Medical Biochemistry Commons^™

Harnessing Transcriptionally Driven Chromosomal Instability Adaptation To Target Therapy-Refractory Lethal Prostate Cancer., Brittiny Dhital, Sandra Santasusagna, Perumalraja Kirthika, Michael Xu, Peiyao Li, Marc Carceles-Cordon, Rajesh K. Soni, Zhuoning Li, Ronald C. Hendrickson, Matthew J. Schiewer, William K. Kelly, Cora N. Sternberg, Jun Luo, Amaia Lujambio, Carlos Cordon-Cardo, Monica Alvarez-Fernandez, Marcos Malumbres, Haojie Huang, Adam Ertel, Josep Domingo-Domenech, Veronica Rodriguez-Bravo

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and …

Semi-Quantitative Detection Of Pseudouridine Modifications And Type I/Ii I/Ii Hypermodifications In Human Mrnas Using Direct Long-Read Sequencing, Sepideh Tavakoli, Mohammad Nabizadeh, Amr Makhamreh, Howard Gamper, Caroline A Mccormick, Neda K Rezapour, Ya-Ming Hou, Meni Wanunu, Sara H Rouhanifard

Department of Biochemistry and Molecular Biology Faculty Papers

Here, we develop and apply a semi-quantitative method for the high-confidence identification of pseudouridylated sites on mammalian mRNAs via direct long-read nanopore sequencing. A comparative analysis of a modification-free transcriptome reveals that the depth of coverage and specific k-mer sequences are critical parameters for accurate basecalling. By adjusting these parameters for high-confidence U-to-C basecalling errors, we identify many known sites of pseudouridylation and uncover previously unreported uridine-modified sites, many of which fall in k-mers that are known targets of pseudouridine synthases. Identified sites are validated using 1000-mer synthetic RNA controls bearing a single pseudouridine in the center position, demonstrating systematic …

Disruption Of The Interaction Between Mutationally Activated Gαq And Gβγ Attenuates Aberrant Signaling, Jenna L Aumiller, Philip B Wedegaertner

Department of Biochemistry and Molecular Biology Faculty Papers

Heterotrimeric G protein stimulation via G protein-coupled receptors promotes downstream proliferative signaling. Mutations can occur in Gα proteins which prevent GTP hydrolysis; this allows the G proteins to signal independently of G protein-coupled receptors and can result in various cancers, such as uveal melanoma (UM). Most UM cases harbor Q209L, Q209P, or R183C mutations in Gαq/11 proteins, rendering the proteins constitutively active (CA). Although it is generally thought that active, GTP-bound Gα subunits are dissociated from and signal independently of Gβγ, accumulating evidence indicates that some CA Gα mutants, such as Gαq/11, retain binding to Gβγ, and this interaction is …

Differentiating Pc12 Cells To Evaluate Neurite Densities Through Live-Cell Imaging, Jordyn Karliner, Diane E Merry

Department of Biochemistry and Molecular Biology Faculty Papers

Although PC12 cells are a valuable tool in neuroscience research, previously published PC12 cell differentiation techniques fail to consider the variability in differentiation rates between different PC12 cell strains and clonal variants. Here, we present a comprehensive protocol to differentiate PC12 cells into equivalent neurite densities through live-cell imaging for morphological, immunocytochemical, and biochemical analyses. We detail steps on optimized substrate coating, plating techniques, culture media, validation steps, and quantification techniques.

