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Identification of Biomarkers of Human Skin Ageing in Both Genders. Wnt Signalling - A Label of Skin Ageing?  [PDF]
Evgenia Makrantonaki, Thore C. Brink, Vasiliki Zampeli, Rana Mohsen Elewa, Barbara Mlody, Amir M. Hossini, Bjoern Hermes, Ulf Krause, Juergen Knolle, Marwa Abdallah, James Adjaye, Christos C. Zouboulis
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050393
Abstract: The goal of our work has been to investigate the mechanisms of gender-independent human skin ageing and examine the hypothesis of skin being an adequate model of global ageing. For this purpose, whole genome gene profiling was employed in sun-protected skin obtained from European Caucasian young and elderly females (mean age 26.7±4 years [n1 = 7] and 70.75±3.3 years [n2 = 4], respectively) and males (mean age 25.8±5.2 years [n3 = 6] and 76±3.8 years [n4 = 7], respectively) using the Illumina array platform. Confirmation of gene regulation was performed by real-time RT-PCR and immunohistochemistry. 523 genes were significantly regulated in female skin and 401 genes in male skin for the chosen criteria. Of these, 183 genes exhibited increased and 340 decreased expression in females whereas 210 genes showed increased and 191 decreased expression in males with age. In total, 39 genes were common in the target lists of significant regulated genes in males and females. 35 of these genes showed increased (16) or decreased (19) expression independent of gender. Only 4 overlapping genes (OR52N2, F6FR1OP2, TUBAL3 and STK40) showed differential regulation with age. Interestingly, Wnt signalling pathway showed to be significantly downregulated in aged skin with decreased gene and protein expression for males and females, accordingly. In addition, several genes involved in central nervous system (CNS) ageing (f.i. APP, TAU) showed to be expressed in human skin and were significanlty regulated with age. In conclusion, our study provides biomarkers of endogenous human skin ageing in both genders and highlight the role of Wnt signalling in this process. Furthermore, our data give evidence that skin could be used as a good alternative to understand ageing of different tissues such as CNS.
Proteomic Biomarkers for Ageing the Mosquito Aedes aegypti to Determine Risk of Pathogen Transmission  [PDF]
Leon E. Hugo, James Monkman, Keyur A. Dave, Leesa F. Wockner, Geoff W. Birrell, Emma L. Norris, Vivian J. Kienzle, Maggy T. Sikulu, Peter A. Ryan, Jeffery J. Gorman, Brian H. Kay
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0058656
Abstract: Biomarkers of the age of mosquitoes are required to determine the risk of transmission of various pathogens as each pathogen undergoes a period of extrinsic incubation in the mosquito host. Using the 2-D Difference Gel Electrophoresis (2-D DIGE) procedure, we investigated the abundance of up to 898 proteins from the Yellow Fever and dengue virus vector, Aedes aegypti, during ageing. By applying a mixed-effects model of protein expression, we identified five common patterns of abundance change during ageing and demonstrated an age-related decrease in variance for four of these. This supported a search for specific proteins with abundance changes that remain tightly associated with ageing for use as ageing biomarkers. Using MALDI-TOF/TOF mass spectrometry we identified ten candidate proteins that satisfied strict biomarker discovery criteria (identified in two out of three multivariate analysis procedures and in two cohorts of mosquitoes). We validated the abundances of the four most suitable candidates (Actin depolymerising factor; ADF, Eukaryotic initiation factor 5A; eIF5A, insect cuticle protein Q17LN8, and Anterior fat body protein; AFP) using semi-quantitative Western analysis of individual mosquitoes of six ages. The redox-response protein Manganese superoxide dismutase (SOD2) and electron shuttling protein Electron transfer oxidoreductase (ETO) were subject to post-translational modifications affecting their charge states with potential effects on function. For the four candidates we show remarkably consistent decreases in abundance during ageing, validating initial selections. In particular, the abundance of AFP is an ideal biomarker candidate for whether a female mosquito has lived long enough to be capable of dengue virus transmission. We have demonstrated proteins to be a suitable class of ageing biomarkers in mosquitoes and have identified candidates for epidemiological studies of dengue and the evaluation of new disease reduction projects targeting mosquito longevity.
