We have done many years of research to create the Metresponse Services and find ways to help other researchers. Here are a few of our latest
publications including the abstracts and links to where you can find the complete article.
Metabolic profiling reveals reprogramming of lipid metabolic pathways in treatment of polycystic ovary syndrome with 3-iodothyronamine
2017 - Ebru S. Selen Alpergin - Zeinab Bolandnazar - Martina Sabatini - Michael Rogowski - Grazia Chiellini - Riccardo Zucchi - Fariba M. Assadi-Porter
Complex diseases such as polycystic ovary syndrome (PCOS) are associated with intricate pathophysiological, hormonal, and metabolic feedbacks that
make their early diagnosis challenging, thus increasing the prevalence risks for obesity, cardiovascular, and fatty liver diseases. To explore the crosstalk
between endocrine and lipid metabolic pathways, we administered 3-iodothyr-onamine (T1AM), a natural analog of thyroid hormone, in a mouse model of
PCOS and analyzed plasma and tissue extracts using multidisciplinary omics and biochemical approaches. T1AM administration induces a profound tissue-
specific antilipogenic effect in liver and muscle by lowering gene expression of key regulators of lipid metabolism, PTP1B and PLIN2, significantly increasing metabolites (glucogenic, amino acids, carnitine, and citrate) levels, while
enhancing protection against oxidative stress. In contrast, T1AM has an opposing effect on the regulation of estrogenic pathways in the ovary by
upregulating STAR, CYP11A1, and CYP17A1. Biochemical measurements pro-vide further evidence of significant reduction in liver cholesterol and triglyc-
erides in post-T1AM treatment. Our results shed light onto tissue-specific metabolic vs. hormonal pathway interactions, thus illuminating the intricacies
within the pathophysiology of PCOS. This study opens up new avenues to design drugs for targeted therapeutics to improve quality of life in complex
metabolic diseases. Keywords: 3-iodothyronamine (T1AM), endocrine, lipid metabolism, metabolomics, Nuclear magnetic resonance (NMR) spectroscopy, polycystic ovary syndrome (PCOS), steroidogenesis.
NMR metabolomics show evidence for mitochondrial oxidative stress in a mouse model of polycystic ovary syndrome.
2015 - E.S. Selin - Z. Bolandnazar - D. Butz, M. Tonelli - J. Haviland - W.P. Porter - F. M. Assadi-Porter
Polycystic ovary syndrome (PCOS) is associated with metabolic and endocrine disorders in women of reproductive age. The etiology of PCOS is still
unknown. Mice prenatally treated with glucocorticoids exhibit metabolic disturbances that are similar to those seen in women with PCOS. We used an untargeted nuclear
magnetic resonance (NMR)-based metabolomics approach to understand the metabolic changes occurring in the plasma and kidney over time in female glucocorticoid-treated
(GC-treated) mice. There are significant changes in plasma amino acid levels (valine, tyrosine, and proline) and their intermediates (2-hydroxybutyrate, 4-aminobutyrate,
and taurine), whereas in kidneys, the TCA cycle metabolism (citrate, fumarate, and succinate) and the pentose phosphate (PP) pathway products (inosine and uracil)
are significantly altered (p < 0.05) from 8 to 16 weeks of age. Levels of NADH, NAD+, NAD+/NADH, and NADH redox in kidneys indicate increased mitochondrial oxidative
stress from 8 to 16 weeks in GC-treated mice. These results indicate that altered metabolic substrates in the plasma and kidneys of treated mice are associated with
altered amino acid metabolism, increased cytoplasmic PP, and increased mitochondrial activity, leading to a more oxidized state. This study identifies biomarkers
associated with metabolic dysfunction in kidney mitochondria of a prenatal gluococorticoid-treated mouse model of PCOS that may be used as early predictive biomarkers
of oxidative stress in the PCOS metabolic disorder in women. Keywords: polycystic ovary syndrome (PCOS); animal model; metabolomics; nuclear magnetic resonance (NMR); oxidative stress; mitochondria
3-iodothyronamine: A high potency metabolic hormone and its potential for therapeutic applications. J. of Endocrinology and Diabetes.
2015 - M. Rogowski - F.M. Assadi-Porter
3-Iodothyronamide (T1AM) is a naturally produced endogenous hormone like molecule. Only recently it has been discovered in the past decade, the proceeding body of
research emerging from its initial discovery has revealed a substantial capacity of T1AM as a new potential hormone that affects numerous physiological processes and
organs. Initially, it was hypothesized to be a byproduct of Thyroid Hormone (TH) metabolism; however, the current body of evidence suggests that its production and
physiological function appear to be uncoupled and dramatically divergent from that of TH. This review summarizes the physiological and biochemical effects of T1AM
reported in the literature along with its proposed mechanisms of action and production pathways. The physiological effects of T1AM appear to be dose specific, in some
cases exerting opposing effects in the same biological processes. Uptake, storage, and degree of effect appear to be tissue specific as well. From the current body of
literature, potential therapeutic applications with T1AM are quite apparent, ranging from sleep/torpidity induction, conferring protection against ischemic injury, and
anti-obesogenic by inducing increased metabolic reliance on lipid oxidation. Future research is needed to understand the specific mechanisms of its dose dependent
and tissue dependent effects, its mechanism of entry into the cell, its cellular targets, and primary site of production.
