Label-free Quantification of Proteins in Single Embryonic Cells with Neural Fate in the Cleavage-Stage Frog (Xenopus laevis) Embryo using CE-ESI-HRMS.

Mol Cell Proteomics. 2016 Jun 17;

Authors: Lombard-Banek C, Reddy S, Moody SA, Nemes P

Abstract
Quantification of protein expression in single cells promises to advance a systems-level understanding of normal development. Using a bottom-up proteomic workflow and multiplexing quantification by tandem mass tags, we recently demonstrated relative quantification between single embryonic cells (blastomeres) in the frog (Xenopus laevis) embryo. In this study, we minimize derivatization steps to enhance analytical sensitivity and use label-free quantification (LFQ) for single Xenopus cells. The technology builds on a custom-designed capillary electrophoresis microflow-electrospray ionization high-resolution mass spectrometry platform and LFQ by MaxLFQ (MaxQuant). By judiciously tailoring performance to peptide separation, ionization, and data-dependent acquisition, we demonstrate an ~75-amol (~11 nM) lower limit of detection and quantification for proteins in complex cell digests. The platform enabled the identification of 438 non-redundant protein groups by measuring 16 ng of protein digest, or <0.2% of the total protein contained in a blastomere in the 16-cell embryo. LFQ intensity was validated as a quantitative proxy for protein abundance. Correlation analysis was performed to compare protein quantities between the embryo and n = 3 different single D11 blastomeres, which are fated to develop into the nervous system. A total of 335 non-redundant protein groups were quantified in union between the single D11 cells spanning a 4 log-order concentration range. LFQ and correlation analysis detected expected proteomic differences between the whole embryo and blastomeres, and also found translational differences between individual D11 cells. LFQ on single cells raises exciting possibilities to study gene expression in other cells and models to help better understand cell processes on a systems biology level.

PMID: 27317400 [PubMed - as supplied by publisher]

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Fenofibrate Suppresses Oral Tumorigenesis via Reprogramming Metabolic Processes: Potential Drug Repurposing for Oral Cancer.

Int J Biol Sci. 2016;12(7):786-98

Authors: Jan CI, Tsai MH, Chiu CF, Huang YP, Liu CJ, Chang NW

Abstract
One anticancer strategy suggests targeting mitochondrial metabolism to trigger cell death through slowing down energy production from the Warburg effect. Fenofibrate is a clinical lipid-lowering agent and an effective anticancer drug. In the present study, we demonstrate that fenofibrate provided novel mechanisms for delaying oral tumor development via the reprogramming of metabolic processes. Fenofibrate induced cytotoxicity by decreasing oxygen consumption rate (OCR) that was accompanied with increasing extracellular acidification rate (ECAR) and reducing ATP content. Moreover, fenofibrate caused changes in the protein expressions of hexokinase II (HK II), pyruvate kinase, pyruvate dehydrogenase, and voltage-dependent anion channel (VDAC), which are associated with the Warburg effect. In addition, fenofibrate reprogrammed the metabolic pathway by interrupting the binding of HK II to VDAC. In an oral cancer mouse model, fenofibrate exhibited both preventive and therapeutic efficacy on oral tumorigenesis. Fenofibrate administration suppressed the incidence rate of tongue lesions, reduced the tumor sizes, decreased the tumor multiplicity, and decreased the immunoreactivities of VDAC and mTOR. The molecular mechanisms involved in fenofibrate's ability to delay tumor development included the down-regulation of mTOR activity via TSC1/2-dependent signaling through activation of AMPK and inactivation of Akt, or via a TSC1/2-independent pathway through direct suppression of raptor. Our findings provide a molecular rationale whereby fenofibrate exerts anticancer and additional beneficial effects for the treatment of oral cancer patients.

PMID: 27313493 [PubMed - in process]

Using Social Media Data to Identify Potential Candidates for Drug Repurposing: A Feasibility Study.

