Medicinal and Pharmaceutical Chemistry Commons^™

A Novel Micropeptide, Slitharin, Exerts Cardioprotective Effects In Myocardial Infarction, Ahmed G. E. Ibrahim, Alessandra Ciullo, Shukuro Yamaguchi, Chang Li, Travis Antes, Xaviar Jones, Liang Li, Ramachandran Murali, Innokentiy Maslennikov, Niveda Sundararaman, Daniel Soetkamp, Eugenio Cingolani, Jennifer Van Eyk, Eduardo Marbán

Pharmacy Faculty Articles and Research

Purpose: Micropeptides are an emerging class of proteins that play critical roles in cell signaling. Here, we describe the discovery of a novel micropeptide, dubbed slitharin (Slt), in conditioned media from Cardiosphere-derived cells (CDCs), a therapeutic cardiac stromal cell type.

Experimental design: We performed mass spectrometry of peptide-enriched fractions from the conditioned media of CDCs and a therapeutically inert cell type (human dermal fibrobasts). We then evaluated the therapeutic capacity of the candidate peptide using an in vitro model of cardiomyocyte injury and a rat model of myocardial infarction.

Results: We identified a novel 24-amino acid micropeptide …

Oxidative Stress And Ion Channels In Neurodegenerative Diseases, Razan Orfali, Adnan Z. Alwatban, Rawan S. Orfali, Liz Lau, Noble Chea, Abdullah M. Alotaibi, Young-Woo Nam, Miao Zhang

Pharmacy Faculty Articles and Research

Numerous neurodegenerative diseases result from altered ion channel function and mutations. The intracellular redox status can significantly alter the gating characteristics of ion channels. Abundant neurodegenerative diseases associated with oxidative stress have been documented, including Parkinson’s, Alzheimer’s, spinocerebellar ataxia, amyotrophic lateral sclerosis, and Huntington’s disease. Reactive oxygen and nitrogen species compounds trigger posttranslational alterations that target specific sites within the subunits responsible for channel assembly. These alterations include the adjustment of cysteine residues through redox reactions induced by reactive oxygen species (ROS), nitration, and S-nitrosylation assisted by nitric oxide of tyrosine residues through peroxynitrite. Several ion channels have been directly …

Amphiphilic Cell-Penetrating Peptides Containing Arginine And Hydrophobic Residues As Protein Delivery Agents, Jonathan Moreno, Khalid Zoghebi, David Salehi, Lois Kim, Sorour Khayyatnejad Shoushtari, Rakesh K. Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

The entry of proteins through the cell membrane is challenging, thus limiting their use as potential therapeutics. Seven cell-penetrating peptides, designed in our laboratory, were evaluated for the delivery of proteins. Fmoc solid-phase peptide synthesis was utilized for the synthesis of seven cyclic or hybrid cyclic–linear amphiphilic peptides composed of hydrophobic (tryptophan (W) or 3,3-diphenylalanine (Dip) and positively-charged arginine (R) residues, such as [WR]4, [WR]9, [WWRR]4, [WWRR]5, [(RW)5K](RW)5, [R5K]W7, and [DipR]5. Confocal microscopy was used to screen the peptides as a protein delivery system of model cargo proteins, green and red fluorescein proteins (GFP and RFP). Based on the confocal …

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Agents, David Salehi, Saghar Mozaffari, Khalid Zoghebi, Sandeep Lohan, Dindyal Mandal, Rakesh Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

A series of cyclic peptides, [(DipR)(WR)₄], [(DipR)₂(WR)₃], [(DipR)₃(WR)₂], [(DipR)₄(WR)], and [DipR]₅, and their linear counterparts containing arginine (R) as positively charged residues and tryptophan (W) or diphenylalanine (Dip) as hydrophobic residues, were synthesized and evaluated for their molecular transporter efficiency. The in vitro cytotoxicity of the synthesized peptides was determined in human epithelial ovary adenocarcinoma cells (SK-OV-3), human lymphoblast peripheral blood cells (CCRF-CEM), human embryonic epithelial kidney healthy cells (HEK-293), human epithelial mammary gland adenocarcinoma cells (MDA-MB-468), pig epithelial kidney normal cells (LLC-PK1), and human epithelial …

Natural Phaeosphaeride A Derivatives Overcome Drug Resistance Of Tumor Cells And Modulate Signaling Pathways, Victoria Abzianidze, Natalia Moiseeva, Diana Suponina, Sofya Zakharenkova, Nadezhda Rogovskaya, Lidia Laletina, Alvin A. Holder, Denis Krivorotov, Alexander Bogachenkov, Alexander Garabadzhiu, Anton Ukolov, Vyacheslav Kosorukov

