Publications by authors named "Ioannis P Androulakis"

114 Publications

Light entrainment of the SCN circadian clock and implications for personalized alterations of corticosterone rhythms in shift work and jet lag.

Sci Rep 2021 09 9;11(1):17929. Epub 2021 Sep 9.

Chemical & Biochemical Engineering Department, Rutgers, Piscataway, USA.

The suprachiasmatic nucleus (SCN) functions as the central pacemaker aligning physiological and behavioral oscillations to day/night (activity/inactivity) transitions. The light signal entrains the molecular clock of the photo-sensitive ventrolateral (VL) core of the SCN which in turn entrains the dorsomedial (DM) shell via the neurotransmitter vasoactive intestinal polypeptide (VIP). The shell converts the VIP rhythmic signals to circadian oscillations of arginine vasopressin (AVP), which eventually act as a neurotransmitter signal entraining the hypothalamic-pituitary-adrenal (HPA) axis, leading to robust circadian secretion of glucocorticoids. In this work, we discuss a semi-mechanistic mathematical model that reflects the essential hierarchical structure of the photic signal transduction from the SCN to the HPA axis. By incorporating the interactions across the core, the shell, and the HPA axis, we investigate how these coupled systems synchronize leading to robust circadian oscillations. Our model predicts the existence of personalized synchronization strategies that enable the maintenance of homeostatic rhythms while allowing for differential responses to transient and permanent light schedule changes. We simulated different behavioral situations leading to perturbed rhythmicity, performed a detailed computational analysis of the dynamic response of the system under varying light schedules, and determined that (1) significant interindividual diversity and flexibility characterize adaptation to varying light schedules; (2) an individual's tolerances to jet lag and alternating shift work are positively correlated, while the tolerances to jet lag and transient shift work are negatively correlated, which indicates trade-offs in an individual's ability to maintain physiological rhythmicity; (3) weak light sensitivity leads to the reduction of circadian flexibility, implying that light therapy can be a potential approach to address shift work and jet lag related disorders. Finally, we developed a map of the impact of the synchronization within the SCN and between the SCN and the HPA axis as it relates to the emergence of circadian flexibility.
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http://dx.doi.org/10.1038/s41598-021-97019-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429702PMC
September 2021

Self-selection of evolutionary strategies: adaptive non-adaptive forces.

Heliyon 2021 May 15;7(5):e06997. Epub 2021 May 15.

Biomecdical Engineering Department, Rutgers University, Piscataway, NJ, USA.

The evolution of complex genetic networks is shaped over the course of many generations through multiple mechanisms. These mechanisms can be broken into two predominant categories: adaptive forces, such as natural selection, and non-adaptive forces, such as recombination, genetic drift, and random mutation. Adaptive forces are influenced by the environment, where individuals better suited for their ecological niche are more likely to reproduce. This adaptive force results in a selective pressure which creates a bias in the reproduction of individuals with beneficial traits. Non-adaptive forces, in contrast, are not influenced by the environment: Random mutations occur in offspring regardless of whether they improve the fitness of the offspring. Both adaptive and non-adaptive forces play critical roles in the development of a species over time, and both forces are intrinsically linked to one another. We hypothesize that even under a simple sexual reproduction model, selective pressure will result in changes in the mutation rate and genome size. We tested this hypothesis by evolving Boolean networks using a modified genetic algorithm. Our results demonstrate that changes in environmental signals can result in selective pressure which affects mutation rate.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141468PMC
May 2021

Circadian Effects of Drug Responses.

Annu Rev Biomed Eng 2021 07 31;23:203-224. Epub 2021 Mar 31.

Department of Biomedical Engineering and Department of Chemical & Biochemical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA; email:

Circadian rhythms describe physiological systems that repeat themselves with a cycle of approximately 24 h. Our understanding of the cellular and molecular origins of these oscillations has improved dramatically, allowing us to appreciate the significant role these oscillations play in maintaining physiological homeostasis. Circadian rhythms allow living organisms to predict and efficiently respond to a dynamically changing environment, set by repetitive day/night cycles. Since circadian rhythms underlie almost every aspect of human physiology, it is unsurprising that they also influence the response of a living organism to disease, stress, and therapeutics. Therefore, not only do the mechanisms that maintain health and disrupt homeostasis depend on our internal circadian clock, but also the way drugs are perceived and function depends on these physiological rhythms. We present a holistic view of the therapeutic process, discussing components such as disease state, pharmacokinetics, and pharmacodynamics, as well as adverse reactions that are critically affected by circadian rhythms. We outline challenges and opportunities in moving toward personalized medicine approaches that explore and capitalize on circadian rhythms for the benefit of the patient.
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http://dx.doi.org/10.1146/annurev-bioeng-082120-034725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525652PMC
July 2021

Pathway-level analysis of genome-wide circadian dynamics in diverse tissues in rat and mouse.

J Pharmacokinet Pharmacodyn 2021 Jun 25;48(3):361-374. Epub 2021 Mar 25.

Biomedical Engineering Department, Rutgers University, Piscataway, NJ, USA.