JMIR Res Protoc. 2016;5(2):e121

Authors: Rastegar-Mojarad M, Liu H, Nambisan P

Abstract
BACKGROUND: Drug repurposing (defined as discovering new indications for existing drugs) could play a significant role in drug development, especially considering the declining success rates of developing novel drugs. Typically, new indications for existing medications are identified by accident. However, new technologies and a large number of available resources enable the development of systematic approaches to identify and validate drug-repurposing candidates. Patients today report their experiences with medications on social media and reveal side effects as well as beneficial effects of those medications.
OBJECTIVE: Our aim was to assess the feasibility of using patient reviews from social media to identify potential candidates for drug repurposing.
METHODS: We retrieved patient reviews of 180 medications from an online forum, WebMD. Using dictionary-based and machine learning approaches, we identified disease names in the reviews. Several publicly available resources were used to exclude comments containing known indications and adverse drug effects. After manually reviewing some of the remaining comments, we implemented a rule-based system to identify beneficial effects.
RESULTS: The dictionary-based system and machine learning system identified 2178 and 6171 disease names respectively in 64,616 patient comments. We provided a list of 10 common patterns that patients used to report any beneficial effects or uses of medication. After manually reviewing the comments tagged by our rule-based system, we identified five potential drug repurposing candidates.
CONCLUSIONS: To our knowledge, this is the first study to consider using social media data to identify drug-repurposing candidates. We found that even a rule-based system, with a limited number of rules, could identify beneficial effect mentions in patient comments. Our preliminary study shows that social media has the potential to be used in drug repurposing.

PMID: 27311964 [PubMed]

Tulane virus recognizes sialic acids as cellular receptors.

Sci Rep. 2015;5:11784

Authors: Tan M, Wei C, Huang P, Fan Q, Quigley C, Xia M, Fang H, Zhang X, Zhong W, Klassen JS, Jiang X

Abstract
The recent discovery that human noroviruses (huNoVs) recognize sialic acids (SAs) in addition to histo-blood group antigens (HBGAs) pointed to a new direction in studying virus-host interactions during calicivirus infection. HuNoVs remain difficult to study due to the lack of an effective cell culture model. In this study, we demonstrated that Tulane virus (TV), a cultivable primate calicivirus, also recognizes SAs in addition to the previously known TV-HBGA interactions. Evidence supporting this discovery includes that TV virions bound synthetic sialoglycoconjugates (SGCs) and that treatment of TV permissive LLC-MK2 cells with either neuraminidases or SA-binding lectins inhibited TV infectivity. In addition, we found that Maackia amurensis leukoagglutinin (MAL), a lectin that recognizes the α-2,3 linked SAs, bound LLC-MK2 cells, as well as TV, by which MAL promoted TV infectivity in cell culture. Our findings further highlight TV as a valuable surrogate for huNoVs, particularly in studying virus-host interactions that may involve two host carbohydrate receptors or co-receptors for infection.

PMID: 26146020 [PubMed - indexed for MEDLINE]

stringgaussnet: from differentially expressed genes to semantic and Gaussian networks generation.

Bioinformatics. 2015 Dec 1;31(23):3865-7

Authors: Chaplais E, Garchon HJ

Abstract
MOTIVATION: Knowledge-based and co-expression networks are two kinds of gene networks that can be currently implemented by sophisticated but distinct tools. We developed stringgaussnet, an R package that integrates both approaches, starting from a list of differentially expressed genes.
CONTACT: henri-jean.garchon@inserm.fr.
AVAILABILITY AND IMPLEMENTATION: Freely available on the web at http://cran.r-project.org/web/packages/stringgaussnet.

PMID: 26231430 [PubMed - indexed for MEDLINE]

The ENCCA-WP7/EuroSarc/EEC/PROVABES/EURAMOS 3rd European Bone Sarcoma Networking Meeting/Joint Workshop of EU Bone Sarcoma Translational Research Networks; Vienna, Austria, September 24-25, 2015. Workshop Report.

Clin Sarcoma Res. 2016;6:3

Authors: Kager L, Whelan J, Dirksen U, Hassan B, Anninga J, Bennister L, Bovée JV, Brennan B, Broto JM, Brugières L, Cleton-Jansen AM, Copland C, Dutour A, Fagioli F, Ferrari S, Fiocco M, Fleuren E, Gaspar N, Gelderblom H, Gerrand C, Gerß J, Gonzato O, van der Graaf W, Hecker-Nolting S, Herrero-Martín D, Klco-Brosius S, Kovar H, Ladenstein R, Lancia C, LeDeley MC, McCabe MG, Metzler M, Myklebost O, Nathrath M, Picci P, Potratz J, Redini F, Richter GH, Reinke D, Rutkowski P, Scotlandi K, Strauss S, Thomas D, Tirado OM, Tirode F, Vassal G, Bielack SS

Abstract
This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas.

PMID: 27315524 [PubMed - as supplied by publisher]

CYP3A pharmacogenetics and tacrolimus disposition in adult heart transplant recipients.