The Mucin Family Of Proteins: Candidates As Potential Biomarkers For Colon Cancer, Kristin E. Cox, Shanglei Liu, Thinzar M. Lwin, Robert M. Hoffman, Surinder K. Batra, Michael Bouvet

Journal Articles: Biochemistry & Molecular Biology

Mucins (MUC1-MUC24) are a family of glycoproteins involved in cell signaling and barrier protection. They have been implicated in the progression of numerous malignancies including gastric, pancreatic, ovarian, breast, and lung cancer. Mucins have also been extensively studied with respect to colorectal cancer. They have been found to have diverse expression profiles amongst the normal colon, benign hyperplastic polyps, pre-malignant polyps, and colon cancers. Those expressed in the normal colon include MUC2, MUC3, MUC4, MUC11, MUC12, MUC13, MUC15 (at low levels), and MUC21. Whereas MUC5, MUC6, MUC16, and MUC20 are absent from the normal colon and are expressed in colorectal …

Microrna-1 Attenuates The Growth And Metastasis Of Small Cell Lung Cancer Through Cxcr4/Foxm1/Rrm2 Axis, Parvez Khan, Jawed A. Siddiqui, Prakash Kshirsagar Dr., Ramakanth Chirravuri Venkata, Shailendra K. Maurya, Tamara Mirzapoiazova, Naveenkumar Perumal, Sanjib Chaudhary, Ranjana K. Kanchan, Mahek Fatima, Md Arafat Khan, Asad Ur Rehman, Imayavaramban Lakshmanan, Sidharth Mahapatra, Geoffrey A. Talmon, Prakash Kulkarni, Apar Kishor Ganti, Maneesh Jain, Ravi Salgia, Surinder K. Batra, Mohd W. Nasser

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood.

METHODS: To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, …

Elevated Paf1-Rad52 Axis Confers Chemoresistance To Human Cancers, Sanchita Rauth, Koelina Ganguly, Pranita Atri, Seema Parte, Rama Krishna Nimmakayala, Venkatesh Varadharaj, Palanisamy Nallasamy, Raghupathy Vengoji, Ayoola O. Ogunleye, Imayavaramban Lakshmanan, Ramakanth Chirravuri, Mika Bessho, Jesse L. Cox, Jason M. Foster, Geoffrey A. Talmon, Tadayoshi Bessho, Apar Kishor Ganti, Surinder K. Batra, Moorthy P. Ponnusamy

Journal Articles: Biochemistry & Molecular Biology

Cisplatin- and gemcitabine-based chemotherapeutics represent a mainstay of cancer therapy for most solid tumors; however, resistance limits their curative potential. Here, we identify RNA polymerase II-associated factor 1 (PAF1) as a common driver of cisplatin and gemcitabine resistance in human cancers (ovarian, lung, and pancreas). Mechanistically, cisplatin- and gemcitabine-resistant cells show enhanced DNA repair, which is inhibited by PAF1 silencing. We demonstrate an increased interaction of PAF1 with RAD52 in resistant cells. Targeting the PAF1 and RAD52 axis combined with cisplatin or gemcitabine strongly diminishes the survival potential of resistant cells. Overall, this study shows clinical evidence that the expression …

Molecular Signaling Network And Therapeutic Developments In Breast Cancer Brain Metastasis, Mercilena Benjamin, Pushkar Malakar, Rohit Anthony Sinha, Mohd Wasim Nasser, Surinder K. Batra, Jawed A. Siddiqui, Bandana Chakravarti

Journal Articles: Biochemistry & Molecular Biology

Breast cancer (BC) is one of the most frequently diagnosed cancers in women worldwide. It has surpassed lung cancer as the leading cause of cancer-related death. Breast cancer brain metastasis (BCBM) is becoming a major clinical concern that is commonly associated with ER-ve and HER2+ve subtypes of BC patients. Metastatic lesions in the brain originate when the cancer cells detach from a primary breast tumor and establish metastatic lesions and infiltrate near and distant organs via systemic blood circulation by traversing the BBB. The colonization of BC cells in the brain involves a complex interplay in the tumor microenvironment (TME), …

Association Of Smoking With Total Oxidant And Antioxidant Levels In Breast Milk, Nesibe Yildiz, Adnan Yilmaz

Makara Journal of Health Research

Background: Breast milk is a natural food that contains all the fluids, energy, and nutrients necessary for the optimum growth and development of newborns. Smoking is a public health problem that has harmful effects on the mother and baby. This study aimed to examine the association of exposure to smoking with total oxidant status (TOS) and total antioxidant status (TAS) in breast milk.

