Foundations and Emerging Paradigms for Computing in Living Cells.

J Mol Biol. 2016 Feb 27;428(5 Pt B):893-915

Authors: Ma KC, Perli SD, Lu TK

Abstract
Genetic circuits, composed of complex networks of interacting molecular machines, enable living systems to sense their dynamic environments, perform computation on the inputs, and formulate appropriate outputs. By rewiring and expanding these circuits with novel parts and modules, synthetic biologists have adapted living systems into vibrant substrates for engineering. Diverse paradigms have emerged for designing, modeling, constructing, and characterizing such artificial genetic systems. In this paper, we first provide an overview of recent advances in the development of genetic parts and highlight key engineering approaches. We then review the assembly of these parts into synthetic circuits from the perspectives of digital and analog logic, systems biology, and metabolic engineering, three areas of particular theoretical and practical interest. Finally, we discuss notable challenges that the field of synthetic biology still faces in achieving reliable and predictable forward-engineering of artificial biological circuits.

PMID: 26908220 [PubMed - indexed for MEDLINE]

Systems biology of immunity to MF59-adjuvanted versus nonadjuvanted trivalent seasonal influenza vaccines in early childhood.

Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):1853-8

Authors: Nakaya HI, Clutterbuck E, Kazmin D, Wang L, Cortese M, Bosinger SE, Patel NB, Zak DE, Aderem A, Dong T, Del Giudice G, Rappuoli R, Cerundolo V, Pollard AJ, Pulendran B, Siegrist CA

Abstract
The dynamics and molecular mechanisms underlying vaccine immunity in early childhood remain poorly understood. Here we applied systems approaches to investigate the innate and adaptive responses to trivalent inactivated influenza vaccine (TIV) and MF59-adjuvanted TIV (ATIV) in 90 14- to 24-mo-old healthy children. MF59 enhanced the magnitude and kinetics of serum antibody titers following vaccination, and induced a greater frequency of vaccine specific, multicytokine-producing CD4(+) T cells. Compared with transcriptional responses to TIV vaccination previously reported in adults, responses to TIV in infants were markedly attenuated, limited to genes regulating antiviral and antigen presentation pathways, and observed only in a subset of vaccinees. In contrast, transcriptional responses to ATIV boost were more homogenous and robust. Interestingly, a day 1 gene signature characteristic of the innate response (antiviral IFN genes, dendritic cell, and monocyte responses) correlated with hemagglutination at day 28. These findings demonstrate that MF59 enhances the magnitude, kinetics, and consistency of the innate and adaptive response to vaccination with the seasonal influenza vaccine during early childhood, and identify potential molecular correlates of antibody responses.

PMID: 26755593 [PubMed - indexed for MEDLINE]

Synthetic Ecology of Microbes: Mathematical Models and Applications.

J Mol Biol. 2016 Feb 27;428(5 Pt B):837-61

Authors: Zomorrodi AR, Segrè D

Abstract
As the indispensable role of natural microbial communities in many aspects of life on Earth is uncovered, the bottom-up engineering of synthetic microbial consortia with novel functions is becoming an attractive alternative to engineering single-species systems. Here, we summarize recent work on synthetic microbial communities with a particular emphasis on open challenges and opportunities in environmental sustainability and human health. We next provide a critical overview of mathematical approaches, ranging from phenomenological to mechanistic, to decipher the principles that govern the function, dynamics and evolution of microbial ecosystems. Finally, we present our outlook on key aspects of microbial ecosystems and synthetic ecology that require further developments, including the need for more efficient computational algorithms, a better integration of empirical methods and model-driven analysis, the importance of improving gene function annotation, and the value of a standardized library of well-characterized organisms to be used as building blocks of synthetic communities.

PMID: 26522937 [PubMed - indexed for MEDLINE]

Report on the Workshop and Regular Meeting of the Imode-CKD and Bcmolmed Marie Curie Training and Research Programs.

Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2015 Dec 1;36(2):235-240

Authors: Krochmal M, Cisek K, Markoska K, Spasovski G, Vlahou A

Abstract
A Workshop and Regular Meeting of the Marie Curie Training and Research Programs iMODECKD (Identification of the Molecular Determinants of established Chronic Kidney Disease) and BCMolMed (Molecular Medicine for Bladder Cancer) was held from 20-22 March at the Macedonian Academy of Science and Arts (MASA). The meeting was hosted by the participating center University of Skopje (SKO) - Goce Spasovski and MASA - Momir Polenakovic (R. Macedonia). The representative from MASA proteomic research center - Katerina Davalieva (R. Macedonia) had presentation on proteomic research in prostate cancer (PCa). 40 researchers from 13 different countries participated at the meeting. The Workshop was devoted on "Chronic Kidney Disease: Clinical Management issues", and consisted of 15 oral presentations given by nephrologists and experts in the field of CKD. Raymond Vanholder (Belgium) - past president of ERA-EDTA had a keynote lecture on "CKD: Questions that need to be answered and are not (or at least not entirely)". The workshop continued in four sessions with lectures from Alberto Ortiz (Spain), Olivera Stojceva-Taneva (R. Macedonia), Dimitrios Goumenos (Greece), Joachim Beige (Germany), Marian Klinger (Poland), Goce Spasovski (R. Macedonia), Joachim Jankowski (Germany), Adalbert Schiller (Romania), Robert Johnson (USA), Franco Ferrario (Italy), Ivan Rychlik (Czech Republic), Fulvio Magni (Italy) and Giovambattista Capasso (Italy), all covering a training theme. Within the meeting there were two lectures on complimentary skills for ethics in science and career advancement from two principal investigators - Goce Spasovski (R. Macedonia) and Joost Schanstra (France). During the Regular Meeting, 13 PhD students i.e. Early Stage Researchers and one Experienced Researcher from both Programs presented their work and progress within iMODE-CKD and BCMolMed projects. This meeting was a great opportunity to exchange experience and ideas in the field of systems biology approaches and translational medicine and planning future collaboration.

PMID: 27442390 [PubMed - as supplied by publisher]

Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis.

Heliyon. 2016 Jul;2(7):e00130

Authors: El-Mowafy AM, Katary MM, Pye C, Ibrahim AS, Elmarakby AA

Abstract
BACKGROUND/AIM: Hepatic injury is a hallmark adverse reaction to Valproate (VPA), a common used drug in the management of numerous CNS disorders, including epilepsy. DHA has a myriad of health benefits, including renal- and hepato-protective effects. Unfortunately, however, the underpinnings of such liver-pertinent VPA- and DHA-actions remain largely undefined. Accordingly, this study attempted to unveil the cellular and molecular triggers whereby VPA evokes, while DHA abates, hepatotoxicity.
METHODS: We evaluated activity and/or expression of cellular markers of oxidative stress, inflammation, and apoptosis in rat liver, following treatment with VPA (500 mg/kg/day) with and without concurrent treatment with DHA (250 mg/kg/day) for two weeks.
RESULTS AND CONCLUSION: VPA promoted hepatic oxidative stress as evidenced by enhancing activity/expression of NADPH-oxidase and its subunits, a ROS-generator, and by accumulation of lipid-peroxides. Moreover, VPA enhanced hepatic phosphorylation/activation of mitogen-activated protein kinase (MAPK), and expression of cyclooxygenase-2(COX-2), as proinflammatory signals. Besides, VPA promoted hepatocellular apoptosis, as attested by enhanced expression of cleaved caspase-9 and increased number of TUNEL-positive hepatocytes. Lastly, VPA upregulated levels of hypoxia-inducible factor-1-alpha (HIF-1α), a multifaceted modulator of hepatocytic biology, and activity of its downstream antioxidant enzyme heme-oxygenase-1(HO-1). These changes were significantly blunted by co-administration of DHA. Our findings demonstrate that VPA activated NADPH-oxidase and HIF-1α to induce oxidative-stress and hypoxia as initiators of hepatic injury. These changes were further aggravated by up-regulation of inflammatory (MAPK and COX-2) and apoptotic cascades, but could be partly lessened by HO-1 activation. Concurrent administration of DHA mitigated all VPA-induced anomalies.

PMID: 27441301 [PubMed]

Noise processing by microRNA-mediated circuits: The Incoherent Feed-Forward Loop, revisited.

