Medicine and Health Sciences Commons^™

A Research Update: Significance Of Cytokine Storm And Diaphragm In Covid-19, Ashwani Mittal, Anita Dua, Sanjeev Gupta, Elisha Injeti

Pharmaceutical Sciences Faculty Publications

Emerging research on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) shows that it is spreading to multiple organs in addition to the respiratory system. Though the SARS-CoV2 enters the human body by binding to ACE2 receptors on pulmonary alveolar cells, recent studies indicate that it is spreading to the central nervous system, cardiac and skeletal muscles leading to various pathological conditions in these organs. In particular, the effects of SARS-CoV-2 on triggering the cytokine storm and its consequential effects on skeletal muscles has generated a lot of discussion. The effects of this virus on muscular function especially in susceptible elderly populations …

Integrated Proteotranscriptomics Of Breast Cancer Reveals Globally Increased Protein-Mrna Concordance Associated With Subtypes And Survival, Wei Tang, Ming Zhou, Tiffany H Dorsey, Darue A Prieto, Xin W Wang, Eytan Ruppin, Timothy Veenstra, Stefan Ambs

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Transcriptome analysis of breast cancer discovered distinct disease subtypes of clinical significance. However, it remains a challenge to define disease biology solely based on gene expression because tumor biology is often the result of protein function. Here, we measured global proteome and transcriptome expression in human breast tumors and adjacent non-cancerous tissue and performed an integrated proteotranscriptomic analysis.

METHODS: We applied a quantitative liquid chromatography/mass spectrometry-based proteome analysis using an untargeted approach and analyzed protein extracts from 65 breast tumors and 53 adjacent non-cancerous tissues. Additional gene expression data from Affymetrix Gene Chip Human Gene ST Arrays were available …

Luteolin Decreases Egfr-Mediated Cell Proliferation And Induces Apoptosis In Glioblastoma Cell Lines., David M. Anson, Rachel M. Wilcox, Eric Huseman, Trevor Stump, Robert L. Paris, Belinda O. Darkwah, Stacy Lin, Andrea O Adegoke, Rebecca J. Gryka, Denise Simpson, Samson Amos

Pharmaceutical Sciences Faculty Publications

Glioblastomas are a subtype of gliomas, which are the most aggressive and deadly form of brain tumours. The epidermal growth factor receptor (EGFR) is over-expressed and amplified in glioblastomas. Luteolin is a common bioflavonoid found in a variety of fruits and vegetables. The aim of the present study was to explore the molecular and biological effects of luteolin on EGF-induced cell proliferation and the potential of luteolin to induce apoptosis in glioblastoma cells. In vitro cell viability assays demonstrated that luteolin decreased cell proliferation in the presence or absence of EGF. Immunoblots revealed that luteolin decreased the protein expression levels …

Evaluation Of The Anticancer Activity Of Bioactive Fraction G Extracted From Pavetta Crassipes In Malignant Brain Tumor Cell Lines, Rachel M. Wilcox, Eric Huseman, Stacy Lin, Belinda O. Darkwah, M. O. Emeje, K. S. Gamaniel, A. Orisadipe, N. Enwerem, B. A. Kefas, Rebecca J. Gryka, Denise Simpson, Samson Amos

Pharmaceutical Sciences Faculty Publications

Objective: Natural products have served as sources of lead compounds that are commonly used in the treatment of human diseases including cancer. Pavetta crassipes has been widely demonstrated to have ethnopharmacological potential in the management of malaria, gastrointestinal conditions, central nervous system behavioral disorders, hypertension, and cancer. The goal of our study was to evaluate the biological and molecular effects of Fraction G, obtained from the plant Pavetta crassipes, on glioblastoma invasive growth and survival.