Clin Transplant. 2016 Jun 17;

Authors: Deininger KM, Vu A, Page RL, Ambardekar AV, Lindenfeld J, Aquilante CL

Abstract
BACKGROUND: Cytochrome P450 (CYP) 3A polymorphisms are associated with variable CYP3A metabolizing enzyme activity and tacrolimus pharmacokinetics. We sought to determine the singular and combined impact of CYP3A4*22 and CYP3A5*3 variants on tacrolimus drug disposition in adult heart transplant recipients.
METHODS: The retrospective study included n=76 patients greater than one year post-heart transplant and receiving tacrolimus. Patients were genotyped for CYP3A4*22 and CYP3A5*3, and combined genotypes were classified as: extensive metabolizers (EM, CYP3A4*1/*1+CYP3A5*1 carriers); intermediate metabolizers (IM, CYP3A4*1/*1+CYP3A5*3/*3, or CYP3A4*22 carriers+CYP3A5*1 carriers), and poor metabolizers (PM, CYP3A4*22 carriers+CYP3A5*3/*3). The primary outcome was tacrolimus dose-adjusted trough concentration (C0 /D, ng/ml per mg/day).
RESULTS: In singular analysis, tacrolimus C0 /D did not differ significantly between CYP3A4*22 genotype groups. However, tacrolimus C0 /D was 1.8-fold lower (p<0.001) in CYP3A5 expressers versus nonexpressers. When combined CYP3A genotype was evaluated, tacrolimus C0 /D was 1.8-fold lower in EMs versus IMs (p<0.001) and EMs versus PMs (p=0.001). Tacrolimus C0 /D did not differ significantly between CYP3A IMs versus PMs.
CONCLUSION: Combined CYP3A genotype was associated with tacrolimus drug disposition in adult heart transplant recipients, but the effect was largely driven by CYP3A5*3. These data suggest that CYP3A4*22 and combined CYP3A genotype are unlikely to provide additional information beyond CYP3A5 genotype. This article is protected by copyright. All rights reserved.

PMID: 27314545 [PubMed - as supplied by publisher]

Implementation of Clinical Pharmacogenomics within a Large Health System: From Electronic Health Record Decision Support to Consultation Services.

Pharmacotherapy. 2016 Jun 17;

Authors: Hicks JK, Stowe D, Willner MA, Wai M, Daly T, Gordon SM, Lashner BA, Parikh S, White R, Teng K, Moss T, Erwin A, Chalmers J, Eng C, Knoer S

Abstract
The number of clinically relevant, gene-based guidelines and recommendations pertaining to drug prescribing continues to grow. Incorporating gene-drug interaction information into the drug prescribing process can help optimize pharmacotherapy outcomes and improve patient safety. However, pharmacogenomic implementation barriers exist such as integration of pharmacogenomic results into electronic health records (EHRs), development and deployment of pharmacogenomic decision-support tools to EHRs, and feasible models for establishing ambulatory pharmacogenomic clinics. We describe the development of pharmacist-managed pharmacogenomic services within a large health system. The Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B*57:01-abacavir, HLA-B*15:02-carbamazepine, and TPMT-thiopurines (i.e., azathioprine, mercaptopurine, and thioguanine) were systematically integrated into patient care. Sixty-three custom rules and alerts (20 for TPMT-thiopurines, 8 for HLA-B*57:01-abacavir, and 35 for HLA-B*15:02-anticonvulsants) were developed and deployed to the EHR for the purpose of providing point-of-care pharmacogenomic decision support. In addition, a pharmacist and physician-geneticist collaboration established a pharmacogenomics ambulatory clinic. This clinic provides genetic testing when warranted, result interpretation along with pharmacotherapy recommendations, and patient education. Our processes for developing these pharmacogenomic services and solutions for addressing implementation barriers are presented. This article is protected by copyright. All rights reserved.

PMID: 27312955 [PubMed - as supplied by publisher]

Association between Prolonged Neutropenia and Reduced Relapse Risk in Pediatric AML: A Report from the Children's Oncology Group.