A computational framework is developed to enable the characterization of genome-wide, multi-tissue circadian dynamics at the level of "functional groupings of genes" defined in the context of signaling, cellular/genetic processing and metabolic pathways in rat and mouse. Our aim is to identify how individual genes come together to generate orchestrated rhythmic patterns and how these may vary within and across tissues. We focus our analysis on four tissues (adipose, liver, lung, and muscle). A genome-wide pathway-centric analysis enables us to develop a comprehensive picture on how the observed circadian variation at the individual gene level, orchestrates functional responses at the pathway level. Such pathway-based "meta-data" analysis enables the rational integration and comparison across platforms and/or experimental designs evaluating emergent dynamics, as opposed to comparisons of individual elements. One of our key findings is that when considering the dynamics at the pathway level, a complex behavior emerges. Our work proposes that tissues tend to coordinate gene's circadian expression in a way that optimizes tissue-specific pathway activity, depending of each tissue's broader role in homeostasis.
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http://dx.doi.org/10.1007/s10928-021-09750-3DOI Listing
June 2021

Circadian rhythms and the HPA axis: A systems view.

WIREs Mech Dis 2021 07 12;13(4):e1518. Epub 2021 Jan 12.

Biomedical Engineering Department, Chemical & Biochemical Engineering Department, Rutgers University, New Brunswick, New Jersey.

The circadian timing system comprises a network of time-keeping clocks distributed across a living host whose responsibility is to allocate resources and distribute functions temporally to optimize fitness. The molecular structures generating these rhythms have evolved to accommodate the rotation of the earth in an attempt to primarily match the light/dark periods during the 24-hr day. To maintain synchrony of timing across and within tissues, information from the central clock, located in the suprachiasmatic nucleus, is conveyed using systemic signals. Leading among those signals are endocrine hormones, and while the hypothalamic-pituitary-adrenal axis through the release of glucocorticoids is a major pacesetter. Interestingly, the fundamental units at the molecular and physiological scales that generate local and systemic signals share critical structural properties. These properties enable time-keeping systems to generate rhythmic signals and allow them to adopt specific properties as they interact with each other and the external environment. The purpose of this review is to provide a broad overview of these structures, discuss their functional characteristics, and describe some of their fundamental properties as these related to health and disease. This article is categorized under: Immune System Diseases > Computational Models Immune System Diseases > Biomedical Engineering.
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http://dx.doi.org/10.1002/wsbm.1518DOI Listing
July 2021

Circadian Disruption in Critical Illness.

Front Neurol 2020 11;11:820. Epub 2020 Aug 11.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States.

Circadian rhythms play a vital role in metabolic, hormonal, and immunologic function and are often disrupted in patients in the ICU. Circadian rhythms modulate the molecular machinery that responds to injury and illness which can impact recovery. Potential factors contributing to the alteration in circadian rhythmicity in intensive care unit (ICU) patients include abnormal lighting, noise, altered feeding schedules, extensive patient care interactions and medications. These alterations in circadian rhythms in ICU patients may affect outcomes and therefore, normalization of circadian rhythmicity in critically ill patients may be an important part of ICU care.
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http://dx.doi.org/10.3389/fneur.2020.00820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431488PMC
August 2020

Modeling Pathway Dynamics of the Skeletal Muscle Response to Intravenous Methylprednisolone (MPL) Administration in Rats: Dosing and Tissue Effects.

Front Bioeng Biotechnol 2020 14;8:759. Epub 2020 Jul 14.

Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, United States.

A model-based approach for the assessment of pathway dynamics is explored to characterize metabolic and signaling pathway activity changes characteristic of the dosing-dependent differences in response to methylprednisolone in muscle. To consistently compare dosing-induced changes we extend the principles of pharmacokinetics and pharmacodynamics and introduce a novel representation of pathway-level dynamic models of activity regulation. We hypothesize the emergence of dosing-dependent regulatory interactions is critical to understanding the mechanistic implications of MPL dosing in muscle. Our results indicate that key pathways, including amino acid and lipid metabolism, signal transduction, endocrine regulation, regulation of cellular functions including growth, death, motility, transport, protein degradation, and catabolism are dependent on dosing, exhibiting diverse dynamics depending on whether the drug is administered acutely of continuously. Therefore, the dynamics of drug presentation offer the possibility for the emergence of dosing-dependent models of regulation. Finally, we compared acute and chronic MPL response in muscle with liver. The comparison revealed systematic response differences between the two tissues, notably that muscle appears more prone to adapt to MPL.
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http://dx.doi.org/10.3389/fbioe.2020.00759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371857PMC
July 2020

Modeling inter-sex and inter-individual variability in response to chronopharmacological administration of synthetic glucocorticoids.

Chronobiol Int 2020 02 4;37(2):281-296. Epub 2019 Dec 4.

Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ.

Endogenous glucocorticoids have diverse physiological effects and are important regulators of metabolism, immunity, cardiovascular function, musculoskeletal health and central nervous system activity. Synthetic glucocorticoids have received widespread attention for their potent anti-inflammatory activity and have become an important class of drugs used to augment endogenous glucocorticoid activity for the treatment of a host of chronic inflammatory conditions. Chronic use of synthetic glucocorticoids is associated with a number of adverse effects as a result of the persistent dysregulation of glucocorticoid sensitive pathways. A failure to consider the pronounced circadian rhythmicity of endogenous glucocorticoids can result in either supraphysiological glucocorticoid exposure or severe suppression of endogenous glucocorticoid secretion, and is thought be a causal factor in the incidence of adverse effects during chronic glucocorticoid therapy. Furthermore, given that synthetic glucocorticoids have potent feedback effects on the hypothalamic-pituitary-adrenal (HPA) axis, physiological factors which can give rise to individual variability in HPA axis activity such as sex, age, and disease state might also have substantial implications for therapy. We use a semi-mechanistic mathematical model of the rodent HPA axis to study how putative sex differences and individual variability in HPA axis regulation can influence the effects of long-term synthetic exposure on endogenous glucocorticoid circadian rhythms. Model simulations suggest that for the same drug exposure, simulated females exhibit less endogenous suppression than males considering differences in adrenal sensitivity and negative feedback to the hypothalamus and pituitary. Simulations reveal that homeostatic regulatory variability and chronic stress-induced regulatory adaptations in the HPA axis network can result in substantial differences in the effects of synthetic exposure on the circadian rhythm of endogenous glucocorticoids. In general, our results provide insight into how the dosage and exposure profile of synthetic glucocorticoids could be manipulated in a personalized manner to preserve the circadian dynamics of endogenous glucocorticoids during chronic therapy, thus potentially minimizing the incidence of adverse effects associated with long-term use of glucocorticoids.
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http://dx.doi.org/10.1080/07420528.2019.1660357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054177PMC
February 2020

At the Interface of Lifestyle, Behavior, and Circadian Rhythms: Metabolic Implications.

