a brief update on emerging evidence suggesting that changes in DNA methylation contribute to pathologies caused by chronic IH and potentially mediate adaptations to chronic sustained hypoxia by affecting the hypoxia-inducible factor (HIF) signaling pathway.
There is no therapeutic intervention proven to prevent the acute respiratory syndrome (ARDS). Novel mechanistic insights into the pathophysiology of ARDS are therefore required. Platelets are implicated in regulating many of the pathogenic processes which occur during ARDS, however the mechanisms remain elusive. The platelet receptor C-type lectin-like 2 (CLEC-2) has been shown to regulate vascular integrity at sites of acute inflammation. Therefore, the purpose of this study was to establish the role of CLEC-2 and its ligand podoplanin in a mouse model of ARDS. Platelet-specific CLEC-2-deficient, as well as alveolar epithelial type I cell (AECI)-specific- or hematopoietic-specific podoplanin deficient mice were established using cre-loxP strategies. Combining these with intratracheal (IT) instillations of lipopolysaccharide (LPS), we demonstrate that arterial oxygen saturation decline in response to IT-LPS in platelet-specific CLEC-2-deficient mice is significantly augmented. An increase in bronchoalveolar lavage (BAL) neutrophils and protein was also observed 48h post IT-LPS, with significant increases in pro-inflammatory chemokines detected in BAL of platelet-specific CLEC-2 deficient animals. Deletion of podoplanin from hematopoietic cells but not AECIs also reduces lung function and increases pro-inflammatory chemokine expression following IT-LPS. Furthermore we demonstrate that following IT-LPS, platelets are present in BAL in aggregates with neutrophils which allows for CLEC-2 interaction with podoplanin expressed on BAL inflammatory alveolar macrophages. Taken together these data suggest that the platelet CLEC-2-podoplanin signaling axis regulates the severity of lung inflammation in mice and is a possible novel target for therapeutic intervention in patients at risk of developing ARDS.
Levosimendan has a calcium-sensitizing effect in the myocardium and opens adenosine-triphosphate-sensitive potassium channels (KATP) in vascular smooth muscle. Since airway smooth muscle also expresses KATP, we characterized the protective potential of levosimendan against increased airway and respiratory tissue resistances. Animals were administered levosimendan alone (Group L), levosimendan after pretreatment with a KATP channel blocker (glibenclamide, Group LG), glibenclamide only (Group G), or solvent alone (dextrose, Group C). Airway resistance (Raw), tissue damping (G) and elastance were determined by forced oscillations under baseline conditions and following provocation tests with intravenous methacholine (MCh). Cardiac output (CO) was assessed by transpulmonary thermodilution. The same sequence of measurements was then repeated during intravenous infusion of levosimendan in Groups L and LG or glucose in Groups G and C. Sham treatments in Group C and G had no effect on lung responsiveness. However, levosimendan treatment in Group L elevated CO and inhibited the MCh-induced airway responses (Raw changes of 87.8±83[SD]% vs. 24.4±16% at 4μg/kg/min MCh, p<0.001), and in G (35.2±12.7% vs. 25.2±12.9%, p<0.05). The preventive affect of levosimendan against lung constriction vanished in the LG group. Levosimendan exerts a KATP-mediated potential to prevent bronchoconstriction and may prohibit adverse lung peripheral changes both in the small bronchi and the pulmonary parenchyma. The identification of a further pleiotropic property of levosimendan that is related to the pulmonary system is of particular importance for patients with decreased cardiorespiratory reserves, for which simultaneous circulatory support is complemented with prevention of adverse respiratory events.
We previously proposed a role for the 2-pore domain potassium (K2P) channel TREK-1 in hyperoxia (HO)-induced lung injury. To determine whether redundancy between the 3 TREK isoforms (TREK-1, TREK-2, TRAAK) could protect from HO-induced injury, we now examined the effect of deletion of all 3 TREK isoforms in a clinically relevant scenario of prolonged HO exposure and mechanical ventilation (MV). We exposed WT and TREK-1/TREK-2/TRAAK-deficient (triple ko) mice to either room air, 72 hours HO, MV (high and low tidal volume), or a combination of HO+MV, and measured quasi-static lung compliance, BAL protein concentration, histologic lung injury scores (LIS), cellular apoptosis, and cytokine levels. We determined surfactant gene and protein expression, and attempted to prevent HO-induced lung injury by prophylactically administering exogenous surfactant (Curosurf). HO treatment increased lung injury in triple ko but not WT mice, including an elevated LIS, BAL protein concentration, markers of apoptosis, decreased lung compliance, and a more proinflammatory cytokine phenotype. MV alone had no effect on lung injury markers. Exposure to HO+MV (low TV) further decreased lung compliance in triple ko but not WT mice, and HO+MV (high TV) was lethal for triple ko mice. In triple ko mice, the HO-induced lung injury was associated with decreased surfactant protein A (SPA) and SPC, but not SPB and SPD expression. However, these changes could not be explained by alterations in the transcription factors NF-1, NKX2.1/TTF or c-jun, or lamellar body levels. Prophylactic Curosurf administration did not improve lung injury scores or compliance in triple ko mice.
