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Article ; Online: Sequential Parameter Estimation for Mammalian Cell Model Based on In Silico Design of Experiments

Zhenyu Wang / Hana Sheikh / Kyongbum Lee / Christos Georgakis

Processes, Vol 6, Iss 8, p

2018 Volume 100

Abstract: Due to the complicated metabolism of mammalian cells, the corresponding dynamic mathematical models usually consist of large sets of differential and algebraic equations with a large number of parameters to be estimated. On the other hand, the measured ... ...

Abstract	Due to the complicated metabolism of mammalian cells, the corresponding dynamic mathematical models usually consist of large sets of differential and algebraic equations with a large number of parameters to be estimated. On the other hand, the measured data for estimating the model parameters are limited. Consequently, the parameter estimates may converge to a local minimum far from the optimal ones, especially when the initial guesses of the parameter values are poor. The methodology presented in this paper provides a systematic way for estimating parameters sequentially that generates better initial guesses for parameter estimation and improves the accuracy of the obtained metabolic model. The model parameters are first classified into four subsets of decreasing importance, based on the sensitivity of the model’s predictions on the parameters’ assumed values. The parameters in the most sensitive subset, typically a small fraction of the total, are estimated first. When estimating the remaining parameters with next most sensitive subset, the subsets of parameters with higher sensitivities are estimated again using their previously obtained optimal values as the initial guesses. The power of this sequential estimation approach is illustrated through a case study on the estimation of parameters in a dynamic model of CHO cell metabolism in fed-batch culture. We show that the sequential parameter estimation approach improves model accuracy and that using limited data to estimate low-sensitivity parameters can worsen model performance.
Keywords	Pharmaceutical Processes ; Mammalian Cell Culture ; sensitivity analysis ; parameter estimation ; Design of Experiments ; Chemical technology ; TP1-1185 ; Chemistry ; QD1-999
Subject code	310
Language	English
Publishing date	2018-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1)

Miok Lee / Srijana Upadhyay / Fuada Mariyam / Greg Martin / Amanuel Hailemariam / Kyongbum Lee / Arul Jayaraman / Robert S. Chapkin / Syng-Ook Lee / Stephen Safe

International Journal of Molecular Sciences, Vol 24, Iss 8152, p

2023 Volume 8152

Abstract: It was recently reported that the hydroxyflavones quercetin and kaempferol bind the orphan nuclear receptor 4A1 (NR4A1, Nur77) and act as antagonists in cancer cells and tumors, and they inhibit pro-oncogenic NR4A1-regulated genes and pathways. In this ... ...

Abstract	It was recently reported that the hydroxyflavones quercetin and kaempferol bind the orphan nuclear receptor 4A1 (NR4A1, Nur77) and act as antagonists in cancer cells and tumors, and they inhibit pro-oncogenic NR4A1-regulated genes and pathways. In this study, we investigated the interactions of flavone, six hydroxyflavones, seven dihydroxyflavones, three trihydroxyflavones, two tetrahydroxyflavones, and one pentahydroxyflavone with the ligand-binding domain (LBD) of NR4A1 using direct-binding fluorescence and an isothermal titration calorimetry (ITC) assays. Flavone and the hydroxyflavones bound NR4A1, and their K D values ranged from 0.36 µM for 3,5,7-trihydroxyflavone (galangin) to 45.8 µM for 3′-hydroxyflavone. K D values determined using ITC and K D values for most (15/20) of the hydroxyflavones were decreased compared to those obtained using the fluorescence assay. The results of binding, transactivation and receptor–ligand modeling assays showed that K D values, transactivation data and docking scores for these compounds are highly variable with respect to the number and position of the hydroxyl groups on the flavone backbone structure, suggesting that hydroxyflavones are selective NR4A1 modulators. Nevertheless, the data show that hydroxyflavone-based neutraceuticals are NR4A1 ligands and that some of these compounds can now be repurposed and used to target sub-populations of patients that overexpress NR4A1.
Keywords	flavone ; hydroxyflavones ; binding ; NR4A1 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Pathways and functions of gut microbiota metabolism impacting host physiology

Krishnan, Smitha / Kyongbum Lee / Nicholas Alden

Current opinion in biotechnology. 2015 Dec., v. 36

2015

Abstract: The bacterial populations in the human intestine impact host physiological functions through their metabolic activity. In addition to performing essential catabolic and biotransformation functions, the gut microbiota produces bioactive small molecules ... ...