Front Nutr 2019 28;6:132. Epub 2019 Aug 28.

Chemical and Biochemical Engineering Department, Rutgers University, Piscataway, NJ, United States.

Nutrient metabolism is under circadian regulation. Disruption of circadian rhythms by lifestyle and behavioral choices such as work schedules, eating patterns, and social jetlag, seriously impacts metabolic homeostasis. Metabolic dysfunction due to chronic misalignment of an organism's endogenous rhythms is detrimental to health, increasing the risk of obesity, metabolic and cardiovascular disease, diabetes, and cancer. In this paper, we review literature on recent findings on the mechanisms that communicate metabolic signals to circadian clocks and , and how human behavioral changes imposed by societal and occupational demands affect the physiological networks integrating peripheral clocks and metabolism. Finally, we discuss factors possibly contributing to inter-individual variability in response to circadian changes in the context of metabolic (dys)function.
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http://dx.doi.org/10.3389/fnut.2019.00132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722208PMC
August 2019

Allostatic adaptation and personalized physiological trade-offs in the circadian regulation of the HPA axis: A mathematical modeling approach.

Sci Rep 2019 08 1;9(1):11212. Epub 2019 Aug 1.

Department of Chemical and Biochemical Engineering, Rutgers, the State University of New Jersey, Piscataway, USA.

The hypothalamic-pituitary-adrenal (HPA) axis orchestrates the physiological response to unpredictable acute stressors. Moreover, the HPA axis exhibits prominent circadian activity and synchronizes peripheral circadian clocks to daily environmental cycles, thereby promoting homeostasis. Persistent disruption of homeostatic glucocorticoid circadian rhythmicity due to chronic stress exposure is correlated with the incidence of various pathological conditions including depression, diabetes and cancer. Allostatic habituation of the HPA axis, such that glucocorticoid levels retain homeostatic levels upon chronic exposure to stress, can therefore confer fitness advantages by preventing the sustained dysregulation of glucocorticoid-responsive signaling pathways. However, such allostatic adaptation results in a physiological cost (allostatic load) that might impair the homeostatic stress-responsive and synchronizing functions of the HPA axis. We use mathematical modeling to characterize specific chronic stress-induced allostatic adaptations in the HPA network. We predict the existence of multiple individualized regulatory strategies enabling the maintenance of homeostatic glucocorticoid rhythms, while allowing for flexible HPA response characteristics. We show that this regulatory variability produces a trade-off between the stress-responsive and time-keeping properties of the HPA axis. Finally, allostatic regulatory adaptations are predicted to cause a time-of-day dependent sensitization of the acute stress response and impair the entrainability of the HPA axis.
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http://dx.doi.org/10.1038/s41598-019-47605-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671996PMC
August 2019

Fluorescence Imaging of Actin Turnover Parses Early Stem Cell Lineage Divergence and Senescence.

Sci Rep 2019 07 17;9(1):10377. Epub 2019 Jul 17.

Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, 08854, USA.

This study describes a new approach to discern early divergence in stem cell lineage progression via temporal dynamics of the cytoskeletal protein, F-actin. The approach involves real-time labeling of human mesenchymal stem cells (MSCs) and longitudinal tracking of the turnover dynamics of a fluorogenic F-actin specific probe, SiR-actin (SA). Cells cultured in media with distinct lineage factors and labeled with SA showed lineage specific reduction in the actin turnover shortly after adipogenic (few minutes) and chondrogenic (3-4 hours) commitment in contrast to osteogenic and basal cultured conditions. Next, composite staining of SA along with the competing F-actin specific fluorescent conjugate, phalloidin, and high-content image analysis of the complementary labels showed clear phenotypic parsing of the sub-populations as early as 1-hour post-induction across all three lineages. Lastly, the potential of SA-based actin turnover analysis to distinguish cellular aging was explored. In-vitro aged cells were found to have reduced actin turnover within 1-hour of simultaneous analysis in comparison to cells of earlier passage. In summary, SiR-actin fluorescent reporter imaging offers a new platform to sensitively monitor emergent lineage phenotypes during differentiation and aging and resolve some of the earliest evident differences in actin turnover dynamics.
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http://dx.doi.org/10.1038/s41598-019-46682-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637207PMC
July 2019

Mathematical modeling informs the impact of changes in circadian rhythms and meal patterns on insulin secretion.

Am J Physiol Regul Integr Comp Physiol 2019 07 1;317(1):R98-R107. Epub 2019 May 1.

Chemical & Biochemical Engineering Department, Rutgers University , Piscataway, New Jersey.

