bims-prodis Biomed News
on Proteomics in disease
Issue of 2018–05–06
ten papers selected by
Nancy Gough, Bioserendipity
  1. The enigmatic seminal plasma: a proteomics insight from ejaculation to fertilization.
  2. Atrial remodeling and metabolic dysfunction in idiopathic isolated fibrotic atrial cardiomyopathy.
  3. Comparative subtractive proteomics based ranking for antibiotic targets against the dirtiest superbug: Acinetobacter baumannii.
  4. Proteomic and Phosphoproteomic Changes Induced by Prolonged Activation of Human Eosinophils with IL-3.
  5. Testosterone and FSH modulate Sertoli cell extracellular secretion: Proteomic analysis.
  6. Protein biomarkers associated with pain mechanisms in osteoarthritis.
  7. Spinal injection of newly identified cerebellin-1 and cerebellin-2 peptides induce mechanical hypersensitivity in mice.
  8. Cochineal dye-induced immediate allergy: Review of Japanese cases and proposed new diagnostic chart.
  9. Liver Proteome of Mice with Distinct Genetic Susceptibilities to Fluorosis Treated with Different Concentrations of F in the Drinking Water.
  10. Proteomic effects of repeated-dose oral exposure to 2-monochloropropanediol and its dipalmitate in rat testes.
  1. Reprod Biol Endocrinol. 2018 Apr 28. 16(1): 41
    The enigmatic seminal plasma: a proteomics insight from ejaculation to fertilization.
    Luna Samanta, Rajeshwari Parida, Tania R Dias, Ashok Agarwal.
       BACKGROUND: The 'omics' approach for a noninvasive diagnosis of male reproductive system disorders has gained momentum during the last decade, particularly from a screening and prognosis point of view. Due to the rapid development in assisted reproductive technologies (ART) over the years, the major focus of proteomic studies has been around the ejaculated spermatozoa. Although seminal plasma is not a requirement for ART, the question arose whether the role of seminal plasma is merely to transport spermatozoa.
    MAIN BODY: Seminal plasma (SP) contains a large diversity of proteins that are essential not only for sperm transport, but also for sperm protection and maturation. Most of the proteins bind to sperm surface through exosomes (epididymosomes and prostasomes), modulating sperm function, interaction with the female reproductive tract and finally fertilization. This review focuses on the state-of-art discoveries regarding SP proteome and its role in fertilization.
    CONCLUSION: Tissue-specific proteins in the SP have emerged as fundamental contributors for protein biomarker discovery. This is important for a noninvasive diagnosis of male infertility and development of new therapeutic approaches. Moreover, ART success rates may be improved by taking into account the critical role of seminal proteome in fertilization.
    Keywords:  Assisted reproductive technologies; Cytokines; Epididymosomes; Exosomes; Female reproductive tract; Male infertility; Prostasomes; Proteomics; Seminal plasma
    DOI:  https://doi.org/10.1186/s12958-018-0358-6
  2. Int J Cardiol. 2018 Apr 26. pii: S0167-5273(17)38039-7. [Epub ahead of print]
    Atrial remodeling and metabolic dysfunction in idiopathic isolated fibrotic atrial cardiomyopathy.
    Chang Cui, Xiaohong Jiang, Weizhu Ju, Jiaxian Wang, Daowu Wang, Zheng Sun, Minglong Chen.
       BACKGROUND: Idiopathic isolated fibrotic atrial cardiomyopathy (IIF-ACM) is a novel subtype of cardiomyopathy characterized by atrial fibrosis that does not involve the ventricular myocardium and is associated with significant atrial tachyarrhythmia. The mechanisms underlying its pathogenesis are unknown.
    METHODS: Atrium samples were obtained from 3 patients with IIF-ACM via surgical intervention. Control samples were consisted of 3 atrium biopsies from patients with congenital heart disease and normal sinus rhythm, matched for gender, age and basic clinical characteristics. Comparative histology, immunofluorescence staining, electron microscopy and proteomics analyses were carried out to explore the unique pathogenesis of IIF-ACM.
    RESULTS: IIF-ACM atria displayed disordered myofibrils, profound fibrosis and mitochondrial damages compared to the control atria. Proteomics profiling identified metabolic pathways as the most profound changes in IIF-ACM.