Methodology: The antiproliferative effects of Fraction G, obtained from Pavetta crassipes, was evaluated using the trypan blue exclusion, (3-(4, 5-Dimethylthiazol- 2yl)-2, 5-Diphenyltetrazolium Bromide; MTT), and …

The Antiproliferative And Apoptotic Effects Of Apigenin On Glioblastoma Cells, Trevor Stump, Brittany Santee, Lauren P. Williams, Rachel Kunze, Chelsae Heinze, Eric Huseman, Rebecca J. Gryka, Denise Simpson, Samson Amos

Pharmaceutical Sciences Faculty Publications

OBJECTIVES: Glioblastoma (GBM) is highly proliferative, infiltrative, malignant and the most deadly form of brain tumour. The epidermal growth factor receptor (EGFR) is overexpressed, amplified and mutated in GBM and has been shown to play key and important roles in the proliferation, growth and survival of this tumour. The goal of our study was to investigate the antiproliferative, apoptotic and molecular effects of apigenin in GBM.

METHODS: Proliferation and viability tests were carried out using the trypan blue exclusion, MTT and lactate dehydrogenase (LDH) assays. Flow cytometry was used to examine the effects of apigenin on the cell cycle check-points. …

Estrogen Metabolites In Human Corpus Luteum Physiology: Differential Effects On Angiogenic Activity, Soledad Henríquez, Paulina Kohen, Xia Xu, Timothy Veenstra, Alex Muñoz, Wilder A Palomino, Jerome F Strauss, Luigi Devoto

Pharmaceutical Sciences Faculty Publications

OBJECTIVE: To determine tissue concentrations of E2, estrone, P, and estrogens metabolites (EMs) 2-methoxyestradiol, 2-methoxyestrone, 4-hydroxyestrone, and 16-ketoestradiol in corpus luteum (CL) of different ages, and after hCG administration; and to examine the effects of EMs on vascular endothelial growth factor (VEGF) secretion and angiogenic activity released by cultured luteinizing granulosa cells in the presence and absence of hCG.

DESIGN: Experimental study.

SETTING: University.

PATIENT(S): Thirty-two healthy women of reproductive age.

INTERVENTION(S): Corpus luteum was collected at the time of minilaparotomy for tubal sterilization, at varying stages of the luteal phase (LP). Late-LP CL was collected 24 hours after IM …

Cell Cycle-Dependent Phosphorylation Of Nucleophosmin And Its Potential Regulation By Peptidyl-Prolyl Cis/Trans Isomerase, Xuelian Zhao, Junfang Ji, Li-Rong Yu, Timothy Veenstra, Xin Wei Wang

Pharmaceutical Sciences Faculty Publications

Nucleophosmin (NPM) is a ubiquitously expressed phosphoprotein involved in many cellular processes. Phosphorylation is considered the major regulatory mechanism of the NPM protein, associated with diverse cellular events. In this study, we characterized the phosphorylation status of several physiological phosphorylation sites of NPM, especially the newly confirmed

Bile Acid Signal-Induced Phosphorylation Of Small Heterodimer Partner By Protein Kinase Cζ Is Critical For Epigenomic Regulation Of Liver Metabolic Genes, Sunmi Seok, Deepthi Kanamaluru, Zhen Xiao, Daniel Ryerson, Sung-E Choi, Kelly Suino-Powell, H. Eric Xu, Timothy D. Veenstra, Jongsook Kim Kemper

Pharmaceutical Sciences Faculty Publications

Bile acids (BAs) are recently recognized key signaling molecules that control integrative metabolism and energy expenditure. BAs activate multiple signaling pathways, including those of nuclear receptors, primarily farnesoid X receptor (FXR), membrane BA receptors, and FXR-induced FGF19 to regulate the fed-state metabolism. Small heterodimer partner (SHP) has been implicated as a key mediator of these BA signaling pathways by recruitment of chromatin modifying proteins, but the key question of how SHP transduces BA signaling into repressive histone modifications at liver metabolic genes remains unknown. Here we show that protein kinase Cζ (PKCζ) is activated by BA or FGF19 and phosphorylates …