Preliminary characterizations of a serum biomarker for sarcoidosis by comparative proteomic approach with tandem-mass spectrometry in ethnic Han Chinese patients
Zhang Yuan,Chen Xianqiu,Hu Yang,Du Shanshan
Respiratory Research , 2013, DOI: 10.1186/1465-9921-14-18
Abstract: Background The diagnosis of sarcoidosis is still a significant challenge in China because of the need to exclude other diseases including granulomatous infections and malignancies that may be clinically and radiographically similar. The specific aim of the study is to search for serum protein biomarkers of sarcoidosis and to validate their clinical usefulness in differential diagnosis. Methods Serum samples were collected from patients with sarcoidosis (n = 37), and compared to those from patients with tuberculosis (n = 20), other pulmonary diseases (n = 20), and healthy volunteers (n = 20) for determination of sarcoidosis-specific or -associated protein expression profiles. The first part of this study focused on proteomic analysis of serum from patients with sarcoidosis to identify a pattern of peptides capable of differentiating the studied populations using the ClinProt profiling technology based on mass spectrometry. Enzyme Linked Immunosorbent Assay (ELISA) was then used to verify corresponding elevation of the serum protein concentration of the potential biomarkers in the same patients sets. Receiver operating characteristic curve (ROC) analyses was performed to determine the optimal cutoff value for diagnosis. Immunohistochemistry was carried out to further confirm the protein expression patterns of the biomarkers in lung tissue. Results An unique protein peak of M/Z 3,210 Daltons (Da) was found to be differentially expressed between the sarcoidosis and control groups and was identified as the N-terminal peptide of 29 amino acids (94-122) of serum amyloid A (SAA). ELISA confirmed that the serum SAA level was significantly higher in the sarcoidosis group than that of the other 3 control groups (p < 0.05). The cutoff for serum SAA concentration determined by ROC analysis was 101.98 ng/ml, with the sensitivity and specificity of 96.3% and 52.5%, respectively. Immunohistochemical staining showed that the SAA depositions in lung tissue of the sarcoidosis patients were also significantly more intense than in non-sarcoid lung tissue (p < 0.05). Conclusion This is the first study to investigate serum protein markers in Chinese subjects with sarcoidosis. This study shows that the serum SAA expression profiles were different between the sarcoidosis and non-sarcoidosis groups. SAA may be a potential serum biomarker for ruling-out the diagnosis of sarcoidosis in Chinese subjects.
A Comprehensive Peptidome Profiling Technology for the Identification of Early Detection Biomarkers for Lung Adenocarcinoma  [PDF]
Koji Ueda,Naomi Saichi,Sachiko Takami,Daechun Kang,Atsuhiko Toyama,Yataro Daigo,Nobuhisa Ishikawa,Nobuoki Kohno,Kenji Tamura,Taro Shuin,Masato Nakayama,Taka-Aki Sato,Yusuke Nakamura,Hidewaki Nakagawa
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018567
Abstract: The mass spectrometry-based peptidomics approaches have proven its usefulness in several areas such as the discovery of physiologically active peptides or biomarker candidates derived from various biological fluids including blood and cerebrospinal fluid. However, to identify biomarkers that are reproducible and clinically applicable, development of a novel technology, which enables rapid, sensitive, and quantitative analysis using hundreds of clinical specimens, has been eagerly awaited. Here we report an integrative peptidomic approach for identification of lung cancer-specific serum peptide biomarkers. It is based on the one-step effective enrichment of peptidome fractions (molecular weight of 1,000–5,000) with size exclusion chromatography in combination with the precise label-free quantification analysis of nano-LC/MS/MS data set using Expressionist proteome server platform. We applied this method to 92 serum samples well-managed with our SOP (standard operating procedure) (30 healthy controls and 62 lung adenocarcinoma patients), and quantitatively assessed the detected 3,537 peptide signals. Among them, 118 peptides showed significantly altered serum levels between the control and lung cancer groups (p<0.01 and fold change >5.0). Subsequently we identified peptide sequences by MS/MS analysis and further assessed the reproducibility of Expressionist-based quantification results and their diagnostic powers by MRM-based relative-quantification analysis for 96 independently prepared serum samples and found that APOA4 273–283, FIBA 5–16, and LBN 306–313 should be clinically useful biomarkers for both early detection and tumor staging of lung cancer. Our peptidome profiling technology can provide simple, high-throughput, and reliable quantification of a large number of clinical samples, which is applicable for diverse peptidome-targeting biomarker discoveries using any types of biological specimens.