    CONCLUSIONS: Our study suggested that metabolic changes in the atrial myocardium caused mitochondrial oxidative stress and potential cell damage, which further led to atrial fibrosis and myofibril disorganization, the characteristic phenotype of IIF-ACM.
    Keywords:  Fibrosis; Histology; IIF-ACM; Metabolism; Oxidative stress; Proteomics
    DOI:  https://doi.org/10.1016/j.ijcard.2018.04.080
  3. J Mol Graph Model. 2018 Apr 21. pii: S1093-3263(18)30020-2. [Epub ahead of print]82 74-92
    Comparative subtractive proteomics based ranking for antibiotic targets against the dirtiest superbug: Acinetobacter baumannii.
    Sajjad Ahmad, Saad Raza, Reaz Uddin, Syed Sikander Azam.
      Multidrug-resistant Acinetobacter baumannii is indeed to be the most successful nosocomial pathogen responsible for myriad infections in modern health care system. Computational methodologies based on genomics and proteomics proved to be powerful tools for providing substantial information about different aspects of A. baumannii biology that made it possible to design new approaches for treating multi, extensive and total drug resistant isolates of A. baumannii. In this current approach, 35 completely annotated proteomes of A. bauamnnii were filtered through a comprehensive subtractive proteomics pipeline for broad-spectrum drug candidates. In total, 10 proteins (KdsA, KdsB, LpxA, LpxC, LpxD, GpsE, PhoB, UvrY, KdpE and OmpR) could serve as ideal candidates for designing novel antibiotics. The work was extended with KdsA enzyme for structure information, prediction of intrinsic disorders, active site details, and structure based virtual screening of library containing natural product-like scaffolds. Most of the enzyme structure has fixed three-dimensional conformation. The selection of inhibitor for KdsA enzyme was based on druglikeness, pharmacokinetics and docking scores. Compound-4636 (5-((3-chloro-5-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)methoxy)-2-(((1-hydroxy-4-methylpentan-2-yl)amino)methyl)phenol) was revealed as the most potent inhibitor against A. baumannii KdsA enzyme having Gold fitness score of 77.68 and Autodock binding energy of -6.2 kcal/mol. The inhibitor completely follows Lipinski rule of five, Ghose rule, and Egan rule. Molecular dynamics simulation for KdsA and KdsA-4636 complex was performed for 100 ns to unveil what conformational changes the enzyme underwent in the absence and presence of the inhibitor, respectively. The average root means square deviation (RMSD) for both systems was found 3.5 Å, which signifies stable structure of the enzyme in both bounded and unbounded states. Absolute binding energy using Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) reflected high affinity and vigorous interactions of the inhibitor with enzyme active residues. Findings of the current study could open up new avenues for experimentalists to design new potent antibiotics by targeting the targets screened in this study.
    Keywords:  Acinetobacter baumannii; AutoDock Vina; GOLD; Inhibitor-4636; KdsA enzyme; MM-GBSA; Subtractive proteomics
    DOI:  https://doi.org/10.1016/j.jmgm.2018.04.005
  4. J Proteome Res. 2018 May 04.
    Proteomic and Phosphoproteomic Changes Induced by Prolonged Activation of Human Eosinophils with IL-3.
    Stephane Esnault, Alexander S Hebert, Nizar N Jarjour, Joshua J Coon, Deane F Mosher.
      Purified human eosinophils treated for 18-24 h with IL-3 adopt a unique activated phenotype marked by increased reactivity to aggregated immunoglobulin-G (IgG). To characterize this phenotype, we quantified protein abundance and phosphorylation by multiplexed isobaric labeling combined with high-resolution mass spectrometry. Purified blood eosinophils of five individuals were treated with IL-3 or no cytokine for 20 h, and comparative data were obtained on abundance of 5385 proteins and phosphorylation at 7330 sites. The 1150 proteins that were significantly up-regulated ( q < 0.05, pairwise t test with Benjamini-Hochberg correction) by IL-3 included the IL3RA and CSF2RB subunits of the IL-3 receptor, the low-affinity receptor for IgG (FCGR2B), 96 proteins involved in protein translation, and 55 proteins involved in cytoskeleton organization. Among the 703 proteins that decreased were 78 mitochondrial proteins. Dynamic regulation of protein phosphorylation was detected at 4218 sites. These included multiple serines in CSF2RB; Y694 of STAT5, a key site of activating phosphorylation downstream of IL3RA/CSF2RB; and multiple sites in RPS6KA1, RPS6, and EIF4B, which are responsible for translational initiation. We conclude that IL-3 up-regulates overall protein synthesis and targets specific proteins for up-regulation, including its own receptor.