NMRFAM-SDF: a protein structure determination framework.
Superimposition of the manual structure (cyan) and automated structure (green) of the protein IscU (D39A)
2015 - M. Dashti, H, Lee, W., Tonelli, M, Cornilescu, G, F. M. Assadi-Porter, Westler, M., Markley, JL.
The computationally demanding nature of automated NMR structure determination necessitates a delicate balancing of factors that
include the time complexity of data collection, the computational complexity of chemical shift assignments, and selection of proper optimization steps. During the past
two decades the computational and algorithmic aspects of several discrete steps of the process have been addressed. Although no single comprehensive solution has emerged,
the incorporation of a validation protocol has gained recognition as a necessary step for a robust automated approach. The need for validation becomes even more
pronounced in cases of proteins with higher structural complexity, where potentially larger errors generated at each step can propagate and accumulate in the process
of structure calculation, thereby significantly degrading the efficacy of any software framework. This paper introduces a complete framework for protein structure
determination with NMR-from data acquisition to the structure determination. The aim is twofold: to simplify the structure determination process for non-NMR experts
whenever feasible, while maintaining flexibility by providing a set of modules that validate each step, and to enable the assessment of error propagations.
This framework, called NMRFAM-SDF (NMRFAM-Structure Determination Framework), and its various components are available for download from the NMRFAM website
( http://nmrfam.wisc.edu/software.htm ). Keywords:ADAPT-NMR; ARECA; Automated protein structure determination framework; CASD-NMR; Non-uniform sampling; PINE; PONDEROSA-C/S; Validation
Metabolomics is an important component of system biology complementing genomics, transcriptomis, and proteomics. The project is
to determine the effects of 6-month green tea polyphenols (GTP) supplementation on the serum and muscle metabolome in middle-aged ovariectomized (OVX) rats. 39 SD
(6-mo-old) rats were sham-operated (n=13) or OVX (n=26). Both sham and OVX animals received no GTP for 6 months. The remaining OVX animals were provided 1.5% w/v GTP
in drinking water for 6 months. Endogenous metabolites in serum and muscle were measured using NMR-based metabolomics. Compared to the sham animals, the OVX animals had
the following observation in serum: (1) suppressed glucose metabolites and Krebs cycle (decreases in acetate, acetoacetate, acetone, glycerol, glucose, lactate,
pyruvate, citrate, succinate and fumarate), (2) altered amino acids metabolites (decreases in alanine, asparagine, glutamine, isoleucine, leucine, valine, tryptophan,
lysine, proline, seruine and threonine; increases in glutamate, glycine, phenylalanine and tyrosine), and (3) reduced lipid metabolites (decreases in myo-inositol).
The similar trend in serum of OVX animals was also observed in that of muscle of OVX animals. Intriguingly, compared to the OVX animals, 6-month GTP supplementation
to the OVX-treated animals reversed the negative impacts of ovariectomy on the middle-aged rats in terms of metabolites of glucose, Kerbs cycle, amino acids,
and lipids. The results suggest that chronic GTP supplementation to the OVX animals affects whole-body metabolism, as shown in serum and muscle. Study supported by
NIH/NCCAM AT006691.
Novel diagnostics of metabolic dysfunction detected in breath and plasma by selective isotope-assisted labeling
2012 - Julia A. Havilanda - Marco Tonelli - Dermot T. Haughey - Warren P. Porter - Fariba M. Assadi-Porter
Metabolomics is the study of a unique fingerprint of small molecules present in biological
systems under healthy and disease conditions. One of the major challenges inmetabolomics is
validation of fingerprint molecules to identify specifically perturbed pathways in metabolic
aberrations. This step is crucial to the understanding of buddingmetabolic pathologies and the
ability to identify early indicators of common diseases such as obesity, type 2 diabetesmellitus,
metabolic syndrome, polycystic ovary syndrome, and cancer. We present a novel approach to
diagnosing aberrations in glucose utilization including metabolic pathway switching in a
disease state. We used a well-defined prenatally exposed glucocorticoid mouse model that
results in adult females with metabolic dysfunction. We applied the complementary
technologies of nuclear magnetic resonance spectroscopy and cavity ring-down
spectroscopy to analyze serial plasma samples and real-time breath measurements
following selective 13C-isotope–assisted labeling. These platforms allowed us to trace
metabolic markers in whole animals and identify key metabolic pathway switching in
prenatally glucocorticoid-treated animals. Total glucose flux is significantly proportionally
increased through the major oxidative pathways of glycolysis and the pentose phosphate
pathway in the prenatally glucocorticoid-treated animals relative to the control animals. This
novel diagnostics approach is fast, noninvasive, and sensitive for determining specific
pathway utilization, and provides a direct translational application in the health care field.