Disruption of circadian rhythms has been associated with metabolic syndromes, including obesity and diabetes. A variety of metabolic activities are under circadian modulation, as local and global clock gene knockouts result in glucose imbalance and increased risk of metabolic diseases. Insulin release from the pancreatic β cells exhibits daily variation, and recent studies have found that insulin secretion, not production, is under circadian modulation. As consideration of daily variation in insulin secretion is necessary to accurately describe glucose-stimulated insulin secretion, we describe a mathematical model that incorporates the circadian modulation via insulin granule trafficking. We use this model to understand the effect of oscillatory characteristics on insulin secretion at different times of the day. Furthermore, we integrate the dynamics of clock genes under the influence of competing environmental signals (light/dark cycle and feeding/fasting cycle) and demonstrate how circadian disruption and meal size distribution change the insulin secretion pattern over a 24-h day.
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http://dx.doi.org/10.1152/ajpregu.00230.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692763PMC
July 2019

Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing.

Gene Regul Syst Bio 2019 15;13:1177625019840282. Epub 2019 Apr 15.

Department of Biomedical Engineering, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.

Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficult; multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared using a model-based assessment of pathway dynamics, extending the principles of pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The model-based approach enabled us to hypothesize on the likely emergence (or disappearance) of indirect dosing-dependent regulatory interactions, pointing to likely mechanistic implications of dosing of MPL transcriptional regulation. Both acute and chronic MPL administration induced a strong core of activity within pathway families including the following: lipid metabolism, amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, regulation of essential organelles, and xenobiotic metabolism pathway families. Pathway activities alter between acute and chronic dosing, indicating that MPL response is dosing dependent. Furthermore, because multiple pathway activities are dominant within a single pathway, we observe that pathways cannot be defined by a single response. Instead, pathways are defined by multiple, complex, and temporally related activities corresponding to different subgroups of genes within each pathway.
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http://dx.doi.org/10.1177/1177625019840282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466473PMC
April 2019

The physiological significance of the circadian dynamics of the HPA axis: Interplay between circadian rhythms, allostasis and stress resilience.

Horm Behav 2019 04 15;110:77-89. Epub 2019 Mar 15.

Chemical & Biochemical Engineering Department, Rutgers University, Piscataway, NJ, United States of America; Biomedical Engineering Department, Rutgers University, Piscataway, NJ, United States of America; Department of Surgery, Rutgers - Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America. Electronic address:

Circadian time-keeping mechanisms preserve homeostasis by synchronizing internal physiology with predictable variations in the environment and temporally organize the activation of physiological signaling mechanisms to promote survival and optimize the allocation of energetic resources. In this paper, we highlight the importance of the robust circadian dynamics of allostatic mediators, with a focus on the hypothalamic-pituitary-adrenal (HPA) axis, for the optimal regulation of host physiology and in enabling organisms to adequately respond and adapt to physiological stressors. We review studies showing how the chronic disruption of circadian rhythms can result in the accumulation of allostatic load, which impacts the appropriate functioning of physiological systems and diminishes the resilience of internal systems to adequately respond to subsequent stressors. A careful consideration of circadian rhythm dynamics leads to a more comprehensive characterization of individual variability in allostatic load and stress resilience. Finally, we suggest that the restoration of circadian rhythms after pathological disruption can enable the re-engagement of allostatic mechanisms and re-establish stress resilience.
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http://dx.doi.org/10.1016/j.yhbeh.2019.02.018DOI Listing
April 2019

Chronopharmacology of glucocorticoids.

Adv Drug Deliv Rev 2019 Nov - Dec;151-152:245-261. Epub 2019 Feb 21.

Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, 98 Brett Road, Piscataway, NJ 08854, United States; Department of Biomedical Engineering, Rutgers The State University of New Jersey, 599 Taylor Road, Piscataway, NJ 08854, United States. Electronic address:

Glucocorticoids influence a wide array of metabolic, anti-inflammatory, immunosuppressive, and cognitive signaling processes, playing an important role in homeostasis and preservation of normal organ function. Synthesis is regulated by the hypothalamic-pituitary-adrenal (HPA) axis of which cortisol is the primary glucocorticoid in humans. Synthetic glucocorticoids are important pharmacological agents that augment the anti-inflammatory and immunosuppressive properties of endogenous cortisol and are widely used for the treatment of asthma, Crohn's disease, and rheumatoid arthritis, amongst other chronic conditions. The homeostatic activity of cortisol is disrupted by the administration of synthetic glucocorticoids and so there is interest in developing treatment options that minimize HPA axis disturbance while maintaining the pharmacological effects. Studies suggest that optimizing drug administration time can achieve this goal. The present review provides an overview of endogenous glucocorticoid activity and recent advances in treatment options that have further improved patient safety and efficacy with an emphasis on chronopharmacology.
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http://dx.doi.org/10.1016/j.addr.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703983PMC
October 2020

The growing role of precision and personalized medicine for cancer treatment.

Technology (Singap World Sci) 2018 Sep-Dec;6(3-4):79-100. Epub 2019 Jan 11.

Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.

Cancer is a devastating disease that takes the lives of hundreds of thousands of people every year. Due to disease heterogeneity, standard treatments, such as chemotherapy or radiation, are effective in only a subset of the patient population. Tumors can have different underlying genetic causes and may express different proteins in one patient versus another. This inherent variability of cancer lends itself to the growing field of precision and personalized medicine (PPM). There are many ongoing efforts to acquire PPM data in order to characterize molecular differences between tumors. Some PPM products are already available to link these differences to an effective drug. It is clear that PPM cancer treatments can result in immense patient benefits, and companies and regulatory agencies have begun to recognize this. However, broader changes to the healthcare and insurance systems must be addressed if PPM is to become part of standard cancer care.
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http://dx.doi.org/10.1142/S2339547818300020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352312PMC
January 2019

Boolean Modeling in Quantitative Systems Pharmacology: Challenges and Opportunities.