    Keywords:  IL-3; eosinophil; mass spectrometry-based proteomics; phosphorylation sites
    DOI:  https://doi.org/10.1021/acs.jproteome.8b00057
  5. Mol Cell Endocrinol. 2018 Apr 25. pii: S0303-7207(18)30120-5. [Epub ahead of print]
    Testosterone and FSH modulate Sertoli cell extracellular secretion: Proteomic analysis.
    Francesca Mancuso, Mario Calvitti, Domenico Milardi, Giuseppe Grande, Giulia Falabella, Iva Arato, Stefano Giovagnoli, Federica Vincenzoni, Francesca Mancini, Claudio Nastruzzi, Maria Bodo, Tiziano Baroni, Massimo Castagnola, Riccardo Marana, Alfredo Pontecorvi, Riccardo Calafiore, Giovanni Luca.
      Spermatogenesis is a highly complicated biological process that occurs in the epithelium of the seminiferous tubules. It is regulated by a complex network of endocrine and paracrine factors and by juxtacrine testicular cross-talk. Sertoli cells (SC) play a key role in spermatogenesis due to their production of trophic, differentiation and immune-modulating factors, but many of the molecular pathways of SC action remain controversial and unclear. Over the last two decades, research has focused on extracellular vesicles as an important mechanism of intercellular communication. The aim of this study was to investigate the presence of extracellular vesicles (EVs) in SC and the modulation of their content in SC after FSH and testosterone stimulation. Highly purified porcine pre-pubertal Sertoli cells were isolated according to previously established methods. After 48 h of culture with FSH or FSH + testosterone stimulation, we identified sertolian EVs containing specific mRNAs. Proteomic analysis of EVs content identified 29 proteins under non-stimulatory conditions, most of which were related to receptor binding activity. FSH stimulation induced increases in inhibin-alpha, inhibin-beta, plakoglobin, haptoglobin, D-3-phosphoglycerate dehydrogenase and sodium/potassium-transporting ATPase in sertolian EVs. Testosterone stimulation enhanced the abundance of inhibin-alpha, inhibin-beta, tissue-type plasminogen activator, epidermal growth factor-like protein 8, elongating factor 1-gamma and D-3-phosphoglycerate dehydrogenase. These results are likely to help determine the unknown molecular secretion of Sertoli cells.
    Keywords:  Extracellular vesicles; Proteomic analysis; Sertoli cells; mRNAs
    DOI:  https://doi.org/10.1016/j.mce.2018.04.001
  6. J Proteomics. 2018 Apr 25. pii: S1874-3919(18)30189-1. [Epub ahead of print]
    Protein biomarkers associated with pain mechanisms in osteoarthritis.
    Christian S Thudium, Henrik Löfvall, Morten A Karsdal, Anne-Christine Bay-Jensen, Asger Reinstrup Bihlet.
      Osteoarthritis (OA) is the most common arthritic disease in the world, leading to debilitating pain and destruction of joint tissues. While pain is the hallmark symptom of osteoarthritis, clear associations between pain and disease processes involved in joint deterioration are lacking. OA pain is multifactorial and may arise from multiple distinct or concurrent mechanisms, and may thus present as different pain sub-types. Several biomarkers developed to reflect important pathological processes are available, and associations between such biomarkers and OA pain may give hints to important pathological features, which have not been possible to assess using clinical, radiographic or magnetic resonance imaging techniques. This review highlights a selection of important, protein-derived biomarkers measured in body fluids from OA patients, which have been associated with different types and aspects of OA pain, and discusses the potential mechanisms behind the associations.
    SIGNIFICANCE: Osteoarthritis (OA) is a heterogenous disease affecting the entire joint, including cartilage, bone and synovium. While pain is the hallmark symptom of osteoarthritis, clear associations between pain and disease processes involved in joint deterioration are lacking. Thus, there is clear need for biomarkers that can accurately describe the underlying processes and distinguish between different disease and pain pathologies. In this review we discuss a selected number of biomarkers which have been directly or indirectly associated with pain mechanisms and development of pain in OA either via structural correlates or as molecular sensitizing agents. We further evaluate the challenges that the OA field faces in the development and application of biomarkers for OA pain.