Dsg3 As A Biomarker For The Ultrasensitive Detection Of Cccult Lymph Node Metastasis In Oral Cancer Using Nanostructured Immunoarrays, Vyomesh Patel, Daniel Martin, Ruchika Malhotra, Christina A. Marsh, Colleen L. Doçi, Timothy D. Veenstra, Cherie-Ann O. Nathan, Uttam K. Sinha, Bhuvanesh Singh, Alfredo A. Molinolo, James F. Rusling, J. Silvio Gutkind

Pharmaceutical Sciences Faculty Publications

OBJECTIVES: The diagnosis of cervical lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) patients constitutes an essential requirement for clinical staging and treatment selection. However, clinical assessment by physical examination and different imaging modalities, as well as by histological examination of routine lymph node cryosections can miss micrometastases, while false positives may lead to unnecessary elective lymph node neck resections. Here, we explored the feasibility of developing a sensitive assay system for desmoglein 3 (DSG3) as a predictive biomarker for lymph node metastasis in HNSCC.

MATERIALS AND METHODS: DSG3 expression was determined in multiple general cancer- and …

A Humanized Pattern Of Aromatase Expression Is Associated With Mammary Hyperplasia In Mice, Hong Zhao, Elizabeth K. Pearson, David C. Brooks, John S. Coon, Dong Chen, Masashi Demura, Ming Zhang, Charles V. Clevenger, Xia Xu, Timothy D. Veenstra, Robert T. Chatterton, Francesco J. Demayo, Serdar E. Bulun

Pharmaceutical Sciences Faculty Publications

Aromatase is essential for estrogen production and is the target of aromatase inhibitors, the most effective endocrine treatment for postmenopausal breast cancer. Peripheral tissues in women, including the breast, express aromatase via alternative promoters. Female mice lack the promoters that drive aromatase expression in peripheral tissues; thus, we generated a transgenic humanized aromatase (Arom(hum)) mouse line containing a single copy of the human aromatase gene to study the link between aromatase expression in mammary adipose tissue and breast pathology. Arom(hum) mice expressed human aromatase, driven by the proximal human promoters II and I.3 and the distal promoter I.4, in breast …

Hormone-Induced 14-3-3Γ Adaptor Protein Regulates Steroidogenic Acute Regulatory Protein Activity And Steroid Biosynthesis In Ma-10 Leydig Cells, Yasaman Aghazadeh, Malena B. Rone, Josip Blonder, Xiaoying Ye, Timothy D. Veenstra, D. Buck Hales, Martine Culty, Vassilios Papadopoulos

Pharmaceutical Sciences Faculty Publications

Cholesterol is the sole precursor of steroid hormones in the body. The import of cholesterol to the inner mitochondrial membrane, the rate-limiting step in steroid biosynthesis, relies on the formation of a protein complex that assembles at the outer mitochondrial membrane called the transduceosome. The transduceosome contains several mitochondrial and cytosolic components, including the steroidogenic acute regulatory protein (STAR). Human chorionic gonadotropin (hCG) induces de novo synthesis of STAR, a process shown to parallel maximal steroid production. In the hCG-dependent steroidogenic MA-10 mouse Leydig cell line, the 14-3-3γ protein was identified in native mitochondrial complexes by mass spectrometry and immunoblotting, …

Concentration Of Endogenous Estrogens And Estrogen Metabolites In The Nci-60 Human Tumor Cell Lines, Xia Xu, Timothy D. Veenstra

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Endogenous estrogens and estrogen metabolites play an important role in the pathogenesis and development of human breast, endometrial, and ovarian cancers. Increasing evidence also supports their involvement in the development of certain lung, colon and prostate cancers.

METHODS: In this study we systemically surveyed endogenous estrogen and estrogen metabolite levels in each of the NCI-60 human tumor cell lines, which include human breast, central nerve system, colon, ovarian, prostate, kidney and non-small cell lung cancers, as well as melanomas and leukemia. The absolute abundances of these metabolites were measured using a liquid chromatography-tandem mass spectrometry method that has been …

Metabolomics: The Final Frontier?, Timothy D. Veenstra

Pharmaceutical Sciences Faculty Publications

No abstract provided.