Heliyon. 2016 Apr;2(4):e00095

Authors: Grigolon S, Di Patti F, De Martino A, Marinari E

Abstract
The intrinsic stochasticity of gene expression is usually mitigated in higher eukaryotes by post-transcriptional regulation channels that stabilise the output layer, most notably protein levels. The discovery of small non-coding RNAs (miRNAs) in specific motifs of the genetic regulatory network has led to identifying noise buffering as the possible key function they exert in regulation. Recent in vitro and in silico studies have corroborated this hypothesis. It is however also known that miRNA-mediated noise reduction is hampered by transcriptional bursting in simple topologies. Here, using stochastic simulations validated by analytical calculations based on van Kampen's expansion, we revisit the noise-buffering capacity of the miRNA-mediated Incoherent Feed Forward Loop (IFFL), a small module that is widespread in the gene regulatory networks of higher eukaryotes, in order to account for the effects of intermittency in the transcriptional activity of the modulator gene. We show that bursting considerably alters the circuit's ability to control static protein noise. By comparing with other regulatory architectures, we find that direct transcriptional regulation significantly outperforms the IFFL in a broad range of kinetic parameters. This suggests that, under pulsatile inputs, static noise reduction may be less important than dynamical aspects of noise and information processing in characterising the performance of regulatory elements.

PMID: 27441269 [PubMed]

Hydrogen peroxide induced cell death: One or two modes of action?

Heliyon. 2015 Dec;1(4):e00049

Authors: Uhl L, Gerstel A, Chabalier M, Dukan S

Abstract
Imlay and Linn show that exposure of logarithmically growing Escherichia coli to hydrogen peroxide (H2O2) leads to two kinetically distinguishable modes of cell killing. Mode one killing is pronounced near 1 mM concentration of H2O2 and is caused by DNA damage, whereas mode-two killing requires higher concentration ([Formula: see text]). The second mode seems to be essentially due to damage to all macromolecules. This phenomenon has also been observed in Fenton in vitro systems with DNA nicking caused by hydroxyl radical ([Formula: see text]). To our knowledge, there is currently no mathematical model for predicting mode one killing in vitro or in vivo after H2O2 exposure. We propose a simple model, using Escherichia coli as a model organism and a set of ordinary differential equations. Using this model, we show that available iron and cell density, two factors potentially involved in ROS dynamics, play a major role in the prediction of the experimental results obtained by our team and in previous studies. Indeed the presence of the mode one killing is strongly related to those two parameters. To our knowledge, mode-one death has not previously been explained. Imlay and Linn (Imlay and Linn, 1986) suggested that perhaps the amount of the toxic species was reduced at high concentrations of H2O2 because hydroxyl (or other) radicals might be quenched directly by hydrogen peroxide with the concomitant formation of superoxide anion (a less toxic species). We demonstrate (mathematically and numerically) that free available iron decrease is necessary to explain mode one killing which cannot appear without it and that H2O2 quenching or consumption is not responsible for mode-one death. We are able to follow ROS concentration (particularly responsible for mode one killing) after exposure to H2O2. This model therefore allows us to understand two major parameters involved in the presence or not of the first killing mode.

PMID: 27441232 [PubMed]

Construction and Evaluation of an Organic Anion Transporter 1 (OAT1)-Centered Metabolic Network.

J Biol Chem. 2016 Jul 20;

Authors: Liu HC, Jamshidi N, Chen Y, Eraly SA, Cho SY, Bhatnagar V, Wu W, Bush KT, Abagyan R, Palsson BO, Nigam SK

Abstract
There has been a recent interest in the broader physiological importance of multispecific drug transporters of the SLC and ABC transporter families. Here, a novel multi-tiered systems biology approach was used to predict metabolites and signaling molecules potentially affected by the in vivo deletion of organic anion transporter 1 (Oat1, Slc22a6, originally NKT), a major kidney-expressed drug transporter. Validation of some predictions in wet-lab assays, together with re-evaluation of existing transport and knockout metabolomics data, generated an experimentally-validated, confidence-ranked set of OAT1-interacting endogenous compounds enabling construction of an OAT1-centered metabolic interaction network. Pathway and enrichment analysis indicated an important role for OAT1 in metabolism involving: the TCA cycle, tryptophan and other amino acids, fatty acids, prostaglandins, cyclic nucleotides, odorants, polyamines, and vitamins. The partly-validated reconstructed network is also consistent with a major role for OAT1 in modulating metabolic and signaling pathways involving uric acid, gut microbiome products and so-called uremic toxins accumulating in chronic kidney disease (CKD). Together, the findings are compatible with the hypothesized role of drug transporters in remote inter-organ and inter-organismal communication (the Remote Sensing and Signaling Hypothesis, Nigam SK. 2015, Nature Rev Drug Disc 14:29). The fact that OAT1 can affect many systemic biological pathways suggests that drug-metabolite interactions (DMI) need to be considered beyond simple competition for the drug transporter itself and may explain aspects of drug-induced metabolic syndromes. Our approach should provide novel mechanistic insights into the role of OAT1 and other drug transporters implicated in metabolic diseases like gout, diabetes and CKD.