Methods: Healthy mothers without any health problems during their pregnancy and lactation periods were selected as subjects. Eighty-eight milk samples (44 in the smoking group and 44 in the nonsmoking group) were examined. TOS and …

In Silico Identification Of A Β2-Adrenoceptor Allosteric Site That Selectively Augments Canonical Β2ar-Gs Signaling And Function, Sushrut D Shah, Christoffer Lind, Francesco De Pascali, Raymond B Penn, Alexander D Mackerell, Deepak A Deshpande

Department of Biochemistry and Molecular Biology Faculty Papers

Activation of β2-adrenoceptors (β2ARs) causes airway smooth muscle (ASM) relaxation and bronchodilation, and β2AR agonists (β-agonists) are front-line treatments for asthma and other obstructive lung diseases. However, the therapeutic efficacy of β-agonists is limited by agonist-induced β2AR desensitization and noncanonical β2AR signaling involving β-arrestin that is shown to promote asthma pathophysiology. Accordingly, we undertook the identification of an allosteric site on β2AR that could modulate the activity of β-agonists to overcome these limitations. We employed the site identification by ligand competitive saturation (SILCS) computational method to comprehensively map the entire 3D structure of in silico-generated β2AR intermediate conformations and identified …

Computer-Aided Drug Discovery For Helicobacter Pylori, Nicole Ann Vita

Theses and Dissertations (ETD)

Helicobacter pylori is a high-priority drug-resistant pathogen and is currently the only bacteria considered to be a class I carcinogen and there is a critical need to identify novel chemical matter to treat H. pylori infections. Hp is responsible for greater than 60% of gastric cancer related deaths and 89% of all gastric cancer morbidities. In a previous study, our lab identified novel Hp thienopyrmidine inhibitors that target respiratory complex I, an essential enzyme in respiration. Respiratory complex I is a large asymmetric multidomain and membrane bound enzyme and due to these innate features, it is not practical for biophysical …

Clinicopathological And Prognostic Significance Of Cxcr4 Expression In Osteosarcoma: A Meta-Analysis, I Gusti Ngurah Ananda Wira Kusuma, Grace Yulia Alphani Yapson, John Nolan, I Gede Eka Wiratnaya, I Gede Putu Supadmanaba

BioMedicine

Background: The C-X-C Motif Chemokine Receptor (CXCR4) is an oncogene that has been widely studied and associated with worse clinicopathological features and prognosis outcomes in many types of cancer. Besides that, significance of CXCR4 expression on clinicopathological features and prognostic factors in osteosarcoma (OS) requires further validation.

Aim: We conducted a meta-analysis to evaluate the association between positive CXCR4 expression with clinicopathological features and prognosis in OS.

Methods: Literature searches on Pubmed, Cochrane Library, and Web of Science were conducted systematically up to December 2021 to find relevant references. The effects of CXCR4 expression on clinicopathological characteristics and prognostic were …

Terminase Subunits From The Pseudomonas-Phage E217, Ravi K Lokareddy, Chun-Feng David Hou, Steven G Doll, Fenglin Li, Richard E Gillilan, Francesca Forti, David S Horner, Federica Briani, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

Pseudomonas phages are increasingly important biomedicines for phage therapy, but little is known about how these viruses package DNA. This paper explores the terminase subunits from the Myoviridae E217, a Pseudomonas-phage used in an experimental cocktail to eradicate P. aeruginosa in vitro and in animal models. We identified the large (TerL) and small (TerS) terminase subunits in two genes ∼58 kbs away from each other in the E217 genome. TerL presents a classical two-domain architecture, consisting of an N-terminal ATPase and C-terminal nuclease domain arranged into a bean-shaped tertiary structure. A 2.05 Å crystal structure of the C-terminal domain revealed …

