bims-prodis Biomed News
on Proteomics in Disease
Issue of 2018‒06‒10
six papers selected by
Nancy Gough
Bioserendipity
  1. Topographic protein profiling of the age-related proteome in the retinal pigment epithelium of Callithrix jacchus with respect to macular degeneration.
  2. Bicalutamide enhances fodrin-mediated apoptosis through calpain in LNCaP.
  3. Omega-3 Fatty Acids Supplementation: Therapeutic Potential in a Mouse Model of Stargardt Disease.
  4. Marine natural products for multi-targeted cancer treatment: A future insight.
  5. Tracking gene expression and oxidative damage of O2-stressed Clostridioides difficile by a multi-omics approach.
  6. Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma.
  1. J Proteomics. 2018 May 30. pii: S1874-3919(18)30228-8. [Epub ahead of print]
    Topographic protein profiling of the age-related proteome in the retinal pigment epithelium of Callithrix jacchus with respect to macular degeneration.
    S König, K Hadrian, S Schlatt, J Wistuba, S Thanos, M R R Böhm.
      In the retinal pigment epithelium (RPE) several factors within the macular compared to peripheral regions cause differences in physiological aging. The molecular mechanisms during aging in the context of topography are not well known. The proteome of RPE of different aged macular-bearing primates Callithrix jacchus was thus analysed with ion mobility mass spectrometry. Macular and periphery of neonate RPE were well differentiated from aged tissues as demonstrated by principal component analysis. This finding was mainly due to proteins involved in major developmental processes and the visual cycle. The distinction of adult from senile tissue and macular from periphery was more subtle. The hypotheses of inflammation increasing with age was supported. High expression levels of proteins related to oxidative stress (e.g., cathepsin B) and chaperones (e.g., HSP 90) were detected in aged RPE as confirmed by Western blot and immunohistochemical analysis. Decreased levels of proteins participating in angiostatic properties (e.g., thrombospondin 1) and the integrity of tissue basement membranes with age (e.g., nidogen 1) were in agreement with neovascularization. This study presents targets for further investigations of the mechanisms of the aging process with the aim to elucidate predictive factors for the conversion of physiological aging into pathological conditions.SIGNIFICANCE: The current study characterized the different protein profiles of the retinal pigment epithelium (RPE) of the macula-bearing, non-human primate Callithrix jacchus during life-time. In addition, the subproteomes of macular and peripheral RPE were investigated. Differently expressed proteins described developmental processes in neonate tissue and destructive mechanisms in aged samples. Insights into the physiological aging process of the RPE and its conversion into pathophysiological conditions were gained. They assist in designing therapeutical approaches to counteract age-related diseases of the retina.
    Keywords:  AMD; Aging; Callithrix jacchus; Proteome; RPE
    DOI:  https://doi.org/10.1016/j.jprot.2018.05.016
  2. Exp Biol Med (Maywood). 2018 Jan 01. 1535370218779780
    Bicalutamide enhances fodrin-mediated apoptosis through calpain in LNCaP.
    Jiyeong Lee, Sora Mun, Arum Park, Doojin Kim, Byung Heun Cha, Hee-Gyoo Kang.
      Prostate cancer is the most common cancer in men, and before it progresses and metastasizes, the anticancer drug bicalutamide is often administered to patients. Many cases of androgen-dependent prostate cancer develop resistance during treatment with bicalutamide. Therefore, the effect of bicalutamide on androgen-dependent LNCaP prostate cancer cells is of clinical interest. The aim of this study was to demonstrate the effects of the anticancer drug bicalutamide on LNCaP prostate cancer cells by using a proteomics approach. Based on the results, 314 proteins were differentially expressed between the LNCaP and LNCaP treated with bicalutamide. The apoptosis pathway associated with differentially expressed proteins was shown in the Kyoto Encyclopedia of Gene and Genome pathway mapper. The Kyoto Encyclopedia of Gene and Genome pathway mapper results revealed that the fodrin-mediated apoptosis pathway is associated with the actions of bicalutamide and Western blotting was performed to validate these results. Impact statement We studied bicalutamide's anticancer action by using proteomics. The effect of bicalutamide on androgen-exposed LNCaP cells was also studied. KEGG identified >1.8-fold differentially expressed proteins between test group cells. KEGG mapper showed fodrin-mediated apoptosis involvement in bicalutamide's action. The anticancer effects of bicalutamide, which was further confirmed using Western blotting. Therefore, this drug is a potential candidate for understanding bicalutamide's effect on LNCaP and fodrin can be used as a biomarker monitoring status in metastatic carcinoma.