The early history of cardiac catheterization has many interesting features. First, although it would be natural to assume that the procedure was initiated by cardiologists, two of the three people who shared the Nobel Prize for the discovery were pulmonologists, while the third was a urologist. The primary objective of the pulmonologists, André Cournand and Dickinson Richards, was to obtain mixed venous blood from the right heart so that they could use to use the Fick principle to calculate total pulmonary blood flow. Cournand's initial catheterization studies were prompted by his reading an account by Werner Forssmann who catheterized himself 12 years before. His bold experiment was one of the most bizarre in medical history. In the earliest studies that followed, Cournand and colleagues first passed catheters into the right atrium, then into the right ventricle, and finally the pulmonary artery. At the time, the investigators did not appreciate the significance of the low vascular pressures, nor that what they had done would revolutionize interventional cardiology. Within a year, William Dock predicted that there would be a very low blood flow at the top of the upright lung, and he proposed that this was the cause of the apical localization of pulmonary tuberculosis. The fact that the pulmonary vascular pressures are very low has many implications in lung disease. Cardiac catheterization changed the face of investigative cardiology, and its instigators were awarded the Nobel Prize in 1956.
| Medical Xpress | HPV vaccination rates lag for vulnerable population of childhood cancer survivors Medical Xpress Persistent infection with certain high-risk strains of HPV can cause cancer of the cervix, vagina, penis, tongue, throat, anus and other sites. Previous studies from St. Jude and others found that childhood cancer survivors are at an increased risk of ... and more » |
| Portsmouth Daily Times | Continuing against cancer Portsmouth Daily Times Clifford was a thyroid cancer survivor and a five year survivor of ovarian cancer before losing her life. She excelled both academically and athletically before dying from ovarian cancer on Feb. 11, 2011, at the age of 28. The scholarships were created ... |
The increased industrialization and improvised human lifestyle lead to a surge in environmental pollution nowadays. Even the chemicals which are known as prophylactic agents were currently liable to be toxic. One among them is inorganic fluoride whose wider application in numerous processes makes it as an inevitable environmental contaminant and industrial pollutant. Although the systemic toxicity of fluoride has been extensively studied, still there is lacuna in the field of pulmonary fluoride toxicity. Hence, we have focused on the molecular mechanism of action of fluoride compounds on pulmonary system. A study of literatures that focused on the potential physiological and toxicological consequences of fluoride on pulmonary system was carried out. The goal of this review is to present an overview of the research carried out till date on the molecular aspects of fluoride exposure with emphasis on pulmonary system and their possible mechanisms.
Nitrogen oxides and smoke are the substantial emissions for the diesel engines. Fuels comprising high-level oxygen content can have low smoke emission due to better oxidation of soot. The objective of the paper is to assess the potential to employ oxygenated fuel, i.e., n-butanol and its blends with the neat diesel from 0 to 30% by volume. The experimental and computational fluid dynamic (CFD) simulation is carried out to estimate the performance, combustion, and exhaust emission characteristics of n-butanol-diesel blends for various injection timings (9°, 12°, 15°, and 18°) using modern twin-cylinder, four-stroke, common rail direct injection (CRDI) engine. Experimental results reveal the increase in brake thermal efficiency (BTE) by ~ 4.5, 6, and 8% for butanol-diesel blends of 10% (Bu10), 20% (Bu20), and 30% (Bu30), respectively, compared to neat diesel (Bu0). Maximum BTE for Bu0 is 38.4%, which is obtained at 12° BTDC; however, for Bu10, Bu20 and Bu30 are 40.19, 40.9, and 41.7%, which are obtained at 15° BTDC, respectively. Higher flame speed of n-butanol-diesel blends burn a large amount of fuel in the premixed phase, which improves the combustion as well as emission characteristics. CFD and experimental results are compared and validated for all fuel blends for in-cylinder pressure and nitrogen oxides (NOx), and found to be in good agreement. Both experimental and simulation results witnessed in reduction of smoke opacity, NOx, and carbon monoxide emissions with the increasing n-butanol percentage in diesel fuel.