Structure Of The Pre-Mrna Leakage 39-Kda Protein Reveals A Single Domain Of Integrated Zf-C3hc And Rsm1 Modules, Hideharu Hashimoto, Daniel H. Ramirez, Ophélie Lautier, Natalie Pawlak, Günter Blobel, Benoît Palancade, Erik W. Debler

Department of Biochemistry and Molecular Biology Faculty Papers

In Saccharomyces cerevisiae, the pre-mRNA leakage 39-kDa protein (ScPml39) was reported to retain unspliced pre-mRNA prior to export through nuclear pore complexes (NPCs). Pml39 homologs outside the Saccharomycetaceae family are currently unknown, and mechanistic insight into Pml39 function is lacking. Here we determined the crystal structure of ScPml39 at 2.5 Å resolution to facilitate the discovery of orthologs beyond Saccharomycetaceae, e.g. in Schizosaccharomyces pombe or human. The crystal structure revealed integrated zf-C3HC and Rsm1 modules, which are tightly associated through a hydrophobic interface to form a single domain. Both zf-C3HC and Rsm1 modules belong to the Zn-containing BIR (Baculovirus IAP …

Effects Of Cannabinoids On Ligand-Gated Ion Channels, Murat Oz, Keun-Hang Susan Yang, Mohamed Omer Mahgoub

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Phytocannabinoids such as Δ⁹-tetrahydrocannabinol and cannabidiol, endocannabinoids such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and synthetic cannabinoids such as CP47,497 and JWH-018 constitute major groups of structurally diverse cannabinoids. Along with these cannabinoids, CB1 and CB2 cannabinoid receptors and enzymes involved in synthesis and degradation of endocannabinoids comprise the major components of the cannabinoid system. Although, cannabinoid receptors are known to be involved in anti-convulsant, anti-nociceptive, anti-psychotic, anti-emetic, and anti-oxidant effects of cannabinoids, in recent years, an increasing number of studies suggest that, at pharmacologically relevant concentrations, these compounds interact with several molecular targets including G-protein coupled receptors, ion …

Novel Varienta Related To Protein S And Folate Deficiency In A Female Patient, Alaa Malik, Diana Polania-Villanueva, Manoj Kumar, Jone Garai, Jovanny Zabaleta, Rinku Majumder

Medical Research Day

Protein S (PS) is a multifunctional protein that exists in a free and bound form in plasma. The free form of PS acts as an anticoagulant in plasma. Traditionally, PS’s role in coagulation is described as a cofactor for Activated Protein C (APC) or Tissue Factor Pathway Inhibitor (TFPI). Both pathways result in decreased thrombin generation and ultimately reduced fibrin formation. Recently, it has been discovered that PS directly inhibits Factor IXa (FIXa), and thereby directly reduces thrombin generation. PS deficiency is a life-threatening condition that can result in an increased risk for developing disseminated intravascular coagulation or venous thromboembolism …

The Effects Of Obesity And Estrogen Based Contraceptive Use On Protein S Levels And Clotting Function In Pre-Menopausal Women, Daniel Ruppert, Alaa Malik, Manoj Kumar, Rinku Majumder

Medical Research Day

Protein S (PS) is an essential natural anticoagulant whose deficiency is a major contributor to acquired hypercoagulability [1]. Acquired hypercoagulability causes myocardial infarction, stroke, and deep vein thrombosis in millions of individuals [2]. Many factors affect plasma PS level; most prominently, the female hormone estrogen alters PS level by suppressing PS gene transcription via the estrogen receptor α (ERα) [3]. Thus, women who use estrogen-based oral contraceptive agents (OCA) experience a decrease in PS level. This contraceptive-induced PS decrease enhances the risk of thrombosis by 3-fold (4). Decreased plasma PS is also associated with obesity; obesity elevates the risk of …