Pressure-Assisted Protein Extraction: A Novel Method For Recovering Proteins From Archival Tissue For Proteomic Analysis, Carol B. Fowler, Timothy J. Waybright, Timothy D. Veenstra, Timothy J. O'Leary, Jeffrey T. Mason

Pharmaceutical Sciences Faculty Publications

Formaldehyde-fixed, paraffin-embedded (FFPE) tissue repositories represent a valuable resource for the retrospective study of disease progression and response to therapy. However, the proteomic analysis of FFPE tissues has been hampered by formaldehyde-induced protein modifications, which reduce protein extraction efficiency and may lead to protein misidentification. Here, we demonstrate the use of heat augmented with high hydrostatic pressure (40,000 psi) as a novel method for the recovery of intact proteins from FFPE mouse liver. When FFPE mouse liver was extracted using heat and elevated pressure, there was a 4-fold increase in protein extraction efficiency, a 3-fold increase in the extraction of …

Comparison Of Estrone And 17Β-Estradiol Levels In Commercial Goat And Cow Milk, D. W. Farlow, X. Xu, T. D. Veenstra

Pharmaceutical Sciences Faculty Publications

Increased levels of estrogen metabolites are believed to be associated with cancers of the reproductive system. One potential dietary source of these metabolites that is commonly consumed worldwide is milk. In North America, dairy cows are the most common source of milk; however, goats are the primary source of milk worldwide. In this study, the absolute concentrations of unconjugated and total (unconjugated plus conjugated) estrone (E(1)) and 17β-estradiol (E(2)) were compared in a variety of commercial cow milks (regular and organic) and goat milk. A lower combined concentration of E(1) and E(2) was found in goat milk than in any …

Looking Back At Genomic Medicine In 2011, Charles Auffray, Timothy Caulfield, Muin J. Khoury, James R. Lupski, Matthias Schwab, Timothy Veenstra

Pharmaceutical Sciences Faculty Publications

No abstract provided.

Histone Demethylase Jumonji D3 (Jmjd3) As A Tumor Suppressor By Regulating P53 Protein Nuclear Stabilization., Chibawanye I. Ene, Lincoln Edwards, Gregory Riddick, Mehmet Baysan, Kevin Woolard, Svetlana Kotliarova, Chen Lai, Galina Belova, Maggie Cam, Jennifer Walling, Ming Zhou, Holly Stevenson, Hong Sug Kim, Keith Killian, Timothy Veenstra, Rolanda Bailey, Hua Song, Wei Zhang, Howard A. Fine

Pharmaceutical Sciences Faculty Publications

Histone methylation regulates normal stem cell fate decisions through a coordinated interplay between histone methyltransferases and demethylases at lineage specific genes. Malignant transformation is associated with aberrant accumulation of repressive histone modifications, such as polycomb mediated histone 3 lysine 27 (H3K27me3) resulting in a histone methylation mediated block to differentiation. The relevance, however, of histone demethylases in cancer remains less clear. We report that JMJD3, a H3K27me3 demethylase, is induced during differentiation of glioblastoma stem cells (GSCs), where it promotes a differentiation-like phenotype via chromatin dependent (INK4A/ARF locus activation) and chromatin independent (nuclear p53 protein stabilization) mechanisms. Our findings indicate …

Sirt2 Maintains Genome Integrity And Suppresses Tumorigenesis Through Regulating Apc/C Activity, Hyun-Seok Kim, Athanassios Vassilopoulos, Rui-Hong Wang, Tyler Lahusen, Zhen Xiao, Xiaoling Xu, Cuiling Li, Timothy D. Veenstra, Bing Li, Hongtao Yu, Junfang Ji, Xin Wei Wang, Seong-Hoon Park, Yong I Cha, David Gius, Chu-Xia Deng

