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Loss Of Prolyl Carboxypeptidase In Two-Kidney, One-Clip Goldblatt Hypertensive Mice, Nadja Grobe, Orly Leiva, Mariana Morris, Khalid M. Elased

Pharmacology and Toxicology Faculty Publications

It is well documented that angiotensin (Ang) II contributes to kidney disease progression. The protease prolyl carboxypeptidase (PRCP) is highly expressed in the kidney and may be renoprotective by degrading Ang II to Ang-(1-7). The aim of the study was to investigate whether renal PRCP protein expression and activity are altered in two-kidney, one-clip (2K1C) Goldblatt hypertensive mice. Left renal artery was constricted by using 0.12 mm silver clips. Blood pressure was measured using telemetry over the eleven weeks of study period and revealed an immediate increase in 2K1C animals during the first week of clip placement which was followed …

Generation Of A Retinoblastoma (Rb)1-Inducible Dominant-Negative (Dn) Mouse Model., Shikha Tarang, Songila M.S.R Doi, Channabasavaiah B. Gurumurthy, Donald W. Harms, Rolen M. Quadros, Sonia M. Rocha-Sanchez

Journal Articles: Genetics, Cell Biology & Anatomy

Retinoblastoma 1 (Rb1) is an essential gene regulating cellular proliferation, differentiation, and homeostasis. To exert these functions, Rb1 is recruited and physically interacts with a growing variety of signaling pathways. While Rb1 does not appear to be ubiquitously expressed, its expression has been confirmed in a variety of hematopoietic and neuronal-derived cells, including the inner ear hair cells (HCs). Studies in transgenic mice demonstrate that complete germline or conditional Rb1 deletion leads to abnormal cell proliferation, followed by massive apoptosis; making it difficult to fully address Rb1's biochemical activities. To overcome these limitations, we developed a tetracycline-inducible TetO-CB-myc6-Rb1 (CBRb) mouse …

Tumor Cell Targeting By Iron Oxide Nanoparticles Is Dominated By Different Factors In Vitro Versus In Vivo, Christian Ndong, Jennifer A. Tate, Warren C. Kett, Jaya Batra, Eugene Demidenko, Lionel D. Lewis, P. Jack Hoopes, Tillmann U. Gerngross, Karl E. Griswold

Dartmouth Scholarship

Realizing the full potential of iron oxide nanoparticles (IONP) for cancer diagnosis and therapy requires selective tumor cell accumulation. Here, we report a systematic analysis of two key determinants for IONP homing to human breast cancers: (i) particle size and (ii) active vs passive targeting. In vitro, molecular targeting to the HER2 receptor was the dominant factor driving cancer cell association. In contrast, size was found to be the key determinant of tumor accumulation in vivo, where molecular targeting increased tumor tissue concentrations for 30 nm but not 100 nm IONP. Similar to the in vitro results, PEGylation …

Molecular Docking And Inhibition Of Matrix Metalloproteinase-2 By Novel Difluorinatedbenzylidene Curcumin Analog, Aamir Ahmad, Afreen Sayed, Kevin R. Ginnebaugh, Vivek Sharma, Anita Suri, Arundhati Saraph, Subhash Padhye, Fazlul H. Sarkar

Department of Pathology

We recently described the synthesis and characterization of a novel difluorinatedbenzylidene analog of curcumin, commonly referred as CDF, which demonstrated significantly enhanced bioavailability and in vivo anticancer activity. CDF targets many factors similar to curcumin, albeit with more potency, as reported previously. To further highlight this differential behavior of CDF, we chose matrix metalloproteinase protein MMP-2 which is involved in the processes of invasion and metastasis of human tumors. Both curcumin and CDF were characterized for their binding characteristics using in silico docking studies; they were also evaluated via biological assays involving gelatin zymography, miRNA analysis, invasion assays and ELISA. …

Anti-Tumoral Effects Of Mir-3189-3p In Glioblastoma, Duane Jeansonne, Mariacristina Deluca, Luis Marrero, Adam Lassak, Marco Pacifici, Dorota Wyczechowska, Anna Wilk, Krzysztof Reiss, Francesca Peruzzi