    Keywords:  Biochemical marker; Biomarker; Cartilage; Osteoarthritis; Pain; Synovium
    DOI:  https://doi.org/10.1016/j.jprot.2018.04.030
  7. Neuropeptides. 2018 Apr 14. pii: S0143-4179(17)30268-8. [Epub ahead of print]
    Spinal injection of newly identified cerebellin-1 and cerebellin-2 peptides induce mechanical hypersensitivity in mice.
    Katalin Sandor, Shibu Krishnan, Nilesh Mohan Agalave, Emerson Krock, Jaira Villarreal Salcido, Teresa Fernandez-Zafra, Payam Emami Khoonsari, Camilla I Svensson, Kim Kultima.
      By screening for neuropeptides in the mouse spinal cord using mass spectrometry (MS), we have previously demonstrated that one of the 78 peptides that is expressed predominantly (> 6-fold) in the dorsal horn compared to the ventral spinal cord is the atypical peptide desCER [des-Ser1]-cerebellin, which originates from the precursor protein cerebellin 1 (CBLN1). Furthermore, we found that intrathecal injection of desCER induces mechanical hypersensitivity in a dose dependent manner. The current study was designed to further investigate the relative expression of other CBLN derived peptides in the spinal cord and to examine whether they share similar nociceptive properties. In addition to the peptides cerebellin (CER) and desCER we identified and relatively quantified nine novel peptides originating from cerebellin precursor proteins CBLN1 (two peptides), CBLN2 (three peptides) and CBLN4 (four peptides). Ten out of eleven peptides displayed statistically significantly (p < 0.05) higher expression levels (200-350%) in the dorsal horn compared to the ventral horn. Intrathecal injection of three of the four CBLN1 and two of the three CBLN2 derived peptides induced mechanical hypersensitivity in response to von Frey filament testing in mice during the first 6 h post-injection compared to saline injected mice, while none of the four CBLN4 derived peptides altered withdrawal thresholds. This study demonstrates that high performance MS is an effective tool for detecting novel neuropeptides in CNS tissues. We show the presence of nine novel atypical peptides originating from CBLN1, CBLN2 and CBLN4 precursor proteins in the mouse dorsal horn, whereof five peptides induce pain-like behavior upon intrathecal injection. Further studies are required to investigate the mechanisms by which CBLN1 and CBLN2 derived peptides facilitate nociceptive signal transmission.
    Keywords:  Cerebellin; Mass spectrometry; Neuropeptides; Nociception; Pain; Peptidomics
    DOI:  https://doi.org/10.1016/j.npep.2018.04.004
  8. Allergol Int. 2018 Apr 25. pii: S1323-8930(18)30033-9. [Epub ahead of print]
    Cochineal dye-induced immediate allergy: Review of Japanese cases and proposed new diagnostic chart.
    Naoko Takeo, Masashi Nakamura, Satoshi Nakayama, Osamu Okamoto, Naoki Sugimoto, Shinichi Sugiura, Nayu Sato, Susumu Harada, Masao Yamaguchi, Naoya Mitsui, Yumiko Kubota, Kayoko Suzuki, Makoto Terada, Akiyo Nagai, Junko Sowa-Osako, Yutaka Hatano, Hiroshi Akiyama, Akiko Yagami, Sakuhei Fujiwara, Kayoko Matsunaga.
       BACKGROUND: Cochineal dye is used worldwide as a red coloring in foods, drinks, cosmetics, quasi-drugs, and drugs. The main component of the red color is carminic acid (CA). Carmine is an aluminum- or calcium-chelated product of CA. CA and carmine usually contain contaminating proteins, including a 38-kDa protein thought to be the primary allergen. Severe allergic reactions manifest as anaphylaxis. The aim of this study was to review all Japanese reported cases and propose useful diagnostic chart.
    METHODS: All reported Japanese cases of cochineal dye-induced immediate allergy were reviewed, and newly registered cases were examined by skin prick test (SPT) with cochineal extract (CE) and measurement of CE and carmine-specific serum IgE test. Two-dimensional (2D) western blotting using patient serum was conducted to identify the antigen.