Pharmaceutical Sciences Faculty Publications

Members of sirtuin family regulate multiple critical biological processes, yet their role in carcinogenesis remains controversial. To investigate the physiological functions of SIRT2 in development and tumorigenesis, we disrupted Sirt2 in mice. We demonstrated that SIRT2 regulates the anaphase-promoting complex/cyclosome activity through deacetylation of its coactivators, APC(CDH1) and CDC20. SIRT2 deficiency caused increased levels of mitotic regulators, including Aurora-A and -B that direct centrosome amplification, aneuploidy, and mitotic cell death. Sirt2-deficient mice develop gender-specific tumorigenesis, with females primarily developing mammary tumors, and males developing more hepatocellular carcinoma (HCC). Human breast cancers and HCC samples exhibited reduced SIRT2 levels compared with …

Novel Membrane-Associated Androgen Receptor Splice Variant Potentiates Proliferative And Survival Responses In Prostate Cancer Cells, Xi Yang, Zhiyong Guo, Feng Sun, Wei Li, Alan Alfano, Hermela Shimelis, Mingyuan Chen, Angela M H Brodie, Hegang Chen, Zhen Xiao, Timothy D. Veenstra, Yun Qiu

Pharmaceutical Sciences Faculty Publications

Progression from the androgen-sensitive to androgen-insensitive (or castration-resistant) stage is the major obstacle for sustained effectiveness of hormonal therapy for prostate cancer. The androgen receptor (AR) and its splice variants play important roles in regulating the transcription program essential for castration resistance. Here, we report the identification of a novel AR splice variant, designated as AR8, which is up-regulated in castration-resistant prostate cancer cells. AR8 is structurally different from other known AR splice variants because it lacks a DNA binding domain and therefore, unlikely functions as a transcription factor on its own. Immunofluorescence staining revealed that AR8 was primarily localized …

The Effect Of Tamoxifen And Raloxifene On Estrogen Metabolism And Endometrial Cancer Risk, Marian Y. Williams-Brown, Sana M. Salih, Xia Xu, Timothy D. Veenstra, Muhammad Saeed, Shaleen K. Theiler, Concepcion R. Diaz-Arrastia, Salama A. Salama

Pharmaceutical Sciences Faculty Publications

Selective estrogen receptor modulators (SERMs) demonstrate differential endometrial cancer (EC) risk. While tamoxifen (TAM) use increases the risk of endometrial hyperplasia and malignancy, raloxifene (RAL) has neutral effects on the uterus. How TAM increases the risk of EC and why TAM and RAL differentially modulate the risk for EC, however, remain elusive. Here, we tested the hypothesis that TAM increases the risk for EC, at least in part, by enhancing the local estrogen biosynthesis and directing estrogen metabolism towards the formation of genotoxic and hormonally active estrogen metabolites. In addition, the differential effects of TAM and RAL in EC risk …

Regulation Of Microtubule-Based Microtubule Nucleation By Mammalian Polo-Like Kinase 1, Yoshikazu Johmura, Nak-Kyun Soung, Jung-Eun Park, Li-Rong Yu, Ming Zhou, Jeong K. Bang, Bo-Yeon Kim, Timothy D. Veenstra, Raymond L. Erikson, Kyung S. Lee

Pharmaceutical Sciences Faculty Publications

Bipolar spindle formation is pivotal for accurate segregation of mitotic chromosomes during cell division. A growing body of evidence suggests that, in addition to centrosome- and chromatin-based microtubule (MT) nucleation, MT-based MT nucleation plays an important role for proper bipolar spindle formation in various eukaryotic organisms. Although a recently discovered Augmin complex appears to play a central role in this event, how Augmin is regulated remains unknown. Here we provide evidence that a mammalian polo-like kinase 1 (Plk1) localizes to mitotic spindles and promotes MT-based MT nucleation by directly regulating Augmin. Mechanistically, we demonstrated that Cdc2-dependent phosphorylation on a γ-tubulin …