Endogenous Bioactive Peptides as Potential Biomarkers for Atherosclerotic Coronary Heart Disease  [PDF]
Takuya Watanabe,Kengo Sato,Fumiko Itoh,Kohei Wakabayashi,Masayoshi Shichiri,Tsutomu Hirano
Sensors , 2012, DOI: 10.3390/s120404974
Abstract: Cardiovascular disease is the leading cause of death worldwide, with high medical costs and rates of disability. It is therefore important to evaluate the use of cardiovascular biomarkers in the early diagnosis of coronary artery disease (CAD). We have screened a variety of recently identified bioactive peptides candidates in anticipation that they would allow detection of atherosclerotic CAD. Especially, we have focused on novel anti-atherogenic peptides as indicators and negative risk factors for CAD. In vitro, in vivo and clinical studies indicated that human adiponectin, heregulin-β1, glucagon-like peptide-1 (GLP-1), and salusin-α, peptides of 244, 71, 30, and 28 amino acids, respectively, attenuate the development and progression of atherosclerotic lesions by suppressing macrophage foam cell formation via down-regulation of acyl-coenzyme A: cholesterol acyltransferase-1. Circulating levels of these peptides in the blood are significantly decreased in patients with CAD compared to patients without CAD. Receiver operating characteristic analyses showed that salusin-α is a more useful biomarker, with better sensitivity and specificity, compared with the others for detecting CAD. Therefore, salusin-α, heregulin-β1, adiponectin, and/or GLP-1, alone or in various combinations, may be useful as biomarkers for atherosclerotic CAD.
Ageing, autoimmunity and arthritis: An introduction
Andrew P Cope
Arthritis Research & Therapy , 2003, DOI: 10.1186/ar992
Abstract: It has long been recognised that there exists a relationship between ageing and susceptibility to infection. It follows from this that defects in the ageing immune system must somehow be to blame. Quite how the immune system ages, and how immune senescence predisposes individuals to disease is still a mystery. Nevertheless, advances in basic cell biology and a better appreciation of how cells integrate and respond to signals acquired from their environment has made it possible to piece together aberrations of the ageing immune system, largely at the cellular level. New laboratory techniques are at our disposal, and these have most certainly facilitated progress. For example, we can now study thymic function, or perhaps more accurately newly generated T cells [3], and we can also utilise biomarkers to define specific cell subsets and correlate genotype and phenotype with function. Particularly important for studying ageing is an appreciation of replicative history and proliferative senescence made possible by the capacity to directly measure it, through analysis of telomere length [4]. And of course a list of experimental approaches wouldn't be complete without mentioning gene expression profiling.Data suggest that while antigen presenting function is relatively well preserved during the ageing process [5], lymphocyte function is perturbed, characterised by depression of both cellular and humoral immunity. Accordingly, to begin to address how ageing influences immunity, a focus on lymphocyte biology seems a good starting point. For example, over the decades numerous studies have reported altered production of T cell progenitors, reductions in the generation of na?ve T cells, ageing of resting and clonally expanding cells, and in particular disrupted intracellular signalling leading to perturbations in cytoskeleton reorganisation and cell migration (reviewed in [6]). In this issue, Goronzy and Weyand begin by exploring how the dynamics of T cell repertoire diversity p
Evidence of accelerated ageing in clinical drug addiction from immune, hepatic and metabolic biomarkers
Albert Reece
Immunity & Ageing , 2007, DOI: 10.1186/1742-4933-4-6