Crit Rev Biomed Eng 2019 ;47(6):473-488

Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA; Department of Chemical & Biochemical Engineering, Rutgers University, Piscataway, NJ, USA; Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.

Drug research and development has a high attrition rate, with many promising drugs failing for efficacy or safety in the clinic. Increased use of detailed modeling approaches like quantitative systems pharmacology (QSP) may help in reducing overall failure rate, by helping the industry in decisions to fail early and cheaply, or to focus on patients and drug combinations that are more likely to respond or synergize, respectively. QSP offers computational methods to simulate how well different therapies may work in a patient, and therefore to better predict drug performance and reduce the cost in the development of new drug therapies. However, the development of detailed models requires a significant amount of biological data, and models often require knowledge of specific mechanisms. Coarse-grained, network-based models, such as Boolean and logic models, provide a tool for simulating complex systems without knowledge of specific mechanisms. These tools can be used to make early predictions about a biological system and can facilitate the development of more complex models. We offer a literature review of how Boolean modeling techniques are used in the identification of novel drug targets, as well as how they fall into the pipeline of developing in-depth ordinary differential equation models.
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http://dx.doi.org/10.1615/CritRevBiomedEng.2020030796DOI Listing
September 2020

Exploration of sexual dimorphism and inter-individual variability in multivariate parameter spaces for a pharmacokinetic compartment model.

Math Biosci 2019 02 15;308:70-80. Epub 2018 Dec 15.

Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, 98 Brett Road, Piscataway, NJ 08854, United States; Department of Biomedical Engineering, Rutgers, The State University of New Jersey, 599 Taylor Road, Piscataway, NJ 08854, United States. Electronic address:

Pharmacokinetic models are particularly useful to study the underlying and complex physiological mechanisms contributing to clinical differences across patient subgroups or special populations. Unfortunately, the inherent variability of biological systems and knowledge gaps in physiological data limit confidence in model predictions for special populations. Sourcing data to reflect the desired physiologies can be resource intensive, particularly for a larger model. Thus, a critical step in model development for special populations involves an in-depth analysis of model inputs, which can be guided by Monte Carlo simulations. Such an approach enables the generation of parameter values by stochastic sampling that are subsequently restricted to the combinations that describe biologically plausible or target model output. Our approach utilized a published pharmacokinetic compartmental model to demonstrate how sampling in conjunction with global sensitivity analysis can be used to explore sexual dimorphism and inter-individual variability in multivariate parameter spaces for differentiation of model input and behavior across phenotypes. Despite limiting the model output to relatively narrow ranges, male and female phenotypes were associated with wide variability in both individual parameter values and combinations of parameters. Through an integrated approach using a support vector machine, principal component analysis and global sensitivity analysis, our approach revealed that specific combinations of parameters gave rise to a certain phenotype, while individual parameters influenced the shape of plasma concentration profile. Augmenting analysis of the model input with global sensitivity analysis enabled an understanding of both sexual dimorphism and inter-individual variability in pharmacokinetics. While the current study revealed how model input could be separated by sex for a simple compartment model, the approach could be extended to other patient factors, such as age or disease, and to a more complex physiologically-based model that describes absorption, distribution, metabolism, and elimination with more detail.
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http://dx.doi.org/10.1016/j.mbs.2018.12.011DOI Listing
February 2019

Modeling the influence of chronopharmacological administration of synthetic glucocorticoids on the hypothalamic-pituitary-adrenal axis.

Chronobiol Int 2018 11 30;35(12):1619-1636. Epub 2018 Jul 30.

a Department of Chemical and Biochemical Engineering , Rutgers, The State University of New Jersey , Piscataway , New Jersey , USA.

Natural glucocorticoids, a class of cholesterol-derived hormones, modulate an array of metabolic, anti-inflammatory, immunosuppressive and cognitive signaling. The synthesis of natural glucocorticoids, largely cortisol in humans, is regulated by the hypothalamic-pituitary-adrenal (HPA) axis and exhibits pronounced circadian variation. Considering the central regulatory function of endogenous glucocorticoids, maintenance of the circadian activity of the HPA axis is essential to host survival and chronic disruption of such activity leads to systemic complications. There is a great deal of interest in synthetic glucocorticoids due to the immunosuppressive and anti-inflammatory properties and the development of novel dosing regimens that can minimize the disruption of endogenous activity, while still maintaining the pharmacological benefits of long-term synthetic glucocorticoid therapy. Synthetic glucocorticoids are associated with an increased risk of developing the pathological disorders related to chronic suppression of cortisol rhythmicity as a result of the potent negative feedback by synthetic glucocorticoids on the HPA axis precursors. In this study, a mathematical model was developed to explore the influence of chronopharmacological dosing of exogenous glucocorticoids on the endogenous cortisol rhythm considering intra-venous and oral dosing. Chronic daily dosing resulted in modification of the circadian rhythmicity of endogenous cortisol with the amplitude and acrophase of the altered rhythm dependent on the administration time. Simulations revealed that the circadian features of the endogenous cortisol rhythm can be preserved by proper timing of administration. The response following a single dose was not indicative of the response following long-term, repeated chronopharmacological dosing of synthetic glucocorticoids. Furthermore, simulations revealed the inductive influence of long-term treatment was only associated with low to moderate doses, while high doses generally led to suppression of endogenous activity regardless of the chronopharmacological dose. Finally, chronic daily dosing was found to alter the responsiveness of the HPA axis, such that a decrease in the amplitude of the cortisol rhythm resulted in a partial loss in the time-of-day dependent response to CRH stimulation, while an increase in the amplitude was associated with a more pronounced time-of-day dependence of the response.
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http://dx.doi.org/10.1080/07420528.2018.1498098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292202PMC
November 2018

Pharmacokinetics and Pharmacodynamics of Curcumin in regulating anti-inflammatory and epigenetic gene expression.