PMID: 27440044 [PubMed - as supplied by publisher]

Mission Critical: The Need for Proteomics in the Era of Next-Generation Sequencing and Precision Medicine.

Hum Mol Genet. 2016 Jul 20;

Authors: Cayer D, Nazor KL, Schork NJ

Abstract
Next generation sequencing (NGS) has ignited an unprecedented pace of discovery in the biomedical sciences that is fundamentally transforming the way that we understand, diagnose and treat disease, and has motivated the belief that true precision medicine - medicine that is tailored to an individual's genetic, biochemical and exposure profile - will be a reality in the near term. With minimal sample requirement, NGS can enable the concurrent genome-wide study of genetic variations, transcriptomes, and certain epigenetic modifications. However, interrogating proteins in as efficiently as DNA and RNA can be interrogated with NGS is lacking and this hampers more comprehensive views of molecular physiology and limits advances in biomedical science and precision medicine. The fact is that innovations in proteomic technologies pale in comparison to advances in NGS, with current methodologies suffering from issues related to reproducibility, sensitivity, sample requirements, and limited multiplexing capacity. The development of proteomic technologies to overcome these limitations would fill the void in systems biology research, catalyze clinical innovations, and expedite the realization of precision medicine.

PMID: 27439388 [PubMed - as supplied by publisher]

Simulation technology and its application in Systems Biology.

Nihon Yakurigaku Zasshi. 2016 Feb;147(2):101-6

Authors: Funahashi A, Hiroi N

PMID: 26860650 [PubMed - indexed for MEDLINE]

CauloBrowser: A systems biology resource for Caulobacter crescentus.

Nucleic Acids Res. 2016 Jan 4;44(D1):D640-5

Authors: Lasker K, Schrader JM, Men Y, Marshik T, Dill DL, McAdams HH, Shapiro L

Abstract
Caulobacter crescentus is a premier model organism for studying the molecular basis of cellular asymmetry. The Caulobacter community has generated a wealth of high-throughput spatiotemporal databases including data from gene expression profiling experiments (microarrays, RNA-seq, ChIP-seq, ribosome profiling, LC-ms proteomics), gene essentiality studies (Tn-seq), genome wide protein localization studies, and global chromosome methylation analyses (SMRT sequencing). A major challenge involves the integration of these diverse data sets into one comprehensive community resource. To address this need, we have generated CauloBrowser (www.caulobrowser.org), an online resource for Caulobacter studies. This site provides a user-friendly interface for quickly searching genes of interest and downloading genome-wide results. Search results about individual genes are displayed as tables, graphs of time resolved expression profiles, and schematics of protein localization throughout the cell cycle. In addition, the site provides a genome viewer that enables customizable visualization of all published high-throughput genomic data. The depth and diversity of data sets collected by the Caulobacter community makes CauloBrowser a unique and valuable systems biology resource.

PMID: 26476443 [PubMed - indexed for MEDLINE]

Parallel Mutual Information Based Construction of Genome-Scale Networks on the Intel® Xeon Phi™ Coprocessor.

IEEE/ACM Trans Comput Biol Bioinform. 2015 Sep-Oct;12(5):1008-20

Authors: Misra S, Pamnany K, Aluru S

Abstract
Construction of whole-genome networks from large-scale gene expression data is an important problem in systems biology. While several techniques have been developed, most cannot handle network reconstruction at the whole-genome scale, and the few that can, require large clusters. In this paper, we present a solution on the Intel Xeon Phi coprocessor, taking advantage of its multi-level parallelism including many x86-based cores, multiple threads per core, and vector processing units. We also present a solution on the Intel® Xeon® processor. Our solution is based on TINGe, a fast parallel network reconstruction technique that uses mutual information and permutation testing for assessing statistical significance. We demonstrate the first ever inference of a plant whole genome regulatory network on a single chip by constructing a 15,575 gene network of the plant Arabidopsis thaliana from 3,137 microarray experiments in only 22 minutes. In addition, our optimization for parallelizing mutual information computation on the Intel Xeon Phi coprocessor holds out lessons that are applicable to other domains.