School of Medicine Faculty Publications

Glioblastoma is one of the most aggressive brain tumors. We have previously found up-regulation of growth differentiation factor 15 (GDF15) in glioblastoma cells treated with the anticancer agent fenofibrate. Sequence analysis of GDF15 revealed the presence of a microRNA, miR-3189, in the single intron. We then asked whether miR-3189 was expressed in clinical samples and whether it was functional in glioblastoma cells. We found that expression of miR-3189-3p was down-regulated in astrocytoma and glioblastoma clinical samples compared with control brain tissue. In vitro, the functionality of miR-3189-3p was tested by RNA-binding protein immunoprecipitation, and miR-3189-3p coimmunoprecipitated with Argonaute 2 together …

Diversification Of Importin-Α Isoforms In Cellular Trafficking And Disease States., Ruth A. Pumroy, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

The human genome encodes seven isoforms of importin α which are grouped into three subfamilies known as α1, α2 and α3. All isoforms share a fundamentally conserved architecture that consists of an N-terminal, autoinhibitory, importin-β-binding (IBB) domain and a C-terminal Arm (Armadillo)-core that associates with nuclear localization signal (NLS) cargoes. Despite striking similarity in amino acid sequence and 3D structure, importin-α isoforms display remarkable substrate specificity in vivo. In the present review, we look at key differences among importin-α isoforms and provide a comprehensive inventory of known viral and cellular cargoes that have been shown to associate preferentially with specific …

Amyloid Precursor-Like Protein 2 (Aplp2) Affects The Actin Cytoskeleton And Increases Pancreatic Cancer Growth And Metastasis., Poomy Pandey, Satyanarayana Rachagani, Srustidhar Das, Parthasarathy Seshacharyulu, Yuri Sheinin, Naava Naslavsky, Zenggang Pan, Brittney L. Smith, Haley L. Peters, Prakash Radhakrishnan, Nicole R. Mckenna, Sai Srinivas Panapakkam Giridharan, Dhanya Haridas, Sukhwinder Kaur, Michael A. Hollingsworth, Richard G. Macdonald, Jane L. Meza, Steve Caplan, Surinder K. Batra, Joyce C. Solheim

Journal Articles: Biochemistry & Molecular Biology

Amyloid precursor-like protein 2 (APLP2) is aberrantly expressed in pancreatic cancer. Here we showed that APLP2 is increased in pancreatic cancer metastases, particularly in metastatic lesions found in the diaphragm and intestine. Examination of matched human primary tumor-liver metastasis pairs showed that 38.1% of the patients had positive APLP2 expression in both the primary tumor and the corresponding liver metastasis. Stable knock-down of APLP2 expression (with inducible shRNA) in pancreatic cancer cells reduced the ability of these cells to migrate and invade. Loss of APLP2 decreased cortical actin and increased intracellular actin filaments in pancreatic cancer cells. Down-regulation of APLP2 …

Method Of Treating Parkinson's Disease In Humans By Convection-Enhanced Infusion Of Glial Cell-Line Derived Neurotrophic Factor To The Putamen, Stephen S. Gill, Don M. Gash, Greg A. Gerhardt

Neuroscience Faculty Patents

A method of treating Parkinson's disease in humans is disclosed, wherein glial cell-line derive neurotrophic factor (GDNF) is chronically administered directly to one or both putamen of a human in need of treatment thereof via convection-enhanced infusion using at least one implantable pump and at least one catheter. In one aspect of the present invention the GDNF is infused directly into one or both putamen through one or more indwelling intraparenchymal multiport brain catheters connected to one or more implantable pumps wherein the flow rate is pulsed.

Method Of Treating Parkinson's Disease In Humans By Convection-Enhanced Infusion Of Glial Cell-Line Derived Neurotrophic Factor To The Putamen, Stephen S. Gill, Don M. Gash, Greg A. Gerhardt

Neuroscience Faculty Patents

A method of treating Parkinson's disease in humans is disclosed, wherein glial cell-line derive neurotrophic factor (GDNF) is chronically administered directly to one or both putamen of a human in need of treatment thereof via convection-enhanced infusion using at least one implantable pump and at least one catheter. In one aspect of the present invention the GDNF is infused directly into one or both putamen through one or more indwelling intraparenchymal mutitiport brain catheters connected to one or more implantable pumps wherein the flow rate is pulsed.

Shbg Gene Polymorphism (Rs1799941) Associates With Metabolic Syndrome In Children And Adolescents, Marquitta J. White, Fatih Eren, Deniz Agirbasli, Scott M. Williams, Mehmet Agirbasli

Dartmouth Scholarship

Background: Metabolic syndrome (MetS) is a complex disorder characterized by coexistence of several cardiometabolic (CM) factors, i.e. hyperlipidemia, obesity, high blood pressure and insulin resistance. The presence of MetS is strongly associated with increased risk of cardiovascular disease (CVD). The syndrome was originally defined as an adult disorder, but MetS has become increasingly recognized in children and adolescents.