Int J Cancer. 2016 Jun 16;

Authors: Sung L, Aplenc R, Alonzo TA, Gerbing RB, Wang YC, Meshinchi S, Gamis AS

Abstract
Objective was to describe the relationship between the number of sterile site infections and duration of neutropenia during the first four cycles of chemotherapy and the risk of recurrence and overall survival. AAML0531 was a Children's Oncology Group (COG) randomized phase 3 clinical trial that included 1022 children with de novo AML. For this analysis, we focused on non-Down syndrome favorable and standard risk patients who completed at least 4 cycles of chemotherapy without recurrence or withdrawal during protocol therapy. Those receiving hematopoietic stem cell transplantation in first remission were excluded. 569 patients were included; 274 (48.2%) were favorable risk. The median cumulative time with neutropenia between Induction II to completion of Intensification II was 96 (range 54-204) days. Number of sterile site infections did not influence the risk of relapse or overall survival. However, longer duration of neutropenia was associated with a lower risk of relapse (hazard ratio 0.81 per 20 days neutropenia, P=0.007). Longer duration of neutropenia was associated with a reduced risk of relapse for children with favorable and standard risk AML. Toxicity may be influenced by pharmacogenomics suggesting that individualized chemotherapy dosing may be an effective strategy. This article is protected by copyright. All rights reserved.

PMID: 27312107 [PubMed - as supplied by publisher]

MicroRNA hsa-miR-25-3p suppresses the expression and drug induction of CYP2B6 in human hepatocytes.

Biochem Pharmacol. 2016 Jun 13;

Authors: Jin Y, Yu D, Tolleson WH, Knox B, Wang Y, Chen S, Ren Z, Deng H, Guo Y, Ning B

Abstract
Cytochrome P450 2B6 (CYP2B6), mainly expressed in the liver and brain, is important for processing a number of widely used drugs. Variations in CYP2B6 expression are associated with decreased drug efficacy or adverse effects in some patients. Although CYP2B6 genetic variants are associated with its differential expression, epigenetic mechanisms affecting CYP2B6 gene regulation have not been established. Sequence analysis identified 29 domains in the CYP2B6 mRNA transcript that could be subject to regulation by microRNAs. Inverse correlations were found in human hepatocytes for the levels of the microRNAs hsa-miR-504-5p and hsa-miR-25-3p compared with CYP2B6 mRNA. Reporter gene assays showed that hsa-miR-25-3p suppresses CYP2B6 expression by targeting a specific sequence in the 3'-untranslated region of the mRNA transcript. Electrophoretic mobility shift assays confirmed that hsa-miR-25-3p forms stable complexes with its cognate mRNA sequence and that it recruits cellular factors, including Ago-4. Transfection of HepaRG cells with hsa-miR-25-3p mimics inhibited expression of the endogenous CYP2B6 gene and it also decreased rifampicin-dependent induction of CYP2B6 at the mRNA and protein levels. In summary, in sillico and in vitro analyses show that hsa-miR-25-3p suppresses CYP2B6 expression in human liver cells via an epigenetic mechanism.

PMID: 27311985 [PubMed - as supplied by publisher]

Comparison of genome sequencing and clinical genotyping for pharmacogenes.

Clin Pharmacol Ther. 2016 Jun 17;

Authors: Yang W, Wu G, Broeckel U, Smith CA, Turner V, Haidar CE, Wang S, Carter R, Karol SE, Neale G, Crews K, Yang JJ, Mullighan CG, Downing JR, Evans WE, Relling MV

Abstract
We compared whole exome sequencing (WES, n=176 patients) and whole genome sequencing (WGS, n=68) and clinical genotyping (DMET array-based approach) for interrogating thirteen genes with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. We focused on 127 CPIC important variants: 103 single nucleotide variations (SNV), 21 insertion/deletions (Indel), HLA-B alleles, and two CYP2D6 structural variations. WES and WGS provided interrogation of non-overlapping sets of 115 SNV/Indels with call rate >98%. Among 68 loci interrogated by both WES and DMET, 64 loci (94.1%, CI:85.6-98.4%) showed no discrepant genotyping calls. Among 66 loci interrogated by both WGS and DMET, 63 loci (95.5%, CI:87.2-99.0%) showed no discrepant genotyping calls. In conclusion, even without optimization to interrogate pharmacogenetic variants, WES and WGS displayed potential to provide reliable interrogation of most pharmacogenes and further validation of genome sequencing in a clinical lab setting is warranted. This article is protected by copyright. All rights reserved.

PMID: 27311679 [PubMed - as supplied by publisher]

Airway remodeling: Systems biology approach, from bench to bedside.