Monocyte chemoattractant protein-1 (MCP-1) overproduction from inflamed adipose tissue is a major contributor to obesity-related metabolic syndromes. 3T3-L1 embryonic fibroblasts were cultured and differentiated into adipocytes using an established protocol. Adipocytes were treated with lipopolysaccharide (LPS) to induce inflammation and thus MCP-1 release. At the same time, varying concentrations of chondroitin sulfate (CS) were added in a physiologically relevant range (10-200 µg/mL) to determine its impact on MCP-1 release. Chondroitin sulfate, a natural glycosaminoglycan of connective tissue including the cartilage extracellular matrix, was chosen on the basis of our previous studies demonstrating its anti-inflammatory effect on macrophages. Because the main action of MCP-1 is to induce monocyte migration, cultured THP-1 monocytes were used to test whether CS at the highest physiologically relevant concentration could inhibit cell migration induced by human recombinant MCP-1. Chondroitin sulfate (100-200 µg/mL) inhibited MCP-1 release from inflamed adipocytes in a dose-dependent manner (P < .01, 95% confidence interval CI: −5.89 to −3.858 at 100 µg/mL and P < .001, 95% CI: −6.028 to −3.996 at 200 µg/mL) but had no effect on MCP-1–driven chemotaxis of THP-1 monocytes. In summary, CS could be expected to reduce macrophage infiltration into adipose tissue by reduction in adipocyte expression and release of MCP-1 and as such might reduce adipose tissue inflammation in response to pro-inflammatory stimuli such as LPS, now increasingly recognized to be relevant in vivo.
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Publication date: Available online 24 August 2017
Source:Clinical Biochemistry
Author(s): Christopher R. McCudden, Joannes F.M. Jacobs, David Keren, Hélène Caillon, Thomas Dejoie, Kristian Andersen
Protein electrophoresis and immunofixation are subject to a variety of analytical interferences that may affect monoclonal protein diagnostics performed in the context of monoclonal gammopathies. Interferences include endogenous substances, such as hemoglobin and fibrinogen, and exogenous compounds, such as radiocontrast dyes, antibiotics, and monoclonal antibody therapies. General approaches to managing interferences begin with recognition of the problem. Provided herein are examples of common, rare, and novel interferences with the goal of providing a comprehensive overview. With each example, specific methods and strategies are provided to manage analytical interferences to ensure that interpretative reports are accurate. Longstanding and newer technologies are also described to contextualize where interferences may be identified and avoided.
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The aim of this study was to evaluate the impact of CSC on insensitivity to radiotherapy in HNSCC.
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Paresis podules are localized areas of Reinke edema that can develop on paretic or paralyzed vocal folds, or on the contralateral vocal fold.
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Abstract This study aimed to determine the speech discriminatory ability of the contralateral ear of users of a unilateral bone-anchored hearing system (BAHS). The Oticon Medical Ponto Pro/Ponto Pro Power device brand was used for all patients. Five BAHS users (3 men, 2 women) participated in the study. Pure-tone air-conduction thresholds at 250 to 6,000 Hz, masked and unmasked bone-conduction thresholds at 250 to 4,000 Hz, and participants' speech discrimination scores in both ears were determined. Speech discrimination tests were carried out in a silent environment with monosyllabic and trisyllabic word lists. After this, the ipsilateral ear (the BAHS side) was masked with wide-band noise using an insert earphone, and the word tests were repeated. A mild decrease was observed in monosyllabic words in ipsilateral masking; however, this was not found to be statistically significant. Conversely, a decrease was not observed in the repetition of trisyllabic words in any participants, even under high-level ipsilateral masking. These results suggested that unilateral BAHS application could prevent or reduce the neural deprivation of the contralateral ear.
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SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting
British Journal of Cancer advance online publication, August 24 2017. doi:10.1038/bjc.2017.271
Authors: Alastair Greystoke, Nicola Steele, Hendrik-Tobias Arkenau, Fiona Blackhall, Noor Md Haris, Colin R Lindsay, Raffaele Califano, Mark Voskoboynik, Yvonne Summers, Karen So, Dana Ghiorghiu, Angela W Dymond, Stuart Hossack, Ruth Plummer & Emma Dean
Targeting apoptosis in acute myeloid leukaemia
British Journal of Cancer advance online publication, August 24 2017. doi:10.1038/bjc.2017.281
Authors: Philippe A Cassier, Marie Castets, Amine Belhabri & Norbert Vey
Cardiovascular disease risk and androgen deprivation therapy in patients with localised prostate cancer: a prospective cohort study
British Journal of Cancer advance online publication, August 24 2017. doi:10.1038/bjc.2017.280
Authors: Reina Haque, Marianne UlcickasYood, Xiaoqing Xu, Andrea E Cassidy-Bushrow, Huei-Ting Tsai, Nancy L Keating, Stephen K Van Den Eeden & Arnold L Potosky
| HPV Vaccination Rates Lag for Vulnerable Population of Childhood Cancer Survivors Newswise (press release) Persistent infection with certain high-risk strains of HPV can cause cancer of the cervix, vagina, penis, tongue, throat, anus and other sites. Previous studies from St. Jude and others found that childhood cancer survivors are at an increased risk of ... and more » |
History provides us with valuable lessons. The tragic Minamata Bay disaster in Japan is a stark reminder that exposure to the element mercury and its compounds can impact human health, causing irreversible neurological damage and other issues such as psychosis. Earth's health is also at risk. In the 2013 Global Mercury Assessment, the UN Environment Programme (UNEP) reported that environmental mercury emissions can reach up to 8900 tonnes annually, of which 90% consist of anthropogenic emissions from processes such as artisanal gold mining, which is often unregulated and involves the forced labour of marginalised communities.
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