Abstract	The bacterial populations in the human intestine impact host physiological functions through their metabolic activity. In addition to performing essential catabolic and biotransformation functions, the gut microbiota produces bioactive small molecules that mediate interactions with the host and contribute to the neurohumoral axes connecting the intestine with other parts of the body. This review discusses recent progress in characterizing the metabolic products of the gut microbiota and their biological functions, focusing on studies that investigate the responsible bacterial pathways and cognate host receptors. Several key areas are highlighted for future development: context-based analysis targeting pathways; integration of analytical approaches; metabolic modeling; and synthetic systems for in vivo manipulation of microbiota functions. Prospectively, these developments could further our mechanistic understanding of hostâmicrobiota interactions.
Keywords	analytical methods ; biotransformation ; human population ; intestinal microorganisms ; intestines ; metabolism ; models ; receptors
Language	English
Dates of publication	2015-12
Size	p. 137-145.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1052045-4
ISSN	1879-0429 ; 0958-1669
ISSN (online)	1879-0429
ISSN	0958-1669
DOI	10.1016/j.copbio.2015.08.015
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Metabolomics of Acute vs. Chronic Spinach Intake in an Apc–Mutant Genetic Background

Ying-Shiuan Chen / Jia Li / Sultan Neja / Sabeeta Kapoor / Jorge Enrique Tovar Perez / Chakrapani Tripathi / Rani Menon / Arul Jayaraman / Kyongbum Lee / Wan Mohaiza Dashwood / Shan Wang / Ke Zhang / Koichi Kobayashi / Praveen Rajendran / Roderick Dashwood

Cells, Vol 11, Iss 573, p

Linoleate and Butanoate Metabolites Targeting HDAC Activity and IFN–γ Signaling

2022 Volume 573

Abstract: There is growing interest in the crosstalk between the gut microbiome, host metabolomic features, and disease pathogenesis. The current investigation compared long–term (26 week) and acute (3 day) dietary spinach intake in a genetic model of colorectal ... ...

Abstract	There is growing interest in the crosstalk between the gut microbiome, host metabolomic features, and disease pathogenesis. The current investigation compared long–term (26 week) and acute (3 day) dietary spinach intake in a genetic model of colorectal cancer. Metabolomic analyses in the polyposis in rat colon (Pirc) model and in wild–type animals corroborated key contributions to anticancer outcomes by spinach–derived linoleate bioactives and a butanoate metabolite linked to increased α–diversity of the gut microbiome. Combining linoleate and butanoate metabolites in human colon cancer cells revealed enhanced apoptosis and reduced cell viability, paralleling the apoptosis induction in colon tumors from rats given long–term spinach treatment. Mechanistic studies in cell–based assays and in vivo implicated the linoleate and butanoate metabolites in targeting histone deacetylase (HDAC) activity and the interferon–γ (IFN–γ) signaling axis. Clinical translation of these findings to at–risk patients might provide valuable quality–of–life benefits by delaying surgical interventions and drug therapies with adverse side effects.
Keywords	Familial Adenomatous Polyposis ; gut microbiome ; histone deacetylase ; interferon–γ signaling ; major histocompatibility complex ; polyposis in rat colon ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of biochemical network modules based on shortest retroactive distances.

Gautham Vivek Sridharan / Soha Hassoun / Kyongbum Lee

PLoS Computational Biology, Vol 7, Iss 11, p e

2011 Volume 1002262

Abstract: Modularity analysis offers a route to better understand the organization of cellular biochemical networks as well as to derive practically useful, simplified models of these complex systems. While there is general agreement regarding the qualitative ... ...

Abstract	Modularity analysis offers a route to better understand the organization of cellular biochemical networks as well as to derive practically useful, simplified models of these complex systems. While there is general agreement regarding the qualitative properties of a biochemical module, there is no clear consensus on the quantitative criteria that may be used to systematically derive these modules. In this work, we investigate cyclical interactions as the defining characteristic of a biochemical module. We utilize a round trip distance metric, termed Shortest Retroactive Distance (ShReD), to characterize the retroactive connectivity between any two reactions in a biochemical network and to group together network components that mutually influence each other. We evaluate the metric on two types of networks that feature feedback interactions: (i) epidermal growth factor receptor (EGFR) signaling and (ii) liver metabolism supporting drug transformation. For both networks, the ShReD partitions found hierarchically arranged modules that confirm biological intuition. In addition, the partitions also revealed modules that are less intuitive. In particular, ShReD-based partition of the metabolic network identified a 'redox' module that couples reactions of glucose, pyruvate, lipid and drug metabolism through shared production and consumption of NADPH. Our results suggest that retroactive interactions arising from feedback loops and metabolic cycles significantly contribute to the modularity of biochemical networks. For metabolic networks, cofactors play an important role as allosteric effectors that mediate the retroactive interactions.
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2011-11-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Biologically Consistent Annotation of Metabolomics Data

Alden, Nicholas / Smitha Krishnan / Vladimir Porokhin / Ravali Raju / Kyle McElearney / Alan Gilbert / Kyongbum Lee

Analytical chemistry. 2017 Dec. 19, v. 89, no. 24

2017

Abstract: Annotation of metabolites remains a major challenge in liquid chromatography–mass spectrometry (LC–MS) based untargeted metabolomics. The current gold standard for metabolite identification is to match the detected feature with an authentic standard ... ...