The Rag1 V(D)J Recombinase/Ubiquitin Ligase Promotes Ubiquitylation Of Acetylated, Phosphorylated Histone 3.3, Jessica M. Jones, Anamika Bhattacharyya, Carrie Simkus, Brice Vallieres, Timothy D. Veenstra, Ming Zhou

Pharmaceutical Sciences Faculty Publications

Histone variant H3.3 is associated with transcriptionally active chromatin and accumulates at loci undergoing preparation for V(D)J recombination, a DNA rearrangement required for the assembly of antigen receptors and development of B and T lymphocytes. Here we demonstrate that the RAG1 V(D)J recombinase protein promotes ubiquitylation of H3.3 that has been heavily acetylated and phosphorylated on serine 31 (acetyl-H3.3 S31p). A fragment of RAG1 promoted formation of a mono-ubiquitylated H3 product that was identified using mass spectrometry as ubiquitylated acetyl-H3.3 S31p. H3 was ubiquitylated at multiple lysine residues, and correspondingly, di-, tri- and higher-order ubiquitylated products were detected at low …

Genome Medicine: Past, Present And Future, Charles Auffray, Timothy Caulfield, Muin J. Khoury, James R. Lupski, Matthias Schwab, Timothy D. Veenstra

Pharmaceutical Sciences Faculty Publications

No abstract provided.

Common Data Elements For Traumatic Brain Injury: Recommendations From The Biospecimens And Biomarkers Working Group, Geoffrey T. Manley, Ramon Diaz-Arrastia, Mary Brophy, Doortje Engel, Clay Goodman, Katrina Gwinn, Timothy D. Veenstra, Geoffrey Ling, Andrew K. Ottens, Frank Tortella, Ronald L. Hayes

Pharmaceutical Sciences Faculty Publications

Recent advances in genomics, proteomics, and biotechnology have provided unprecedented opportunities for translational research and personalized medicine. Human biospecimens and biofluids represent an important resource from which molecular data can be generated to detect and classify injury and to identify molecular mechanisms and therapeutic targets. To date, there has been considerable variability in biospecimen and biofluid collection, storage, and processing in traumatic brain injury (TBI) studies. To realize the full potential of this important resource, standardization and adoption of best practice guidelines are required to insure the quality and consistency of these specimens. The aim of the Biospecimens and Biomarkers …

Sirt1 Deacetylates And Inhibits Srebp-1c Activity In Regulation Of Hepatic Lipid Metabolism, Bhaskar Ponugoti, Dong-Hyun Kim, Zhen Xiao, Zachary Smith, Ji Miao, Mengwei Zang, Shwu-Yuan Wu, Cheng-Ming Chiang, Timothy D. Veenstra, Jongsook Kim Kemper

Pharmaceutical Sciences Faculty Publications

The SIRT1 deacetylase inhibits fat synthesis and stimulates fat oxidation in response to fasting, but the underlying mechanisms remain unclear. Here we report that SREBP-1c, a key lipogenic activator, is an in vivo target of SIRT1. SIRT1 interaction with SREBP-1c was increased during fasting and decreased upon feeding, and consistently, SREBP-1c acetylation levels were decreased during fasting in mouse liver. Acetylated SREBP-1c levels were also increased in HepG2 cells treated with insulin and glucose to mimic feeding conditions, and down-regulation of p300 by siRNA decreased the acetylation. Depletion of hepatic SIRT1 by adenoviral siRNA increased acetylation of SREBP-1c with increased …

Comparison Of Estrogens And Estrogen Metabolites In Human Breast Tissue And Urine, Emanuela Taioli, Annie Im, Xia Xu, Timothy D. Veenstra, Gretchen Ahrendt, Seymour Garte

Pharmaceutical Sciences Faculty Publications

BACKGROUND: An important aspect of the link between estrogen and breast cancer is whether urinary estrogen levels are representative of the intra-tissue levels of bioavailable estrogens.