Technol Health Care. 2016 Jun 10;

Authors: Najafi A, Ghanei M, Jamalkandi SA

Abstract
Airway Remodeling, a patho-physiologic process, is considered as a key feature of chronic airway diseases. In recent years, our understanding of the complex diseases has increased significantly by the use of combined approaches, including systems biology, which may contribute to the development of personalized and predictive medicine approaches. Integrative analysis, along with the cooperation of clinicians, computer scientists, research scientists, and bench scientists, has become an important part of the experimental design and therapeutic strategies in the era of omics. The airway remodeling process is the result of the dysregulation of several signaling pathways that modulate the airway regeneration; therefore, high-throughput experiments and systems biology approach can help to understand this process better. The study reviews related literature and is consistent with the existing clinical evidence.

PMID: 27315153 [PubMed - as supplied by publisher]

Differential RNA-seq, Multi-Network Analysis and Metabolic Regulation Analysis of Kluyveromyces marxianus Reveals a Compartmentalised Response to Xylose.

PLoS One. 2016;11(6):e0156242

Authors: Schabort DT, Letebele PK, Steyn L, Kilian SG, du Preez JC

Abstract
We investigated the transcriptomic response of a new strain of the yeast Kluyveromyces marxianus, in glucose and xylose media using RNA-seq. The data were explored in a number of innovative ways using a variety of networks types, pathway maps, enrichment statistics, reporter metabolites and a flux simulation model, revealing different aspects of the genome-scale response in an integrative systems biology manner. The importance of the subcellular localisation in the transcriptomic response is emphasised here, revealing new insights. As was previously reported by others using a rich medium, we show that peroxisomal fatty acid catabolism was dramatically up-regulated in a defined xylose mineral medium without fatty acids, along with mechanisms to activate fatty acids and transfer products of β-oxidation to the mitochondria. Notably, we observed a strong up-regulation of the 2-methylcitrate pathway, supporting capacity for odd-chain fatty acid catabolism. Next we asked which pathways would respond to the additional requirement for NADPH for xylose utilisation, and rationalised the unexpected results using simulations with Flux Balance Analysis. On a fundamental level, we investigated the contribution of the hierarchical and metabolic regulation levels to the regulation of metabolic fluxes. Metabolic regulation analysis suggested that genetic level regulation plays a major role in regulating metabolic fluxes in adaptation to xylose, even for the high capacity reactions, which is unexpected. In addition, isozyme switching may play an important role in re-routing of metabolic fluxes in subcellular compartments in K. marxianus.

PMID: 27315089 [PubMed - as supplied by publisher]

Heterologous vaccine effects.

Vaccine. 2016 Jun 13;

Authors: Saadatian-Elahi M, Aaby P, Shann F, Netea MG, Levy O, Louis J, Picot V, Greenberg M, Warren W

Abstract
The heterologous or non-specific effects (NSEs) of vaccines, at times defined as "off-target effects" suggest that they can affect the immune response to organisms other than their pathogen-specific intended purpose. These NSEs have been the subject of clinical, immunological and epidemiological studies and are increasingly recognized as an important biological process by a growing group of immunologists and epidemiologists. Much remain to be learned about the extent and underlying mechanisms for these effects. The conference "Off-target effects of vaccination" held in Annecy-France (June 8-10 2015) intended to take a holistic approach drawing from the fields of immunology, systems biology, epidemiology, bioinformatics, public health and regulatory science to address fundamental questions of immunological mechanisms, as well as translational questions about vaccines NSEs. NSE observations were examined using case-studies on live attenuated vaccines and non-live vaccines followed by discussion of studies of possible biological mechanisms. Some possible pathways forward in the study of vaccines NSE were identified and discussed by the expert group.

PMID: 27312214 [PubMed - as supplied by publisher]

A Systems Biology Approach for Identifying Hepatotoxicant Groups Based on Similarity in Mechanisms of Action and Chemical Structure.