Methods: Genetic variants influence biological components common to the CM factors that comprise MetS. We investigated single locus associations between six single nucleotide polymorphisms (SNPs), previously shown to modulate lipid or sex hormone binding globulin (SHBG) levels, with MetS in a Turkish …

Disrupting Sumoylation Enhances Transcriptional Function And Ameliorates Polyglutamine Androgen Receptor-Mediated Disease., Jason P Chua, Satya L Reddy, Zhigang Yu, Elisa Giorgetti, Heather L Montie, Sarmistha Mukherjee, Jake Higgins, Richard C Mceachin, Diane M Robins, Diane E Merry, Jorge A Iñiguez-Lluhí, Andrew P Lieberman

Department of Biochemistry and Molecular Biology Faculty Papers

Expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from polyQ-mediated proteotoxicity by enhancing the transcriptional activity of polyQ AR. To accomplish this, we bypassed the inhibitory effect of AR SUMOylation (where SUMO indicates small ubiquitin-like modifier) by mutating conserved lysines in the polyQ AR that …

Fungal Mediator Tail Subunits Contain Classical Transcriptional Activation Domains, Zhongle Liu, Lawrence C. Myers

Dartmouth Scholarship

Classical activation domains within DNA-bound eukaryotic transcription factors make weak interactions with coactivator complexes, such as Mediator, to stimulate transcription. How these interactions stimulate transcription, however, is unknown. The activation of reporter genes by artificial fusion of Mediator subunits to DNA binding domains that bind to their promoters has been cited as evidence that the primary role of activators is simply to recruit Mediator. We have identified potent classical transcriptional activation domains in the C termini of several tail module subunits of Saccharomyces cerevisiae, Candida albicans, and Candida dubliniensis Mediator, while their N-terminal domains are necessary and sufficient for their …

Epigenetics As An Answer To Darwin’S “Special Difficulty,” Part 2: Natural Selection Of Metastable Epialleles In Honey Bee Castes, Douglas M. Ruden, Pablo E. Cingolani, Arko Sen, Wen Qu, Luan Wang, Marie-Claude Senut, Mark D. Garfinkel, Vincent E. Sollars, Xiangyi Lu

Biochemistry and Microbiology

In a recent perspective in this journal, Herb (2014) discussed how epigenetics is a possible mechanism to circumvent Charles Darwin’s “special difficulty” in using natural selection to explain the existence of the sterile-fertile dimorphism in eusocial insects. Darwin’s classic book “On the Origin of Species by Means of Natural Selection” explains how natural selection of the fittest individuals in a population can allow a species to adapt to a novel or changing environment. However, in bees and other eusocial insects, such as ants and termites, there exist two or more castes of genetically similar females, from fertile queens to multiple …

Cytometric Characterization Of Circulating Tumor Cells Captured By Microfiltration And Their Correlation To The Cellsearch(®) Ctc Test., Daniel L Adams, Steingrimur Stefansson, Christian Haudenschild, Stuart S Martin, Monica Charpentier, Saranya Chumsri, Massimo Cristofanilli, Cha-Mei Tang, R Katherine Alpaugh

Pathology Faculty Publications

Recent studies reporting hundreds, to thousands, of circulating tumor cells (CTCs) in the blood of cancer patients have raised questions regarding the prevalence of CTCs, as enumerated by the CellSearch(®) CTC Test. Although CellSearch has been shown to consistently detect clinically relevant CTCs; the ability to only capture EpCAM positive cells has led to speculation that it captures limited subsets of CTCs. In contrast, alternative approaches to CTC isolation are often cited as capturing large numbers of CTCs from patient blood. Not surprisingly the number of cells isolated by alternative approaches show poor correlations when compared to CellSearch, even when …

The Role Of Parental Cognitive, Behavioral, And Motor Profiles In Clinical Variability In Individuals With Chromosome 16p11.2 Deletions, Andres Moreno-De-Luca, David W. Evans, K B. Boomer, Ellen Hanson, R Bernier, R. P. Goin-Kochel, S. M. Myers, Thomas D. Challman, Daniel Moreno-De-Luca, Mylissa M. Slane, Abby E. Hare, W K. Chung, J. Spiro, W. A. Faucett, C. L. Martin, David H. Ledbetter

Faculty Journal Articles

Importance Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood.