Biopharm Drug Dispos 2018 Jun;39(6):289-297

Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.

Chronic inflammation is a key driver of cancer development. Nitrite levels, which are regulated by inducible nitric oxide synthase (iNOS), play a critical role in inflammation. While the anti-oxidant and anti-inflammatory effects of curcumin, a natural product present in the roots of Curcuma longa have been studied widely, the acute pharmacokinetics (PK) and pharmacodynamics (PD) of curcumin in suppressing pro-inflammatory markers and epigenetic modulators remain unclear. This study evaluated the PK and PD of curcumin-induced suppression of lipopolysaccharide (LPS)-mediated inflammation in rat lymphocytes. LPS was administered intravenously either alone or with curcumin to female Sprague-Dawley rats. Plasma samples were analysed for curcumin concentration and mRNA expression was quantified in lymphocytes. The relative gene expression of several inflammatory and epigenetic modulators was analysed. To investigate the relationship between curcumin concentration and iNOS, TNF-α, and IL-6 gene expression, PK/PD modeling using Jusko's indirect response model (IDR) integrating transit compartments (TC) describing the delayed response was conducted. The concentration-time profile of curcumin exhibited a bi-exponential decline, which was well described by a two-compartmental pharmacokinetic model. Importantly the results demonstrate that LPS induced gene expression of pro-inflammatory markers in lymphocytes, with peak expression at approximately 3 h and curcumin suppressed the gene expression in animals administered with LPS. These effects were well captured using the IDR model and an IDR model with the transit compartments. In summary, the PK/PD modeling approach could potentially provide a robust quantitative framework for evaluating the acute anti-inflammatory and epigenetic effects of curcumin in future clinical trials.
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http://dx.doi.org/10.1002/bdd.2136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078813PMC
June 2018

Modeling the Influence of Seasonal Differences in the HPA Axis on Synchronization of the Circadian Clock and Cell Cycle.

Endocrinology 2018 04;159(4):1808-1826

Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, New Jersey.

Synchronization of biological functions to environmental signals enables organisms to anticipate and appropriately respond to daily external fluctuations and is critical to the maintenance of homeostasis. Misalignment of circadian rhythms with environmental cues is associated with adverse health outcomes. Cortisol, the downstream effector of hypothalamic-pituitary-adrenal (HPA) activity, facilitates synchronization of peripheral biological processes to the environment. Cortisol levels exhibit substantial seasonal rhythmicity, with peak levels occurring during the short-photoperiod winter months and reduced levels occurring in the long-photoperiod summer season. Seasonal changes in cortisol secretion could therefore alter its entraining capabilities, resulting in a season-dependent modification in the alignment of biological activities with the environment. We develop a mathematical model to investigate the influence of photoperiod-induced seasonal differences in the circadian rhythmicity of the HPA axis on the synchronization of the peripheral circadian clock and cell cycle in a heterogeneous cell population. Model simulations predict that the high-amplitude cortisol rhythms in winter result in the greatest entrainment of peripheral oscillators. Furthermore, simulations predict a circadian gating of the cell cycle with respect to the expression of peripheral clock genes. Seasonal differences in cortisol rhythmicity are also predicted to influence mitotic synchrony, with a high-amplitude winter rhythm resulting in the greatest synchrony and a shift in timing of the cell cycle phases, relative to summer. Our results highlight the primary interactions among the HPA axis, the peripheral circadian clock, and the cell cycle and thereby provide an improved understanding of the implications of circadian misalignment on the synchronization of peripheral regulatory processes.
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http://dx.doi.org/10.1210/en.2017-03226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044315PMC
April 2018

A framework for 2-stage global sensitivity analysis of GastroPlus™ compartmental models.

J Pharmacokinet Pharmacodyn 2018 04 8;45(2):309-327. Epub 2018 Feb 8.

Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, 98 Brett Road, Piscataway, NJ, 08854, USA.

Parameter sensitivity and uncertainty analysis for physiologically based pharmacokinetic (PBPK) models are becoming an important consideration for regulatory submissions, requiring further evaluation to establish the need for global sensitivity analysis. To demonstrate the benefits of an extensive analysis, global sensitivity was implemented for the GastroPlus™ model, a well-known commercially available platform, using four example drugs: acetaminophen, risperidone, atenolol, and furosemide. The capabilities of GastroPlus were expanded by developing an integrated framework to automate the GastroPlus graphical user interface with AutoIt and for execution of the sensitivity analysis in MATLAB. Global sensitivity analysis was performed in two stages using the Morris method to screen over 50 parameters for significant factors followed by quantitative assessment of variability using Sobol's sensitivity analysis. The 2-staged approach significantly reduced computational cost for the larger model without sacrificing interpretation of model behavior, showing that the sensitivity results were well aligned with the biopharmaceutical classification system. Both methods detected nonlinearities and parameter interactions that would have otherwise been missed by local approaches. Future work includes further exploration of how the input domain influences the calculated global sensitivity measures as well as extending the framework to consider a whole-body PBPK model.
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http://dx.doi.org/10.1007/s10928-018-9573-1DOI Listing
April 2018

On the analysis of complex biological supply chains: From Process Systems Engineering to Quantitative Systems Pharmacology.