PMID: 26451815 [PubMed - indexed for MEDLINE]

Systems analysis of cis-regulatory motifs in C4 photosynthesis genes using maize and rice leaf transcriptomic data during a process of de-etiolation.

J Exp Bot. 2016 Jul 19;

Authors: Xu J, Bräutigam A, Li Y, Weber AP, Zhu XG

Abstract
Identification of potential cis-regulatory motifs controlling the development of C4 photosynthesis is a major focus of current research. In this study, we used time-series RNA-seq data collected from etiolated maize and rice leaf tissues sampled during a de-etiolation process to systematically characterize the expression patterns of C4-related genes and to further identify potential cis elements in five different genomic regions (i.e. promoter, 5'UTR, 3'UTR, intron, and coding sequence) of C4 orthologous genes. The results demonstrate that although most of the C4 genes show similar expression patterns, a number of them, including chloroplast dicarboxylate transporter 1, aspartate aminotransferase, and triose phosphate transporter, show shifted expression patterns compared with their C3 counterparts. A number of conserved short DNA motifs between maize C4 genes and their rice orthologous genes were identified not only in the promoter, 5'UTR, 3'UTR, and coding sequences, but also in the introns of core C4 genes. We also identified cis-regulatory motifs that exist in maize C4 genes and also in genes showing similar expression patterns as maize C4 genes but that do not exist in rice C3 orthologs, suggesting a possible recruitment of pre-existing cis-elements from genes unrelated to C4 photosynthesis into C4 photosynthesis genes during C4 evolution.

PMID: 27436282 [PubMed - as supplied by publisher]

Training in metabolomics research. I. Designing the experiment, collecting and extracting samples and generating metabolomics data.

J Mass Spectrom. 2016 Jul;51(7):461-75

Authors: Barnes S, Benton HP, Casazza K, Cooper SJ, Cui X, Du X, Engler J, Kabarowski JH, Li S, Pathmasiri W, Prasain JK, Renfrow MB, Tiwari HK

Abstract
The study of metabolism has had a long history. Metabolomics, a systems biology discipline representing analysis of known and unknown pathways of metabolism, has grown tremendously over the past 20 years. Because of its comprehensive nature, metabolomics requires careful consideration of the question(s) being asked, the scale needed to answer the question(s), collection and storage of the sample specimens, methods for extraction of the metabolites from biological matrices, the analytical method(s) to be employed and the quality control of the analyses, how collected data are correlated, the statistical methods to determine metabolites undergoing significant change, putative identification of metabolites and the use of stable isotopes to aid in verifying metabolite identity and establishing pathway connections and fluxes. The National Institutes of Health Common Fund Metabolomics Program was established in 2012 to stimulate interest in the approaches and technologies of metabolomics. To deliver one of the program's goals, the University of Alabama at Birmingham has hosted an annual 4-day short course in metabolomics for faculty, postdoctoral fellows and graduate students from national and international institutions. This paper is the first part of a summary of the training materials presented in the course to be used as a resource for all those embarking on metabolomics research. The complete set of training materials including slide sets and videos can be viewed at http://www.uab.edu/proteomics/metabolomics/workshop/workshop_june_2015.php. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 27434804 [PubMed - in process]

Animal Models of Chemical Carcinogenesis: Driving Breakthroughs in Cancer Research for 100 Years.