Objectives To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs.

Design, Setting, and Participants Family-based study design with a volunteer sample of 56 individuals with de novo 16p11.2 …

Elucidation Of The Cellular And Molecular Mechanisms Of Missense Mutations Associated With Familial Exudative Vitreoretinopathy And Congenital Myasthenic Syndrome, Reham Mahmoud Mohammed Milhem

Dissertations

The endoplasmic reticulum (ER), within eukaryotic cells, is a hub for protein folding and assembly. Misfolded proteins and unassembled subunits of protein complexes are retained in the ER and degraded by a process termed endoplasmic reticulum associated degradation (ERAD). Frizzled class receptor 4 (FZD4) and muscle, skeletal, receptor tyrosine kinase (MuSK) are Wnt receptors. These proteins contain the frizzled cysteine-rich domain (Fz-CRD) required for dimerization in the ER. Mutations in FZD4 and MuSK genes are known to cause familial exudative vitreoretinopathy (FEVR, an autosomal dominant disease) and congenital myasthenic syndrome (CMS, an autosomal recessive disease), respectively. It was hypothesized that …

Tcr Alpha Lcr And Non-Lcr Cis-Elements Contributing To Tissue Specific Expression Of The Tcr Alpha Gene In Thymic And Peripheral T Cells, Martina Kucerova-Levisohn

Dissertations, Theses, and Capstone Projects

Orchestrated expression of multiple genes residing in the complex TCRα/δ/Dad1 locus requires tight control from multiple cis-acting elements. The TCRα locus control region (LCR), is positioned between TCRα and Dad1 gene, and has been implicated in the differential expression of both genes. In this study, we focus our work on the hypersensitive site (HS)1 prime (HS1'), located 3' of the classical Eα enhancer, within the TCRα LCR. We investigated its non- redundant role in TCRα expression in thymic and peripheral T cells as assayed by in vivo and in vitro studies. Furthermore, formation of HS1' in both lymphoid and …

Overview Of Microrna Biology, Ashley M. Mohr, Justin L. Mott

Journal Articles: Biochemistry & Molecular Biology

In considering an overview of microRNA biology, it is useful to consider microRNAs as a part of cellular communication. At the simplest level, microRNAs act to decrease the expression of mRNAs that contain stretches of sequence complementary to the microRNA. This function can be likened to the function of endogenous or synthetic short interfering RNA (siRNA). However, microRNA function is more complicated and nuanced than this ‘on-off’ model would suggest. Further, many microRNA targets are themselves non-coding RNAs. In this review, we will discuss the role of microRNAs in shaping the proteome of the cell in a way that is …

Breast Cancer Screening: Early Detection Is Not Enough, Judy A. Tjoe

Journal of Patient-Centered Research and Reviews

N/A

Short Course In The Microbiome, Kimberly Falana, Rob Knight, Camilia R. Martin, Romina Goldszmid, K. Leigh Greathouse, Joanne Gere, Howard Young, Winston Patrick Kuo

United States Public Health Resources

Over the past decade, it has become evident that the microbiome is an important environmental factor that affects many physiological processes, such as cell proliferation and differentiation, behaviour, immune function and metabolism. More importantly, it may contribute to a wide variety of diseases, including cancer, inflammatory diseases, metabolic diseases and responses to pathogens. We expect that international, integrative and interdisciplinary translational research teams, along with the emergence of FDA-approved platforms, will set the framework for microbiome-based therapeutics and diagnostics. We recognize that the microbiome ecosystem offers new promise for personalized/precision medicine and targeted treatment for a variety of diseases. The …

Il-1Α Signaling Is Critical For Leukocyte Recruitment After Pulmonary Aspergillus Fumigatus Challenge, Alayna K. Caffrey, Margaret M. Lehmann, Julianne M. Zickovich, Vanessa Espinosa, Kelly M. Shepardson, Christopher P. Watschke, Kimberly M. Hilmer, Arsa Thammahong, Bridget M. Barker, Amariliz Rivera, Robert A. Cramer, Joshua J. Obar

Dartmouth Scholarship

Aspergillus fumigatus is a mold that causes severe pulmonary infections. Our knowledge of how A. fumigatus growth is controlled in the respiratory tract is developing, but still limited. Alveolar macrophages, lung resident macrophages, and airway epithelial cells constitute the first lines of defense against inhaled A. fumigatus conidia. Subsequently, neutrophils and inflammatory CCR2+ monocytes are recruited to the respiratory tract to prevent fungal growth. However, the mechanism of neutrophil and macrophage recruitment to the respiratory tract after A. fumigatus exposure remains an area of ongoing investigation. Here we show that A. fumigatus pulmonary challenge induces expression of the inflammasome-dependent cytokines …