    RESULTS: Twenty-two Japanese cases have been reported. SPT and the level of specific IgE test indicated that six cases should be newly registered as cochineal dye allergy. All cases were adult females, and all cases except three involved anaphylaxis; 13 cases involved past history of local symptoms associated with cosmetics use. Japanese strawberry juice and fish-meat sausage, and European processed foods (especially macarons made in France) and drinks were recent major sources of allergen. 2D western blotting showed that patient IgE reacted to the 38-kDa protein and other proteins. Serum from healthy controls also weakly reacted with these proteins.
    CONCLUSIONS: SPT with CE and determination of the level of CE and carmine-specific IgE test are useful methods for the diagnosis of cochineal dye allergy.
    Keywords:  Carminic acid; Cochineal dye; Immediate allergy; Skin prick test; Two dimensional western blotting
    DOI:  https://doi.org/10.1016/j.alit.2018.02.012
  9. Biol Trace Elem Res. 2018 Apr 29.
    Liver Proteome of Mice with Distinct Genetic Susceptibilities to Fluorosis Treated with Different Concentrations of F in the Drinking Water.
    Zohaib Nisar Khan, Isabela Tomazini Sabino, Carina Guimarães de Souza Melo, Tatiana Martini, Heloísa Aparecida Barbosa da Silva Pereira, Marília Afonso Rabelo Buzalaf.
      Appropriate doses of fluoride (F) have therapeutic action against dental caries, but higher levels can cause disturbances in soft and mineralized tissues. Interestingly, the susceptibility to the toxic effects of F is genetically determined. This study evaluated the effects of F on the liver proteome of mice susceptible (A/J) or resistant (129P3/J) to the effects of F. Weanling male A/J (n = 12) and 129P3/J (n = 12) mice were housed in pairs and assigned to two groups given low-F food and drinking water containing 15 or 50 ppm F for 6 weeks. Liver proteome profiles were examined using nano-LC-ESI-MS/MS. Difference in expression among the groups was determined using the PLGS software. Treatment with the lower F concentration provoked more pronounced alterations in fold change in liver proteins in comparison to the treatment with the higher F concentration. Interestingly, most of the proteins with fold change upon treatment with 15 ppm F were increased in the A/J mice compared with their 129P3/J counterparts, suggesting an attempt of the former to fight the deleterious effects of F. However, upon treatment with 50 ppm F, most proteins with fold change were decreased in the A/J mice compared with their 129P3/J counterparts, especially proteins related to oxidative stress and protein folding, which might be related to the higher susceptibility of the A/J animals to the deleterious effects of F. Our findings add light into the mechanisms underlying genetic susceptibility to fluorosis.
    Keywords:  Fluoride; Fluorosis; Genetic susceptibility; Liver; Proteomics
    DOI:  https://doi.org/10.1007/s12011-018-1344-8
  10. Food Chem Toxicol. 2018 Apr 26. pii: S0278-6915(18)30277-1. [Epub ahead of print]116(Pt B): 354-359
    Proteomic effects of repeated-dose oral exposure to 2-monochloropropanediol and its dipalmitate in rat testes.
    Falko Frenzel, Axel Oberemm, Alfonso Lampen, Albert Braeuning.
      2- and 3-monochloropropanediol (2-MCPD) and their fatty acid esters are food contaminants which are concomitantly formed upon thermal treatment of foodstuff containing fats and salt. Exposure to 2- or 3-MCPD thus results, for example, from refined vegetable oils, in instant meals or infant formula, as well as in cereals or pastries. The molecular mechanisms of 2-MCPD toxicity are poorly understood. Here, we performed a comprehensive proteomic analysis of 2-MCDP-induced alterations in the testes from rats following oral administration of 10 mg/kg body weight per day 2-MCPD, or an equimolar dose of 2-MCPD dipalmitate as a representative 2-MCPD fatty acid ester. In the absence of overt histopathologically detectable toxicity, moderate alterations in cellular proteomic signatures were recorded. The observations are in line with the assumption that the molecular mechanisms of 2-MCPD and 3-MCPD toxicity differ. Observed proteomic alterations point towards effects of 2-MCPD on mitogen-dependent signaling and mitochondrial energy utilization. Presented data for the first time provide insight into proteomic effects of 2-MCPD in testicular tissue.
    Keywords:  2-MCPD; 3-MCPD; Heat-induced food contaminants; Toxicoproteomics
    DOI:  https://doi.org/10.1016/j.fct.2018.04.055
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