Cold Spring Harb Protoc. 2015 Oct;2015(10):865-74

Authors: Kemp CJ

Abstract
The identification of carcinogens in the workplace, diet, and environment through chemical carcinogenesis studies in animals has directly contributed to a reduction of cancer burden in the human population. Reduced exposure to these carcinogens through lifestyle changes, government regulation, or change in industry practices has reduced cancer incidence in exposed populations. In addition to providing the first experimental evidence for cancer's relationship to chemical and radiation exposure, animal models of environmentally induced cancer have and will continue to provide important insight into the causes, mechanisms, and conceptual frameworks of cancer. More recently, combining chemical carcinogens with genetically engineered mouse models has emerged as an invaluable approach to study the complex interaction between genotype and environment that contributes to cancer development. In the future, animal models of environmentally induced cancer are likely to provide insight into areas such as the epigenetic basis of cancer, genetic modifiers of cancer susceptibility, the systems biology of cancer, inflammation and cancer, and cancer prevention.

PMID: 26430259 [PubMed - indexed for MEDLINE]

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Top-down, Bottom-up and Middle-out Strategies for Drug Cardiac Safety Assessment via Modeling and Simulations.

Curr Pharmacol Rep. 2016;2:171-177

Authors: Tylutki Z, Polak S, Wiśniowska B

Abstract
Cardiac safety is an issue causing early terminations at various stages of drug development. Efforts are put into the elimination of false negatives as well as false positives resulting from the current testing paradigm. In silico approaches offer mathematical system and data description from the ion current, through cardiomyocytes level, up to incorporation of inter-individual variability at the population level. The article aims to review three main modelling and simulation approaches, i.e. "top-down" which refers to models built on the observed data, "bottom-up", which stands for a mechanistic description of human physiology, and "middle-out" which combines both strategies. Modelling and simulation is a well-established tool in the assessment of drug proarrhythmic potency with an impact on research and development as well as on regulatory decisions, and it is certainly here to stay. What is more, the shift to systems biology and physiology-based models makes the cardiac effect more predictable.

PMID: 27429898 [PubMed - as supplied by publisher]

2016 ISCB Overton Prize awarded to Debora Marks.

F1000Res. 2016;5

Authors: Fogg CN, Kovats DE

Abstract
The International Society for Computational Biology (ISCB) recognizes the achievements of an early- to mid-career scientist with the Overton Prize each year. The Overton Prize was established to honor the untimely loss of Dr. G. Christian Overton, a respected computational biologist and founding ISCB Board member. Winners of the Overton Prize are independent investigators in the early to middle phases of their careers who are selected because of their significant contributions to computational biology through research, teaching, and service. 2016 will mark the fifteenth bestowment of the ISCB Overton Prize.  ISCB is pleased to confer this award the to Debora Marks, Assistant Professor of Systems Biology and director of the Raymond and Beverly Sackler Laboratory for Computational Biology at Harvard Medical School.

PMID: 27429747 [PubMed - as supplied by publisher]

Guidelines for reproducibly building and simulating systems biology models.

IEEE Trans Biomed Eng. 2016 Jul 18;

Authors: Medley JK, Goldberg A, Karr JR

Abstract
Reproducibility is the cornerstone of the scientific method. However, currently, many systems biology models cannot easily be reproduced. This paper presents methods that address this problem.
METHODS: We analyzed the recent Mycoplasma genitalium whole-cell (WC) model to determine the requirements for reproducible modeling.
RESULTS: We determined that reproducible modeling requires both repeatable model building and repeatable simulation.
CONCLUSION: New standards and simulation software tools are needed to enhance and verify the reproducibility of modeling. New standards are needed to explicitly document every data source and assumption, and new deterministic parallel simulation tools are needed to quickly simulate large, complex models.
SIGNIFICANCE: We anticipate that these new standards and software will enable researchers to reproducibly build and simulate more complex models, including WC models.

PMID: 27429432 [PubMed - as supplied by publisher]

SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.

Cell Chem Biol. 2016 Jul 9;

Authors: Quinti L, Casale M, Moniot S, Pais TF, Van Kanegan MJ, Kaltenbach LS, Pallos J, Lim RG, Naidu SD, Runne H, Meisel L, Rauf NA, Leyfer D, Maxwell MM, Saiah E, Landers JE, Luthi-Carter R, Abagyan R, Dinkova-Kostova AT, Steegborn C, Marsh JL, Lo DC, Thompson LM, Kazantsev AG

Abstract
There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2 (SIRT2) with neuroprotective activity in ex vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity. MIND compounds induced NRF2 activation responses in neuronal and non-neuronal cells and reduced production of reactive oxygen species and nitrogen intermediates. These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders.

PMID: 27427231 [PubMed - as supplied by publisher]