Targeting Cell Cycle Proteins In Breast Cancer Cells With Sirna By Using Lipid-Substituted Polyethylenimines, Manoj Parmar, Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Cezary Kucharski, Robert Maranchuk, Judith C. Hugh, Hasan Uludag

Pharmacy Faculty Articles and Research

The cell cycle proteins are key regulators of cell cycle progression whose de-regulation is one of the causes of breast cancer. RNA interference (RNAi) is an endogenous mechanism to regulate gene expression and it could serve as the basis of regulating aberrant proteins including cell cycle proteins. Since the delivery of small interfering RNA (siRNA) is a main barrier for implementation of RNAi therapy, we explored the potential of a non-viral delivery system, 2.0 kDa polyethylenimines substituted with linoleic acid and caprylic acid, for this purpose. Using a library of siRNAs against cell cycle proteins, we identified cell division cycle …

Opposing Regulation Of Endolysosomal Pathways By Long-Acting Nanoformulated Antiretroviral Therapy And Hiv-1 In Human Macrophages., Mariluz Araínga, Dongwei Guo, Jayme Wiederin, Pawel Ciborowski, Joellyn Mcmillan, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Long-acting nanoformulated antiretroviral therapy (nanoART) is designed to improve patient regimen adherence, reduce systemic drug toxicities, and facilitate clearance of human immunodeficiency virus type one (HIV-1) infection. While nanoART establishes drug depots within recycling and late monocyte-macrophage endosomes, whether or not this provides a strategic advantage towards viral elimination has not been elucidated.

RESULTS: We applied quantitative SWATH-MS proteomics and cell profiling to nanoparticle atazanavir (nanoATV)-treated and HIV-1 infected human monocyte-derived macrophages (MDM). Native ATV and uninfected cells served as controls. Both HIV-1 and nanoATV engaged endolysosomal trafficking for assembly and depot formation, respectively. Notably, the pathways were deregulated …

Opposing Regulation Of Endolysosomal Pathways By Long-Acting Nanoformulated Antiretroviral Therapy And Hiv-1 In Human Macrophages., Mariluz Araínga, Dongwei Guo, Jayme Wiederin, Pawel Ciborowski, Joellyn Mcmillan, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Long-acting nanoformulated antiretroviral therapy (nanoART) is designed to improve patient regimen adherence, reduce systemic drug toxicities, and facilitate clearance of human immunodeficiency virus type one (HIV-1) infection. While nanoART establishes drug depots within recycling and late monocyte-macrophage endosomes, whether or not this provides a strategic advantage towards viral elimination has not been elucidated.

RESULTS: We applied quantitative SWATH-MS proteomics and cell profiling to nanoparticle atazanavir (nanoATV)-treated and HIV-1 infected human monocyte-derived macrophages (MDM). Native ATV and uninfected cells served as controls. Both HIV-1 and nanoATV engaged endolysosomal trafficking for assembly and depot formation, respectively. Notably, the pathways were deregulated …

Pact/Rax Regulates The Migration Of Cerebellar Granule Neurons In The Developing Cerebellum, Yue Yong, Ya Meng, Hanqing Ding, Zhiqin Fan, Yifen Tang, Chenghua Zhou, Jia Luo, Zun-Ji Ke

Pharmacology and Nutritional Sciences Faculty Publications

PACT and its murine ortholog RAX were originally identified as a protein activator for the dsRNA-dependent, interferon-inducible protein kinase PKR. Recent studies indicated that RAX played a role in embryogenesis and neuronal development. In this study, we investigated the expression of RAX during the postnatal development of the mouse cerebellum and its role in the migration of cerebellar granule neurons (CGNs). High expression of RAX was observed in the cerebellum from postnatal day (PD) 4 to PD9, a period when the CGNs migrate from the external granule layer (EGL) to the internal granule layer (IGL). The migration of the EGL …

Hidden Formaldehyde In E-Cigarette Aerosols, R. Paul Jensen, Wentai Luo, James F. Pankow, Robert M. Strongin, David H. Peyton

Chemistry Faculty Publications and Presentations

This letter reports a chemical analysis of vapor from electronic cigarettes that shows high levels of formaldehyde, a known carcinogen. The authors project that the associated incremental lifetime risk of cancer could be higher than that from long-term smoking.