METHODS: This study compares 15 estrogen and estrogen metabolite levels in breast tissue and urine of 9 women with primary breast cancer using a quantitative liquid chromatography-mass spectrometry method.

RESULTS: The average levels of estrogens (estrone, 17 beta-estradiol) were significantly higher in breast tissue than in urine. Both the 2 and the 16-hydroxylation pathways were less represented in breast tissue than urine; no components of the 4-hydroxypathway were detected in breast tissue, while 4-hydroxyestrone …

A New Approach To Measuring Estrogen Exposure And Metabolism In Epidemiologic Studies, R. G. Ziegler, J. M. Faupel-Badger, L. Y. Sue, B. J. Fuhrman, R. T. Falk, J. Boyd-Morin, M. K. Henderson, R. N. Hoover, Timothy D. Veenstra, L. K. Keefer, X. Xu

Pharmaceutical Sciences Faculty Publications

Endogenous estrogen plays an integral role in the etiology of breast and endometrial cancer, and conceivably ovarian cancer. However, the underlying mechanisms and the importance of patterns of estrogen metabolism and specific estrogen metabolites have not been adequately explored. Long-standing hypotheses, derived from laboratory experiments, have not been tested in epidemiologic research because of the lack of robust, rapid, accurate measurement techniques appropriate for large-scale studies. We have developed a stable isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS(2)) method that can measure concurrently all 15 estrogens and estrogen metabolites (EM) in urine and serum with high sensitivity (level of detection=2.5-3.0fmol …

Fxr Acetylation Is Normally Dynamically Regulated By P300 And Sirt1 But Constitutively Elevated In Metabolic Disease States, Jongsook Kim Kemper, Zhen Xiao, Bhaskar Ponugoti, Ji Miao, Sungsoon Fang, Deepthi Kanamaluru, Stephanie Tsang, Shwu-Yuan Wu, Cheng-Ming Chiang, Timothy D. Veenstra

Pharmaceutical Sciences Faculty Publications

The nuclear bile acid receptor FXR is critical for regulation of lipid and glucose metabolism. Here, we report that FXR is a target of SIRT1, a deacetylase that mediates nutritional and hormonal modulation of hepatic metabolism. Lysine 217 of FXR is the major acetylation site targeted by p300 and SIRT1. Acetylation of FXR increases its stability but inhibits heterodimerization with RXRalpha, DNA binding, and transactivation activity. Downregulation of hepatic SIRT1 increased FXR acetylation with deleterious metabolic outcomes. Surprisingly, in mouse models of metabolic disease, FXR interaction with SIRT1 and p300 was dramatically altered, FXR acetylation levels were elevated, and overexpression …

Using A Global Proteomic Approach To Identify Proteins Affected By Estrogen Therapy, Timothy D. Veenstra

Pharmaceutical Sciences Faculty Publications

With the increase in technological capabilities for measuring biological molecules, there is a greater trend to conduct non-biased, discovery-driven studies that collect information on hundreds of molecules in a single study. The hope is that novel findings can be detected within these large datasets. For protein analysis, these non-biased studies are particularly challenging as no technology is presently capable of providing a view of the entire proteome. The ability of non-biased studies to accurately detect specific differences within the proteomes of samples obtained from differentially treated individuals must be conclusively demonstrated before investigators will routinely adopt these methods as part …

How Close Is The Bench To The Bedside? Metabolic Profiling In Cancer Research, Que N. Van, Timothy D. Veenstra

Pharmaceutical Sciences Faculty Publications

Metabolic profiling using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) is integral to the rapidly expanding field of metabolomics, which is making progress in toxicology, plant science and various diseases, including cancer. In the area of oncology and metabolic phenotyping, researchers have probed the known changes in malignant cellular pathways using new experimental techniques to gain more insights, and others are exploiting these same cellular pathways for therapeutic drug targets and for novel cancer biomarkers, with the ultimate goal of translation to the clinic. Here, we discuss the challenges and opportunities in metabolic phenotyping for discovering novel cancer …