Abstract: 12,093 clinical laboratory results 1995–2006 were reviewed. To make the age ranges of the medical and addicted groups comparable the age range was restricted to 15–45 years.739 drug addicted (DA) and 5834 general medical (GM) age matched blood samples were compared. Significant elevation of immune parameters was noted in the C-reactive protein, erythrocyte sedimentation rate, total lymphocyte count, serum globulins and the globulin:albumin ratio (P < 0.01). Alanine aminotranferase, creatinine, urea, and insulin like growth factor-1 were also significantly higher (P < 0.01) in the DA group. Albumin, body mass index and dihydroepiandrosterone sulphate were unchanged and cholesterol was lower (all P < 0.05).These data demonstrate for the first time that addiction is associated with an altered profile of common biomarkers of ageing raising the possibility that the ageing process may be altered in this group. Infective and immune processes may be centrally involved. They suggest that addiction forms an interesting model to further examine the contribution of immune suppression and hyperstimulation to the ageing process.Addictive disorders are well known to be associated with a high level of physical and psychological disorders [1]. Most chronic chemical addictions are also associated with very elevated rates of mortality [2] which have been estimated to be 10–70 [3,4] times that of non-clinical populations. Addictive drugs are known to impair cell growth and division [5-7] and therefore might be presumed to impact particularly dividing cells such as stem and progenitor cell pools [8,9]. They are also known either singly or in combination to potentiate apoptosis [10-14] thereby adding to this effect. Ageing medicine has recently emerged as a distinct scientific discipline. The cellular hypothesis of ageing suggests that the ageing phenotype of the organism is associated with cellular correlates of age related change including cell loss, reduced rates of cell renewal, and
Proteomic Profiling of Exosomes Leads to the Identification of Novel Biomarkers for Prostate Cancer  [PDF]
Diederick Duijvesz, Kristin E. Burnum-Johnson, Marina A. Gritsenko, A. Marije Hoogland, Mirella S. Vredenbregt-van den Berg, Rob Willemsen, Theo Luider, Ljiljana Pa?a-Toli?, Guido Jenster
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082589
Abstract: Background Current markers for prostate cancer, such as PSA lack specificity. Therefore, novel biomarkers are needed. Unfortunately, the complexity of body fluids often hampers biomarker discovery. An attractive alternative approach is the isolation of small vesicles, i.e. exosomes, ~100 nm, which contain proteins that are specific to the tissue from which they are derived and therefore can be considered as treasure chests for disease-specific biomarker discovery. Materials and Methods Exosomes were isolated from 2 immortalized primary prostate epithelial cells (PNT2C2 and RWPE-1) and 2 PCa cell lines (PC346C and VCaP) by ultracentrifugation. After tryptic digestion, proteomic analyses utilized a nanoLC coupled with an LTQ-Orbitrap operated in tandem MS (MS/MS) mode. Accurate Mass and Time (AMT) tag approach was employed for peptide identification and quantitation. Candidate biomarkers were validated by Western blotting and Immunohistochemistry. Results Proteomic characterization resulted in the identification of 248, 233, 169, and 216 proteins by at least 2 peptides in exosomes from PNT2C2, RWPE-1, PC346C, and VCaP, respectively. Statistical analyses revealed 52 proteins differently abundant between PCa and control cells, 9 of which were more abundant in PCa. Validation by Western blotting confirmed a higher abundance of FASN, XPO1 and PDCD6IP (ALIX) in PCa exosomes. Conclusions Identification of exosomal proteins using high performance LC-FTMS resulted in the discovery of PDCD6IP, FASN, XPO1 and ENO1 as new candidate biomarkers for prostate cancer.