Viral Small Terminase: A Divergent Structural Framework For A Conserved Biological Function., Ravi K. Lokareddy, Chun-Feng David Hou, Fenglin Li, Ruoyu Yang, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

The genome packaging motor of bacteriophages and herpesviruses is built by two terminase subunits, known as large (TerL) and small (TerS), both essential for viral genome packaging. TerL structure, composition, and assembly to an empty capsid, as well as the mechanisms of ATP-dependent DNA packaging, have been studied in depth, shedding light on the chemo-mechanical coupling between ATP hydrolysis and DNA translocation. Instead, significantly less is known about the small terminase subunit, TerS, which is dispensable or even inhibitory in vitro, but essential in vivo. By taking advantage of the recent revolution in cryo-electron microscopy (cryo-EM) and building upon a …

The Role Of Ubiquitination In Spinal And Bulbar Muscular Atrophy, Medha Sengupta, Anna Pluciennik, Diane E. Merry

Department of Biochemistry and Molecular Biology Faculty Papers

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative and neuromuscular genetic disease caused by the expansion of a polyglutamine-encoding CAG tract in the androgen receptor (AR) gene. The AR is an important transcriptional regulator of the nuclear hormone receptor superfamily; its levels are regulated in many ways including by ubiquitin-dependent degradation. Ubiquitination is a post-translational modification (PTM) which plays a key role in both AR transcriptional activity and its degradation. Moreover, the ubiquitin-proteasome system (UPS) is a fundamental component of cellular functioning and has been implicated in diseases of protein misfolding and aggregation, including polyglutamine (polyQ) repeat expansion diseases …

Young Transposable Elements Rewired Gene Regulatory Networks In Human And Chimpanzee Hippocampal Intermediate Progenitors, Sruti Patoori, Samantha M Barnada, Christopher Large, John I Murray, Marco Trizzino

Department of Biochemistry and Molecular Biology Faculty Papers

The hippocampus is associated with essential brain functions, such as learning and memory. Human hippocampal volume is significantly greater than expected compared with that of non-human apes, suggesting a recent expansion. Intermediate progenitors, which are able to undergo multiple rounds of proliferative division before a final neurogenic division, may have played a role in evolutionary hippocampal expansion. To investigate the evolution of gene regulatory networks underpinning hippocampal neurogenesis in apes, we leveraged the differentiation of human and chimpanzee induced pluripotent stem cells into TBR2 (or EOMES)-positive hippocampal intermediate progenitor cells (hpIPCs). We found that the gene networks active in hpIPCs …

Enhanced Membrane Binding Of Oncogenic G Protein Αqq209l Confers Resistance To Inhibitor Ym-254890, Clinita E. Randolph, Morgan B. Dwyer, Jenna L. Aumiller, Alethia J. Dixon, Asuka Inoue, Patrick Osei-Owusu, Philip B. Wedegaertner

Department of Biochemistry and Molecular Biology Faculty Papers

Heterotrimeric G proteins couple activated G protein-coupled receptors (GPCRs) to intracellular signaling pathways. They can also function independently of GPCR activation upon acquiring mutations that prevent GTPase activity and result in constitutive signaling, as occurs with the αqQ209L mutation in uveal melanoma. YM-254890 (YM) can inhibit signaling by both GPCR-activated WT αq and GPCR-independent αqQ209L. Although YM inhibits WT αq by binding to αq-GDP and preventing GDP/GTP exchange, the mechanism of YM inhibition of cellular αqQ209L remains to be fully understood. Here, we show that YM promotes a subcellular redistribution of αqQ209L from the plasma membrane (PM) to the cytoplasm. …

Isc10, An Inhibitor Of The Smk1 Mapk, Prevents Activation Loop Autophosphorylation And Substrate Phosphorylation Through Separate Mechanisms, Abhimannyu Rimal, Thomas M Swayne, Zeal P Kamdar, Madison A Tewey, Edward Winter