    Keywords:  Apoptosis; LNCaP; bicalutamide; calpain; fodrin; proteomics
    DOI:  https://doi.org/10.1177/1535370218779780
  3. Invest Ophthalmol Vis Sci. 2018 Jun 01. 59(7): 2757-2767
    Omega-3 Fatty Acids Supplementation: Therapeutic Potential in a Mouse Model of Stargardt Disease.
    Ekatherine Prokopiou, Panagiotis Kolovos, Maria Kalogerou, Anastasia Neokleous, Orthodoxia Nicolaou, Kleitos Sokratous, Kyriacos Kyriacou, Tassos Georgiou.
      Purpose: To evaluate the therapeutic effects of omega-3 (ω3) fatty acids on retinal degeneration in the ABCA4-/- model of Stargardt disease when the blood level of arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio is between 1 and 1.5.Methods: Eight-month-old mice were allocated to three groups: wild type (129S1), ABCA4-/- untreated, and ABCA4-/- ω3 treated. ω3 treatment lasted 3 months and comprised daily gavage administration of EPA and docosahexaenoic acid (DHA). Blood and retinal fatty acid analysis was performed using gas chromatography to adjust the blood AA/EPA ∼1 to 1.5. Eyecups were histologically examined using transmission electron microscopy and confocal microscopy to evaluate lipofuscin granules and the photoreceptor layer. Retinal N-retinylidene-N-retinylethanolamine (A2E), a major component of retinal pigment epithelium lipofuscin, was quantified using liquid chromatography and tandem mass spectrometry, in addition to retinal proteomic analysis to determine changes in inflammatory proteins.
    Results: EPA levels increased and AA levels decreased in the blood and retinas of the treatment group. Significantly less A2E and lipofuscin granules were observed in the treatment group. The thickness of the outer nuclear layer was significantly greater in the treatment group (75.66 ± 4.80 μm) than in the wild-type (61.40 ± 1.84 μm) or untreated ABCA4-/- (56.50 ± 3.24 μm) groups. Proteomic analysis indicated lower levels of complement component 3 (C3) in the treatment group, indicative of lower complement-induced inflammatory response.
    Conclusions: Three months of ω3 supplementation (AA/EPA ∼1-1.5) reduces A2E levels, lipofuscin granules, and C3 levels in the ABCA4-/- mouse model of Stargardt disease, consistent with slowing of the disease.
    DOI:  https://doi.org/10.1167/iovs.17-23523
  4. Biomed Pharmacother. 2018 May 30. pii: S0753-3322(18)31217-4. [Epub ahead of print]105 233-245
    Marine natural products for multi-targeted cancer treatment: A future insight.
    Maushmi S Kumar, Kaveri M Adki.
      Cancer is world's second largest alarming disease, which involves abnormal cell growth and have potential to spread to other parts of the body. Most of the available anticancer drugs are designed to act on specific targets by altering the activity of involved transporters and genes. As cancer cells exhibit complex cellular machinery, the regeneration of cancer tissues and chemo resistance towards the therapy has been the main obstacle in cancer treatment. This fact encourages the researchers to explore the multitargeted use of existing medicines to overcome the shortcomings of chemotherapy for alternative and safer treatment strategies. Recent developments in genomics-proteomics and an understanding of the molecular pharmacology of cancer have also challenged researchers to come up with target-based drugs. The literature supports the evidence of natural compounds exhibiting antioxidant, antimitotic, anti-inflammatory, antibiotic as well as anticancer activity. In this review, we have selected marine sponges as a prolific source of bioactive compounds which can be explored for their possible use in cancer and have tried to link their role in cancer pathway. To prove this, we revisited the literature for the selection of cancer genes for the multitargeted use of existing drugs and natural products. We used Cytoscape network analysis and Search tool for retrieval of interacting genes/ proteins (STRING) to study the possible interactions to show the links between the antioxidants, antibiotics, anti-inflammatory and antimitotic agents and their targets for their possible use in cancer. We included total 78 pathways, their genes and natural compounds from the above four pharmacological classes used in cancer treatment for multitargeted approach. Based on the Cytoscape network analysis results, we shortlist 22 genes based on their average shortest path length connecting one node to all other nodes in a network. These selected genes are CDKN2A, FH, VHL, STK11, SUFU, RB1, MEN1, HRPT2, EXT1, 2, CDK4, p14, p16, TSC1, 2, AXIN2, SDBH C, D, NF1, 2, BHD, PTCH, GPC3, CYLD and WT1. The selected genes were analysed using STRING for their protein-protein interactions. Based on the above findings, we propose the selected genes to be considered as major targets and are suggested to be studied for discovering marine natural products as drug lead in cancer treatment.