Methods Mol Biol. 2016;1425:339-59

Authors: Hebels DG, Rasche A, Herwig R, van Westen GJ, Jennen DG, Kleinjans JC

Abstract
When evaluating compound similarity, addressing multiple sources of information to reach conclusions about common pharmaceutical and/or toxicological mechanisms of action is a crucial strategy. In this chapter, we describe a systems biology approach that incorporates analyses of hepatotoxicant data for 33 compounds from three different sources: a chemical structure similarity analysis based on the 3D Tanimoto coefficient, a chemical structure-based protein target prediction analysis, and a cross-study/cross-platform meta-analysis of in vitro and in vivo human and rat transcriptomics data derived from public resources (i.e., the diXa data warehouse). Hierarchical clustering of the outcome scores of the separate analyses did not result in a satisfactory grouping of compounds considering their known toxic mechanism as described in literature. However, a combined analysis of multiple data types may hypothetically compensate for missing or unreliable information in any of the single data types. We therefore performed an integrated clustering analysis of all three data sets using the R-based tool iClusterPlus. This indeed improved the grouping results. The compound clusters that were formed by means of iClusterPlus represent groups that show similar gene expression while simultaneously integrating a similarity in structure and protein targets, which corresponds much better with the known mechanism of action of these toxicants. Using an integrative systems biology approach may thus overcome the limitations of the separate analyses when grouping liver toxicants sharing a similar mechanism of toxicity.

PMID: 27311473 [PubMed - in process]

Molecular profiles to biology and pathways: a systems biology approach.

Chin J Cancer. 2016;35(1):53

Authors: Van Laere S, Dirix L, Vermeulen P

Abstract
Interpreting molecular profiles in a biological context requires specialized analysis strategies. Initially, lists of relevant genes were screened to identify enriched concepts associated with pathways or specific molecular processes. However, the shortcoming of interpreting gene lists by using predefined sets of genes has resulted in the development of novel methods that heavily rely on network-based concepts. These algorithms have the advantage that they allow a more holistic view of the signaling properties of the condition under study as well as that they are suitable for integrating different data types like gene expression, gene mutation, and even histological parameters.

PMID: 27311441 [PubMed - in process]

Overexpression of Catalase Diminishes Oxidative Cysteine Modifications of Cardiac Proteins.

PLoS One. 2015;10(12):e0144025

Authors: Yao C, Behring JB, Shao D, Sverdlov AL, Whelan SA, Elezaby A, Yin X, Siwik DA, Seta F, Costello CE, Cohen RA, Matsui R, Colucci WS, McComb ME, Bachschmid MM

Abstract
Reactive protein cysteine thiolates are instrumental in redox regulation. Oxidants, such as hydrogen peroxide (H2O2), react with thiolates to form oxidative post-translational modifications, enabling physiological redox signaling. Cardiac disease and aging are associated with oxidative stress which can impair redox signaling by altering essential cysteine thiolates. We previously found that cardiac-specific overexpression of catalase (Cat), an enzyme that detoxifies excess H2O2, protected from oxidative stress and delayed cardiac aging in mice. Using redox proteomics and systems biology, we sought to identify the cysteines that could play a key role in cardiac disease and aging. With a 'Tandem Mass Tag' (TMT) labeling strategy and mass spectrometry, we investigated differential reversible cysteine oxidation in the cardiac proteome of wild type and Cat transgenic (Tg) mice. Reversible cysteine oxidation was measured as thiol occupancy, the ratio of total available versus reversibly oxidized cysteine thiols. Catalase overexpression globally decreased thiol occupancy by ≥1.3 fold in 82 proteins, including numerous mitochondrial and contractile proteins. Systems biology analysis assigned the majority of proteins with differentially modified thiols in Cat Tg mice to pathways of aging and cardiac disease, including cellular stress response, proteostasis, and apoptosis. In addition, Cat Tg mice exhibited diminished protein glutathione adducts and decreased H2O2 production from mitochondrial complex I and II, suggesting improved function of cardiac mitochondria. In conclusion, our data suggest that catalase may alleviate cardiac disease and aging by moderating global protein cysteine thiol oxidation.

PMID: 26642319 [PubMed - indexed for MEDLINE]

Systems biology of IL-6, IL-12 family cytokines.

Cytokine Growth Factor Rev. 2015 Oct;26(5):595-602

Authors: Dittrich A, Hessenkemper W, Schaper F

Abstract
Interleukin-6-type cytokines play important roles in the communication between cells of multicellular organisms. They are involved in the regulation of complex cellular processes such as proliferation and differentiation and act as key player during inflammation and immune response. A major challenge is to understand how these complex non-linear processes are connected and regulated. Systems biology approaches are used to tackle this challenge in an iterative process of quantitative experimental and mathematical analyses. Here we review quantitative experimental studies and systems biology approaches dealing with the function of Interleukin-6-type cytokines in physiological and pathophysiological conditions. These approaches cover the analyses of signal transduction on a cellular level up to pharmacokinetic and pharmacodynamic studies on a whole organism level.

PMID: 26187858 [PubMed - indexed for MEDLINE]