Department of Biochemistry and Molecular Biology Faculty Papers

Many eukaryotic protein kinases are activated by the intramolecular autophosphorylation of activation loop residues. Smk1 is a meiosis-specific mitogen-activated protein kinase (MAPK) in yeast that autophosphorylates its activation loop tyrosine and thereby upregulates catalytic output. This reaction is controlled by an inhibitor, Isc10, that binds the MAPK during meiosis I and an activator, Ssp2, that binds Smk1/Isc10 during meiosis II. Upon completion of the meiotic divisions, Isc10 is degraded, and Smk1 undergoes autophosphorylation to generate the high activity form of the MAPK that controls spore formation. How Isc10 inhibits Smk1 is not clear. Here, we use a bacterial coexpression/reconstitution system …

G Protein-Coupled Receptor Kinase 6 (Grk6) Regulates Insulin Processing And Secretion Via Effects On Proinsulin Conversion To Insulin, Matthew J Varney, Wouter Steyaert, Paul J Coucke, Joris R Delanghe, David E Uehling, Babu Joseph, Richard Marcellus, Rima Al-Awar, Jeffrey L Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

Recent studies identified a missense mutation in the gene coding for G protein-coupled receptor kinase 6 (GRK6) that segregates with type 2 diabetes (T2D). To better understand how GRK6 might be involved in T2D, we used pharmacological inhibition and genetic knockdown in the mouse β-cell line, MIN6, to determine whether GRK6 regulates insulin dynamics. We show inhibition of GRK5 and GRK6 increased insulin secretion but reduced insulin processing while GRK6 knockdown revealed these same processing defects with reduced levels of cellular insulin. GRK6 knockdown cells also had attenuated insulin secretion but enhanced proinsulin secretion consistent with decreased processing. In support …

The Pro-Fibrotic Response To Lens Injury Is Signaled In A Pi3k Isoform-Specific Manner, A. Sue Menko, Janice L. Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The signaling inputs that function to integrate biochemical and mechanical cues from the extracellular environment to alter the wound-repair outcome to a fibrotic response remain poorly understood. Here, using a clinically relevant post-cataract surgery wound healing/fibrosis model, we investigated the role of Phosphoinositide-3-kinase (PI3K) class I isoforms as potential signaling integrators to promote the proliferation, emergence and persistence of collagen I-producing alpha smooth muscle actin (αSMA+) myofibroblasts that cause organ fibrosis. Using PI3K isoform specific small molecule inhibitors, our studies revealed a requisite role for PI3K p110α in signaling the CD44+ mesenchymal leader cell population that we previously identified as …

Mistranslating Trnas Alter The Heat Shock Activation By Hsf1, Rebecca Dib

Undergraduate Student Research Internships Conference

Translation, or the production of protein from an mRNA blueprint, is among the most fundamental processes to life as we know it. tRNAs are essential to accurate translation, as they decode the codons of mRNA and recruit corresponding amino acids. Variant tRNAs with anticodon mutations can decrease translational fidelity by recruiting the incorrect amino acid, an aberrant process known as mistranslation. When proteins are produced with incorrect amino acid sequences, they may misfold. The heat shock response functions to alleviate cellular stress caused by misfolded proteins, either by refolding or targeting misfolded proteins for degradation. Hsf1 acts as a transcriptional …

The Effect Of Type 1 Diabetes On The Metabolic Response To Exercise, Theres Tijo

Undergraduate Student Research Internships Conference

Type 1 Diabetes Mellitus (T1DM) is an autoimmune disorder that results in insufficient endogenous insulin production. Regular exercise has numerous health benefits for individuals with T1DM, however, most insulin-dependent diabetics avoid physical activity due to the fear of exercise-induced hypoglycemia (low blood glucose/BG).

The risk of hypoglycemia in this population may be partly due to lower liver glycogen stores which is a major source of blood glucose during exercise. However, the mechanism that leads to lower glycogen stores in T1DM is unknown.