    Keywords:  Anti-inflammatory agents; Antibiotics; Anticancer; Antimitotics; Antioxidants; Marine sponges; Multitargeted approach
    DOI:  https://doi.org/10.1016/j.biopha.2018.05.142
  5. Anaerobe. 2018 May 31. pii: S1075-9964(18)30103-3. [Epub ahead of print]
    Tracking gene expression and oxidative damage of O2-stressed Clostridioides difficile by a multi-omics approach.
    Meina Neumann-Schaal, Nicole G Metzendorf, Daniel Troitzsch, Aaron Mischa Nuss, Julia Danielle Hofmann, Michael Beckstette, Petra Dersch, Andreas Otto, Susanne Sievers.
      Clostridioides difficile is the major pathogen causing diarrhea following antibiotic treatment. It is considered to be a strictly anaerobic bacterium, however, previous studies have shown a certain and strain-dependent oxygen tolerance. In this study, the model strain C. difficile 630Δerm was shifted to micro-aerobiosis and was found to stay growing to the same extent as anaerobically growing cells with only few changes in the metabolite pattern. However, an extensive change in gene expression was determined by RNA-Seq. The most striking adaptation strategies involve a change in the reductive fermentation pathways of the amino acids proline, glycine and leucine. But also a far-reaching restructuring in the carbohydrate metabolism was detected with changes in the phosphotransferase system (PTS) facilitated uptake of sugars and a repression of enzymes of glycolysis and butyrate fermentation. Furthermore, a temporary induction in the synthesis of cofactor riboflavin was detected possibly due to an increased demand for flavin mononucleotid (FMN) and flavin adenine dinucleotide (FAD) in redox reactions. However, biosynthesis of the cofactors thiamin pyrophosphate and cobalamin were repressed deducing oxidation-prone enzymes and intermediates in these pathways. Micro-aerobically shocked cells were characterized by an increased demand for cysteine and a thiol redox proteomics approach revealed a dramatic increase in the oxidative state of cysteine in more than 800 peptides after 15 min of micro-aerobic shock. This provides not only a catalogue of oxidation-prone cysteine residues in the C. difficile proteome but also puts the amino acid cysteine into a key position in the oxidative stress response. Our study suggests that tolerance of C. difficile towards O2 is based on a complex and far-reaching adjustment of global gene expression which leads to only a slight change in phenotype.
    Keywords:  Clostridioides difficile; Cysteine modification; Metabolomics; Oxidative stress; RNA-Seq; Redox proteomics
    DOI:  https://doi.org/10.1016/j.anaerobe.2018.05.018
  6. EBioMedicine. 2018 May 30. pii: S2352-3964(18)30188-9. [Epub ahead of print]
    Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma.
    Zhaoxi Wang, Yongyue Wei, Ruyang Zhang, Li Su, Stephanie M Gogarten, Geoffrey Liu, Paul Brennan, John K Field, James D McKay, Jolanta Lissowska, Beata Swiatkowska, Vladimir Janout, Ciprian Bolca, Milica Kontic, Ghislaine Scelo, David Zaridze, Cathy C Laurie, Kimberly F Doheny, Elizabeth K Pugh, Beth A Marosy, Kurt N Hetrick, Xiangjun Xiao, Claudio Pikielny, Rayjean J Hung, Christopher I Amos, Xihong Lin, David C Christiani.
      Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium revealed a SNP (rs12614710) in EPAS1 associated with NSCLC that reached genome-wide significance (OR = 1.50; 95% CI: 1.31-1.72; p = 7.75 × 10-9). Using imputed data, we found that this SNP remained significant in the entire TRICL-ILCCO consortium (p = .03). Additional functional studies are warranted to better understand interrelationships among genetic polymorphisms, DNA methylation status, and EPAS1 expression.
    Keywords:  Hypoxia-inducible factor; Integrated analysis; Lung adenocarcinoma; Network analysis; Non-small cell lung cancer
    DOI:  https://doi.org/10.1016/j.ebiom.2018.05.024
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