Abstract	Annotation of metabolites remains a major challenge in liquid chromatography–mass spectrometry (LC–MS) based untargeted metabolomics. The current gold standard for metabolite identification is to match the detected feature with an authentic standard analyzed on the same equipment and using the same method as the experimental samples. However, there are substantial practical challenges in applying this approach to large data sets. One widely used annotation approach is to search spectral libraries in reference databases for matching metabolites; however, this approach is limited by the incomplete coverage of these libraries. An alternative computational approach is to match the detected features to candidate chemical structures based on their mass and predicted fragmentation pattern. Unfortunately, both of these approaches can match multiple identities with a single feature. Another issue is that annotations from different tools often disagree. This paper presents a novel LC–MS data annotation method, termed Biologically Consistent Annotation (BioCAn), that combines the results from database searches and in silico fragmentation analyses and places these results into a relevant biological context for the sample as captured by a metabolic model. We demonstrate the utility of this approach through an analysis of CHO cell samples. The performance of BioCAn is evaluated against several currently available annotation tools, and the accuracy of BioCAn annotations is verified using high-purity analytical standards.
Keywords	chemical structure ; data collection ; databases ; equipment ; liquid chromatography ; mass spectrometry ; metabolites ; metabolomics ; models
Language	English
Dates of publication	2017-1219
Size	p. 13097-13104.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.7b02162
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Metabolic flux analysis of mitochondrial uncoupling in 3T3-L1 adipocytes.

Yaguang Si / Hai Shi / Kyongbum Lee

PLoS ONE, Vol 4, Iss 9, p e

2009 Volume 7000

Abstract: BACKGROUND:Increasing energy expenditure at the cellular level offers an attractive option to limit adiposity and improve whole body energy balance. In vivo and in vitro observations have correlated mitochondrial uncoupling protein-1 (UCP1) expression ... ...

Abstract	BACKGROUND:Increasing energy expenditure at the cellular level offers an attractive option to limit adiposity and improve whole body energy balance. In vivo and in vitro observations have correlated mitochondrial uncoupling protein-1 (UCP1) expression with reduced white adipose tissue triglyceride (TG) content. The metabolic basis for this correlation remains unclear. METHODOLOGY/PRINCIPAL FINDINGS:This study tested the hypothesis that mitochondrial uncoupling requires the cell to compensate for the decreased oxidation phosphorylation efficiency by up-regulating lactate production, thus redirecting carbon flux away from TG synthesis. Metabolic flux analysis was used to characterize the effects of non-lethal, long-term mitochondrial uncoupling (up to 18 days) on the pathways of intermediary metabolism in differentiating 3T3-L1 adipocytes. Uncoupling was induced by forced expression of UCP1 and chemical (FCCP) treatment. Chemical uncoupling significantly decreased TG content by ca. 35%. A reduction in the ATP level suggested diminished oxidative phosphorylation efficiency in the uncoupled adipocytes. Flux analysis estimated significant up-regulation of glycolysis and down-regulation of fatty acid synthesis, with chemical uncoupling exerting quantitatively larger effects. CONCLUSIONS/SIGNIFICANCE:The results of this study support our hypothesis regarding uncoupling-induced redirection of carbon flux into glycolysis and lactate production, and suggest mitochondrial proton translocation as a potential target for controlling adipocyte lipid metabolism.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2009-09-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Rational identification of diet-derived postbiotics for improving intestinal microbiota function

Klemashevich, Cory / Arul Jayaraman / Charmian Wu / Daniel Howsmon / Kyongbum Lee / Robert C. Alaniz

Current opinion in biotechnology. 2014 Apr., v. 26

2014

Abstract: The intestinal microbiota plays an important role in a wide range of functions and whole body homeostasis. Recent advances have linked microbiota dysbiosis to conditions ranging from Crohn's disease to cancer. The restoration or strengthening of the ... ...