The purpose of this study was to determine the effect of an acute bout of moderate-intensity aerobic exercise …

Subtype-Selective Positive Modulation Of KCa2.3 Channels Increases Cilia Length, Young-Woo Nam, Rajasekharreddy Pala, Naglaa Salem El-Sayed, Denisse Laren-Henriquez, Farideh Amirrad, Grace Yang, Mohammad Asikur Rahman, Razan Orfali, Myles Downey, Keykavous Parang, Surya M. Nauli, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca²⁺-activated potassium (K_Ca2.x) channels are gated exclusively by intracellular Ca²⁺. The activation of K_Ca2.3 channels induces hyperpolarization, which augments Ca²⁺ signaling in endothelial cells. Cilia are specialized Ca²⁺ signaling compartments. Here, we identified compound 4 that potentiates human K_Ca2.3 channels selectively. The subtype selectivity of compound 4 for human K_Ca2.3 over rat K_Ca2.2a channels relies on an isoleucine residue in the HA/HB helices. Positive modulation of K_Ca2.3 channels by compound 4 increased flow-induced Ca²⁺ signaling and cilia length, while negative …

Screening Tcf19 And Kif18b To Determine Co-Regulation With Mybl1 In Triple Negative Breast Cancer Patient Tissues, Tyra Sharda Ivory

Theses (2016-Present)

The aggressive behavior in triple-negative breast cancer (TNBC) is due to genetic signaling events, which call for the comprehensive analyses of genes differentially regulated in the cancers. Our laboratory previously found that MYBL1 was over-expressed in a fraction of the TNBC, compared to some luminal, and other breast cancer subtypes. The MYBL1 gene is a proto-oncogene that serves as a strong transcriptional activator. The gene is involved in signaling events related to cell cycle signaling, differentiation, proliferation, and apoptosis, all which are differentially regulated in cancers. Because MYBL1 is a transcription regulator, involved in cancer-related mechanisms and differentially expressed in …

Glucose Uptake By Glut1 In Photoreceptors Is Essential For Outer Segment Renewal And Rod Photoreceptor Survival, Lauren L. Daniele, John Y.S. Han, Ivy S Samuels, Ravikiran Komirisetty, Nikhil Mehta, Jessica L Mccord, Minzhong Yu, Yekai Wang, Kathleen Boesze-Battaglia, Brent A Bell, Jianhai Du, Neal S Peachey, Nancy J. Philp

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Photoreceptors consume glucose supplied by the choriocapillaris to support phototransduction and outer segment (OS) renewal. Reduced glucose supply underlies photoreceptor cell death in inherited retinal degeneration and age-related retinal disease. We have previously shown that restricting glucose transport into the outer retina by conditional deletion of Slc2a1 encoding GLUT1 resulted in photoreceptor loss and impaired OS renewal. However, retinal neurons, glia, and the retinal pigment epithelium play specialized, synergistic roles in metabolite supply and exchange, and the cell-specific map of glucose uptake and utilization in the retina is incomplete. In these studies, we conditionally deleted Slc2a1 in a pan-retinal or …

Synthesis And Evaluation Of Anti-Hiv Activity Of Mono- And Di-Substituted Phosphonamidate Conjugates Of Tenofovir, Aaminat Qureshi, Louise A. Ouattara, Naglaa Salem El-Sayed, Amita Verma, Gustavo F. Doncel, Muhammad Iqbal Choudhary, Hina Siddiqui, Keykavous Parang

Pharmacy Faculty Articles and Research

The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the conjugation or combination of the lipophilic amide bond with nucleotide-based tenofovir (TFV) (1) could improve the anti-HIV activity. During the current study, the hydroxyl group of phosphonates in TFV was conjugated with the amino group of L-alanine, L-leucine, L-valine, and glycine amino acids and other long fatty ester hydrocarbon chains to synthesize 43 derivatives. Several …