Comput Chem Eng 2017 Dec 3;107:100-110. Epub 2017 Jun 3.

Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, 98 Brett Road, Piscataway, NJ 08854.

The use of models in biology has become particularly relevant as it enables investigators to develop a mechanistic framework for understanding the operating principles of living systems as well as in quantitatively predicting their response to both pathological perturbations and pharmacological interventions. This application has resulted in a synergistic convergence of systems biology and pharmacokinetic-pharmacodynamic modeling techniques that has led to the emergence of quantitative systems pharmacology (QSP). In this review, we discuss how the foundational principles of chemical process systems engineering inform the progressive development of more physiologically-based systems biology models.
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http://dx.doi.org/10.1016/j.compchemeng.2017.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773066PMC
December 2017

Mathematical analysis of circadian disruption and metabolic re-entrainment of hepatic gluconeogenesis: the intertwining entraining roles of light and feeding.

Am J Physiol Endocrinol Metab 2018 06 9;314(6):E531-E542. Epub 2018 Jan 9.

Chemical & Biochemical Engineering Department, Rutgers University , Piscataway, New Jersey.

The circadian rhythms influence the metabolic activity from molecular level to tissue, organ, and host level. Disruption of the circadian rhythms manifests to the host's health as metabolic syndromes, including obesity, diabetes, and elevated plasma glucose, eventually leading to cardiovascular diseases. Therefore, it is imperative to understand the mechanism behind the relationship between circadian rhythms and metabolism. To start answering this question, we propose a semimechanistic mathematical model to study the effect of circadian disruption on hepatic gluconeogenesis in humans. Our model takes the light-dark cycle and feeding-fasting cycle as two environmental inputs that entrain the metabolic activity in the liver. The model was validated by comparison with data from mice and rat experimental studies. Formal sensitivity and uncertainty analyses were conducted to elaborate on the driving forces for hepatic gluconeogenesis. Furthermore, simulating the impact of Clock gene knockout suggests that modification to the local pathways tied most closely to the feeding-fasting rhythms may be the most efficient way to restore the disrupted glucose metabolism in liver.
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http://dx.doi.org/10.1152/ajpendo.00271.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032066PMC
June 2018

Pharmacokinetics and Pharmacodynamics of the Triterpenoid Ursolic Acid in Regulating the Antioxidant, Anti-inflammatory, and Epigenetic Gene Responses in Rat Leukocytes.

Mol Pharm 2017 11 25;14(11):3709-3717. Epub 2017 Oct 25.

Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854, United States.

The triterpenoid ursolic acid (UA) has been proposed as a potential cancer chemopreventive agent in many preclinical and clinical studies. In the present work, we aimed to characterize the pharmacokinetics (PK) of UA and to quantitatively assess the antioxidative and anti-inflammatory effects of UA, which are potentially linked to its chemopreventive efficacy. UA was administered intravenously (i.v., 20 mg/kg) or by oral gavage (100 mg/kg) to male Sprague-Dawley rats, and blood samples were collected at a series of designated time points. The plasma concentration of UA was determined using a validated liquid chromatography-mass spectrometry (LC-MS) approach. A biexponential decline in the UA plasma concentration was observed after i.v. dosing and was fitted to a two-compartmental model. The expression levels of phase II drug metabolism (DM)/antioxidant genes and the inflammatory iNos gene in corresponding treatment arms were measured using qPCR as a pharmacodynamic (PD) marker. The expression of phase II DM/antioxidant genes increased and peaked approximately 3 h after 20 mg/kg UA treatment. In a lipopolysaccharide (LPS)-induced acute inflammation model, UA inhibited LPS-stimulated iNos expression and that of the epigenetic markers the DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) in leukocytes. A PK-PD model using Jusko's indirect response model (IDR) with transition compartments (TC) was established to describe the time delay and magnitude of the gene expression elicited by UA. The PK-PD model provided reasonable fitting linking the plasma concentration of UA simultaneously with the PD response based on leukocyte mRNA expression. Overall, our results indicate that UA is effective at inducing various phase II DM/antioxidant genes and inhibiting pro-inflammatory genes in vivo. This PK-PD modeling approach may provide a conceptual framework for the future clinical evaluation of dietary chemopreventive agents in humans.
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http://dx.doi.org/10.1021/acs.molpharmaceut.7b00469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697757PMC
November 2017

The Hepato-Hypothalamic-Pituitary-Adrenal-Renal Axis: Mathematical Modeling of Cortisol's Production, Metabolism, and Seasonal Variation.

J Biol Rhythms 2017 Oct 25;32(5):469-484. Epub 2017 Sep 25.

Biomedical Engineering Department, Rutgers University, Piscataway, New Jersey.

Cortisol dynamics are governed by the integration of influences from the suprachiasmatic nucleus (SCN), the hypothalamic-pituitary-adrenal (HPA) axis, and metabolic enzymes, such as the 11β-hydroxysteroid dehydrogenase (HSD) family, which are highly expressed in hepatic and renal tissue. The coordinated regulation of cortisol dynamics is essential for the maintenance of a healthy state, and aberrant cortisol circadian rhythms are associated with various pathophysiological conditions. The duration of the light-dark cycle, or photoperiod, which regulates SCN activity, varies seasonally, and the shorter photoperiod winter season is associated with elevated cortisol levels, peak inflammatory disease incidence, and symptom exacerbation. Elevated expression and activity of 11β-HSD1 protein, assumed to also occur during the winter, have been allied with numerous inflammatory conditions. A comprehensive understanding of the communication between the underlying regulatory mechanisms of cortisol as well as how changes in their activity could lead to the development of disease is yet to be elucidated. In this work, we propose the use of a semimechanistic mathematical model to explore the impact of the hepato-hypothalamic-pituitary-adrenal-renal axis in modulating neuroendocrine-immune system dynamics. Our model predicts the predominance of a winter proinflammatory state and that genetic variations could alter 11β-HSD enzyme functionality, rendering certain subpopulations more susceptible to disease as a consequence of HPA axis dysregulation.
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http://dx.doi.org/10.1177/0748730417729929DOI Listing
October 2017

Modeling the Sex Differences and Interindividual Variability in the Activity of the Hypothalamic-Pituitary-Adrenal Axis.