Abstract	The intestinal microbiota plays an important role in a wide range of functions and whole body homeostasis. Recent advances have linked microbiota dysbiosis to conditions ranging from Crohn's disease to cancer. The restoration or strengthening of the intestinal microbiota through diet-based approaches such as probiotics and prebiotics has been proposed for combating the onset or progression of these diseases. In this review, we highlight the importance of postbiotics for the manipulation of the intestinal microbiota, with special emphasis on systems biology computational tools and targeted metabolomics for the rational discovery and identification of these bioactive molecules. The identification of novel postbiotics and the pathways responsible for their production should lead to improved mechanistic understanding of the role that specific probiotics, prebiotics, and postbiotics have in restoring intestinal microbiota composition and function.
Keywords	bioinformatics ; Crohn disease ; homeostasis ; intestinal microorganisms ; metabolomics ; neoplasms ; prebiotics ; probiotics
Language	English
Dates of publication	2014-04
Size	p. 85-90.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1052045-4
ISSN	1879-0429 ; 0958-1669
ISSN (online)	1879-0429
ISSN	0958-1669
DOI	10.1016/j.copbio.2013.10.006
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages

Smitha Krishnan / Yufang Ding / Nima Saedi / Maria Choi / Gautham V. Sridharan / David H. Sherr / Martin L. Yarmush / Robert C. Alaniz / Arul Jayaraman / Kyongbum Lee

Cell Reports, Vol 23, Iss 4, Pp 1099-

2018 Volume 1111

Abstract: Summary: The gut microbiota plays a significant role in the progression of fatty liver disease; however, the mediators and their mechanisms remain to be elucidated. Comparing metabolite profile differences between germ-free and conventionally raised mice ...

Abstract	Summary: The gut microbiota plays a significant role in the progression of fatty liver disease; however, the mediators and their mechanisms remain to be elucidated. Comparing metabolite profile differences between germ-free and conventionally raised mice against differences between mice fed a low- and high-fat diet (HFD), we identified tryptamine and indole-3-acetate (I3A) as metabolites that depend on the microbiota and are depleted under a HFD. Both metabolites reduced fatty-acid- and LPS-stimulated production of pro-inflammatory cytokines in macrophages and inhibited the migration of cells toward a chemokine, with I3A exhibiting greater potency. In hepatocytes, I3A attenuated inflammatory responses under lipid loading and reduced the expression of fatty acid synthase and sterol regulatory element-binding protein-1c. These effects were abrogated in the presence of an aryl-hydrocarbon receptor (AhR) antagonist, indicating that the effects are AhR dependent. Our results suggest that gut microbiota could influence inflammatory responses in the liver through metabolites engaging host receptors. : Dysbiosis of the intestinal microbiota is an emerging factor contributing to the progression of fatty liver disease. Krishnan et al. utilize metabolomics and biochemical assays in conjunction with animal and cell culture models to identify microbiota-dependent metabolites that engage a host receptor to affect liver inflammatory responses under lipid loading. Keywords: nonalcoholic fatty liver disease, gut microbiota, metabolomics, indole-3-acetate, inflammation, aryl hydrocarbon receptor
Keywords	Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: N-acetylglucosamine 6-phosphate deacetylase (nagA) is required for N-acetyl glucosamine assimilation in Gluconacetobacter xylinus.

Vikas Yadav / Bruce Panilaitis / Hai Shi / Keiji Numuta / Kyongbum Lee / David L Kaplan

PLoS ONE, Vol 6, Iss 6, p e

2011 Volume 18099

Abstract: Metabolic pathways for amino sugars (N-acetylglucosamine; GlcNAc and glucosamine; Gln) are essential and remain largely conserved in all three kingdoms of life, i.e., microbes, plants and animals. Upon uptake, in the cytoplasm these amino sugars undergo ... ...

Abstract	Metabolic pathways for amino sugars (N-acetylglucosamine; GlcNAc and glucosamine; Gln) are essential and remain largely conserved in all three kingdoms of life, i.e., microbes, plants and animals. Upon uptake, in the cytoplasm these amino sugars undergo phosphorylation by phosphokinases and subsequently deacetylation by the enzyme N-acetylglucosamine 6-phosphate deacetylase (nagA) to yield glucosamine-6-phosphate and acetate, the first committed step for both GlcNAc assimilation and amino-sugar-nucleotides biosynthesis. Here we report the cloning of a DNA fragment encoding a partial nagA gene and its implications with regard to amino sugar metabolism in the cellulose producing bacterium Glucoacetobacter xylinus (formally known as Acetobacter xylinum). For this purpose, nagA was disrupted by inserting tetracycline resistant gene (nagA::tet(r); named as ΔnagA) via homologous recombination. When compared to glucose fed conditions, the UDP-GlcNAc synthesis and bacterial growth (due to lack of GlcNAc utilization) was completely inhibited in nagA mutants. Interestingly, that inhibition occured without compromising cellulose production efficiency and its molecular composition under GlcNAc fed conditions. We conclude that nagA plays an essential role for GlcNAc assimilation by G. xylinus thus is required for the growth and survival for the bacterium in presence of GlcNAc as carbon source. Additionally, G. xylinus appears to possess the same molecular machinery for UDP-GlcNAc biosynthesis from GlcNAc precursors as other related bacterial species.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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