The Tmao-Generating Enzyme Flavin Monooxygenase 3 Is A Central Regulator Of Cholesterol Balance, Manya Warrier, Diana M. Shih, Amy C. Burrows, Daniel Ferguson, Anthony D. Gromovsky, Amanda L. Brown, Stephanie Marshall, Allison Mcdaniel, Rebecca C. Schugar, Zeneng Wang, Jessica Sacks, Xin Rong, Thomas De Aguiar Vallim, Jeff Chou, Pavlina T. Ivanova, David S. Myers, H. Alex Brown, Richard G. Lee, Rosanne M. Crooke, Mark J. Graham, Xiuli Liu, Paolo Parini, Peter Tontonoz, Aldon J. Lusis, Stanley L. Hazen, Ryan E. Temel, J. Mark Brown

Saha Cardiovascular Research Center Faculty Publications

Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here, we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT) and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic endoplasmic reticulum (ER) stress …

Zhx2 Enhances The Cytotoxicity Of Chemotherapeutic Drugs In Liver Tumor Cells By Repressing Mdr1 Via Interfering With Nf-Ya, Hongxin Ma, Xuetian Yue, Lifen Gao, Xiaohong Liang, Wenjiang Yan, Zhenyu Zhang, Haixia Shan, Hualin Zhang, Brett T. Spear, Chunhong Ma

Microbiology, Immunology, and Molecular Genetics Faculty Publications

We previously reported the tumor suppressor function of Zinc-fingers and homeoboxes 2 (ZHX2) in hepatocellular carcinoma (HCC). Other studies indicate the association of increased ZHX2 expression with improved response to high dose chemotherapy in multiple myeloma. Here, we aim to test whether increased ZHX2 levels in HCC cells repress multidrug resistance 1(MDR1) expression resulting in increased sensitivity to chemotherapeutic drugs. We showed evidence that increased ZHX2 levels correlated with reduced MDR1 expression and enhanced the cytotoxicity of CDDP and ADM in different HCC cell lines. Consistently, elevated ZHX2 significantly reduced ADM efflux in HepG2 cells and greatly increased the CDDP-mediated …

Pyruvate Carboxylase Is Critical For Non-Small-Cell Lung Cancer Proliferation, Katherine Sellers, Matthew P. Fox, Michael Bousamra Ii, Stephen P. Slone, Richard M. Higashi, Donald M. Miller, Yali Wang, Jun Yan, Mariia O. Yuneva, Rahul Deshpande, Andrew N. Lane, Teresa W-M Fan

Toxicology and Cancer Biology Faculty Publications

Anabolic biosynthesis requires precursors supplied by the Krebs cycle, which in turn requires anaplerosis to replenish precursor intermediates. The major anaplerotic sources are pyruvate and glutamine, which require the activity of pyruvate carboxylase (PC) and glutaminase 1 (GLS1), respectively. Due to their rapid proliferation, cancer cells have increased anabolic and energy demands; however, different cancer cell types exhibit differential requirements for PC- and GLS-mediated pathways for anaplerosis and cell proliferation. Here, we infused patients with early-stage non-small-cell lung cancer (NSCLC) with uniformly 13C-labeled glucose before tissue resection and determined that the cancerous tissues in these patients had enhanced PC activity. …

Effects Of (R)-(-)-5-Methyl-1-Nicotinoyl-2-Pyrazoline On Glutamate Transporter 1 And Cysteine/Glutamate Exchanger As Well As Ethanol Drinking Behavior In Male, Alcohol-Preferring Rats, Munaf Aal-Aaboda, Hasan Alhaddad, Francis Osowik, Surya M. Nauli, Youssef Sari

Pharmacy Faculty Articles and Research

Alcohol consumption is largely associated with alterations in the extracellular glutamate concentrations in several brain reward regions. We recently showed that glutamate transporter 1 (GLT-1) is downregulated following chronic exposure to ethanol for 5 weeks in alcohol-preferring (P) rats and that upregulation of the GLT-1 levels in nucleus accumbens and prefrontal cortex results, in part, in attenuating ethanol consumption. Cystine glutamate antiporter (xCT) is also downregulated after chronic ethanol exposure in P rats, and its upregulation could be valuable in attenuating ethanol drinking. This study examines the effect of a synthetic compound, (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), on ethanol drinking and expressions of …