Endocrinology 2017 11;158(11):4017-4037

Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854.

Significant sex differences exist in the activity of the hypothalamic-pituitary-adrenal (HPA) axis. These differences are thought to contribute to the disparity in the prevalence of various autoimmune and infectious diseases between males and females. We used a mathematical model of the HPA axis to evaluate the hypothesis that differential sensitivity and negative feedback of the HPA axis network are causal factors for the observed sex differences in its activity. In doing so, we implicitly accounted for the differential influence of gonadal hormones on the HPA axis. Furthermore, we determined whether the putative mechanisms responsible for differences in basal HPA axis activity might also contribute to the observed differences in its stimulus-driven response. Model simulations predicted that the female HPA axis has greater adrenal sensitivity and weaker negative feedback. We identified two distinct sex-specific parameter spaces that generate corticosterone profiles in qualitative agreement with experimental results. We propose that these parameter subspaces indicate the interindividual variability in the regulatory mechanisms of the HPA axis. Furthermore, the model predicts that the maintenance of homeostatic rhythms in response to chronic stress requires specific regulatory adaptations resulting in a phenotype of allostatically driven chronic stress-sensitization. We propose that these adaptations indicate a physiological cost of adaptation to chronic stress. Model simulations suggest that individuals with high adrenal sensitivity are more vulnerable to chronic stress sensitization and might be more susceptible to the development of neuropsychiatric disorders. These results contribute to the study of sex differences in physiological feedback systems within a quantitative framework.
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http://dx.doi.org/10.1210/en.2017-00544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695828PMC
November 2017

Allostatic breakdown of cascading homeostat systems: A computational approach.

Heliyon 2017 Jul 17;3(7):e00355. Epub 2017 Jul 17.

Biomedical Engineering Department, Rutgers University, United States.

Homeostasis posits that physiological systems compensate setpoint deviations in an attempt to maintain a state of internal constancy. Allostasis, on the other hand, suggests that physiological regulation is more appropriately described by predictive modulatory actions that, by adjusting setpoints, anticipate and react to changes in internal and external demand. In other words, "maintaining stability through change." The allostatic perspective enabled the rationalization of predictive and reactive homeostasis. While the latter reflects external perturbations, the former refers to systemic adaptation in response to anticipated changes - not necessarily related to unexpected external disturbances. Therefore, the concept of allostasis accounts also for adaptation to circadian variations (seasonal, circannual or other predictive variability) and interprets the system's adaptation of its setpoints not as reactive/subnormal adjustments, but rather as a proper response. Therefore, systemic entrainment to periodic demands is handled by predicting and implementing setpoint changes. Given the important role of circadian variability and regulation in maintaining health, and the loss of circadian entrainment as a predisposing factor and sequel of stress, we elaborate on an allostasis model which demonstrates the ability of the systems to adapt to circadian demands and quantifies the deteriorative natural wear and tear of a system constantly adapting, i.e. the irreversible damage and its consequences on system function and overall survival. While developing a system of cascaded nature, we demonstrate the importance of phase coordination and the implications of maintaining proper phase relations. The disruption of these relations is a hallmark of circadian disruption, a predisposing factor to increased vulnerability and/or a sequel to chronic stress.
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http://dx.doi.org/10.1016/j.heliyon.2017.e00355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522379PMC
July 2017

The Synergistic Role of Light-Feeding Phase Relations on Entraining Robust Circadian Rhythms in the Periphery.

Gene Regul Syst Bio 2017 20;11:1177625017702393. Epub 2017 Apr 20.

Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.

The feeding and fasting cycles are strong behavioral signals that entrain biological rhythms of the periphery. The feeding rhythms synchronize the activities of the metabolic organs, such as liver, synergistically with the light/dark cycle primarily entraining the suprachiasmatic nucleus. The likely phase misalignment between the feeding rhythms and the light/dark cycles appears to induce circadian disruptions leading to multiple physiological abnormalities motivating the need to investigate the mechanisms behind joint light-feeding circadian entrainment of peripheral tissues. To address this question, we propose a semimechanistic mathematical model describing the circadian dynamics of peripheral clock genes in human hepatocyte under the control of metabolic and light rhythmic signals. The model takes the synergistically acting light/dark cycles and feeding rhythms as inputs and incorporates the activity of sirtuin 1, a cellular energy sensor and a metabolic enzyme activated by nicotinamide adenine dinucleotide. The clock gene dynamics was simulated under various light-feeding phase relations and intensities, to explore the feeding entrainment mechanism as well as the convolution of light and feeding signals in the periphery. Our model predicts that the peripheral clock genes in hepatocyte can be completely entrained to the feeding rhythms, independent of the light/dark cycle. Furthermore, it predicts that light-feeding phase relationship is a critical factor in robust circadian oscillations.
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http://dx.doi.org/10.1177/1177625017702393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404903PMC
April 2017
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