Enhanced Antioxidant Capacity and Anti-Ageing Biomarkers after Diet Micronutrient Supplementation  [PDF]
Aneta Balcerczyk,Agnieszka Gajewska,Ewa Macierzyńska-Piotrowska,Tomasz Pawelczyk,Grzegorz Bartosz,Janusz Szemraj
Molecules , 2014, DOI: 10.3390/molecules190914794
Abstract: A growing number of studies confirm an important effect of diet, lifestyle and physical activity on health status, the ageing process and many metabolic disorders. This study focuses on the influence of a diet supplement, NucleVital ?Q10 Complex, on parameters related to redox homeostasis and ageing. An experimental group of 66 healthy volunteer women aged 35–55 supplemented their diet for 12 weeks with the complex, which contained omega-3 acids (1350 mg/day), ubiquinone (300 mg/day), astaxanthin (15 mg/day), lycopene (45 mg/day), lutein palmitate (30 mg/day), zeaxanthine palmitate (6 mg/day), L-selenomethionine (330 mg/day), cholecalciferol (30 μg/day) and α-tocopherol (45 mg/day). We found that NucleVital ?Q10 Complex supplementation significantly increased total antioxidant capacity of plasma and activity of erythrocyte superoxide dismutase, with slight effects on oxidative stress biomarkers in erythrocytes; MDA and 4-hydroxyalkene levels. Apart from the observed antioxidative effects, the tested supplement also showed anti-ageing activity. Analysis of expression of SIRT1 and 2 in PBMCs showed significant changes for both genes on a mRNA level. The level of telomerase was also increased by more than 25%, although the length of lymphocyte telomeres, determined by RT-PCR, remained unchanged. Our results demonstrate beneficial effects concerning the antioxidant potential of plasma as well as biomarkers related to ageing even after short term supplementation of diet with NucleVital ?Q10 Complex.
Metabolite Profiling in the Pursuit of Biomarkers for IVF Outcome: The Case for Metabolomics Studies  [PDF]
C. McRae,V. Sharma,J. Fisher
International Journal of Reproductive Medicine , 2013, DOI: 10.1155/2013/603167
Abstract: Background. This paper presents the literature on biomarkers of in vitro fertilisation (IVF) outcome, demonstrating the progression of these studies towards metabolite profiling, specifically metabolomics. The need for more, and improved, metabolomics studies in the field of assisted conception is discussed. Methods. Searches were performed on ISI Web of Knowledge SM for literature associated with biomarkers of oocyte and embryo quality, and biomarkers of IVF outcome in embryo culture medium, follicular fluid (FF), and blood plasma in female mammals. Results. Metabolomics in the field of female reproduction is still in its infancy. Metabolomics investigations of embryo culture medium for embryo selection have been the most common, but only within the last five years. Only in 2012 has the first metabolomics investigation of FF for biomarkers of oocyte quality been reported. The only metabolomics studies of human blood plasma in this context have been aimed at identifying women with polycystic ovary syndrome (PCOS). Conclusions. Metabolomics is becoming more established in the field of assisted conception, but the studies performed so far have been preliminary and not all potential applications have yet been explored. With further improved metabolomics studies, the possibility of identifying a method for predicting IVF outcome may become a reality. 1. Introduction Infertility is an extremely prevalent problem, affecting one in every seven couples [1, 2], and as result in vitro fertilisation (IVF) has become increasingly popular since it was pioneered in 1978. In 2010, 45?264 women were treated by IVF in the UK [3], whereas in 1992, 14?057 women were treated [4]. As understanding of fertility and embryology has developed, the procedures and techniques in assisted conception have been ever improving, and as a result, the number of live births resulting from IVF or ICSI has increased since the early 90s [3]. The UK live birth rate per IVF cycle in 1991 was 14.0% and this increased to 24.1% by 2009 [3]. In 2009 the live birth rate per ART treatment in Canada was higher, at 27.4% [5] and higher still in the USA at 31% [6] but lower in Australia and New Zealand at 17.2% [7]. While improved, these success rates are still unsatisfactorily low. The development of controlled ovarian stimulation in the 1980s [8] enabled the production of multiple mature oocytes and hence multiple embryo transfer, improving the chances of pregnancy in an IVF cycle. Today, gonadotrophins are routinely administered to women undergoing IVF in an attempt to improve the chances of
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