Chemistry & Biochemistry Faculty Publications

n the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds synthesized turned out to have better efficacy than PPA towards the tumor cell lines listed. Among them, three compounds exhibited an ability to overcome the drug resistance of tumor cells associated with the overexpression of the P-glycoprotein by modulating the work of this transporter. Luminex xMAP technology was used to assess the effect of five synthesized compounds …

Novel Biomarkers Of Ciliary Extracellular Vesicles Interact With Ciliopathy And Alzheimer’S Associated Proteins, Ashraf M. Mohieldin, Amal Alachkar, John R. Yates Iii, Surya M. Nauli

Pharmacy Faculty Articles and Research

Ciliary extracellular vesicles (ciEVs), released from primary cilia, contain functional proteins that play an important role in cilia structure and functions. We have recently shown that ciEVs and cytosolic extracellular vesicles (cyEVs) have unique and distinct biomarkers. While ciEV biomarkers have shown some interactions with known ciliary proteins, little is known about the interaction of ciEV proteins with proteins involved in ciliopathy and neurodegenerative disorders. Here, we reveal for the first time the protein-protein interaction (PPI) between the top five ciEVs biomarkers with ciliopathy and Alzheimer disease (AD) proteins. These results support the growing evidence of the critical physiological roles …

Physiological Roles Of Mammalian Transmembrane Adenylyl Cyclase Isoforms, Katrina F. Ostrom, Justin E. Lavigne, Tarsis F. Brust, Roland Seifert, Carmen Dessauer, Val J. Watts, Rennolds S. Ostrom

Pharmacy Faculty Articles and Research

Adenylyl cyclases (ACs) catalyze the conversion of ATP to the ubiquitous second messenger cAMP. Mammals possess nine isoforms of transmembrane ACs, dubbed AC1-9, that serve as major effector enzymes of G protein-coupled receptors. The transmembrane ACs display varying expression patterns across tissues, giving potential for them having a wide array of physiologic roles. Cells express multiple AC isoforms, implying that ACs have redundant functions. Furthermore, all transmembrane ACs are activated by Gα_s so it was long assumed that all ACs are activated by Gα_s-coupled GPCRs. AC isoforms partition to different microdomains of the plasma membrane and form …

A Comparison Of Calcium Aggregation And Ultracentrifugation Methods For The Preparation Of Rat Brain Microsomes For Drug Metabolism Studies, Barent N. Dubois, Farideh Amirrad, Reza Mehvar

Pharmacy Faculty Articles and Research

Preparation of brain microsomes by the calcium chloride aggregation method has been suggested as an alternative to the ultracentrifugation method. However, the effects of the calcium chloride concentration on the quality of the microsomal fractions are not known. Brain microsomes were prepared from the adult rat brains using the high-speed ultracentrifugation and low-speed calcium chloride (10–100 mM) aggregation methods (n = 5–6 per group). The microsomal protein yield (spectrometry), the cytochrome P450 reductase (CPR) activity (spectrometry), and the monooxygenase activities (UPLC-MS/MS) of CYP2D and CYP2E1 were determined in the obtained fractions. Increasing the concentrations of calcium chloride progressively increased …

Proteoglycan-4 Is An Essential Regulator Of Synovial Macrophage Polarization And Inflammatory Macrophage Joint Infiltration, Marwa Qadri, Gregory D. Jay, Ling X. Zhang, Tannin A. Schmidt, Jennifer Totonchy, Khaled A. Elsaid

Pharmacy Faculty Articles and Research

Background

Synovial macrophages perform a multitude of functions that include clearance of cell debris and foreign bodies, tissue immune surveillance, and resolution of inflammation. The functional diversity of macrophages is enabled by distinct subpopulations that express unique surface markers. Proteoglycan-4 (PRG4) is an important regulator of synovial hyperplasia and fibrotic remodeling, and the involvement of macrophages in PRG4’s synovial role is yet to be defined. Our objectives were to study the PRG4’s importance to macrophage homeostatic regulation in the synovium and infiltration of pro-inflammatory macrophages in acute synovitis and investigate whether macrophages mediated synovial fibrosis in Prg4 gene-trap (Prg4 …

Design And Application Of Hybrid Cyclic-Linear Peptide-Doxorubicin Conjugates As A Strategy To Overcome Doxorubicin Resistance And Toxicity, Saghar Mozaffari, David Salehi, Parvin Mahdipoor, Richard Beuttler, Rakesh Tiwari, Hamidreza Montazeri Aliabadi, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin (Dox) is used for breast cancer, leukemia, and lymphoma treatment as an effective chemotherapeutic agent. However, Dox use is restricted due to inherent and acquired resistance and an 8-fold increase in the risk of potentially fatal cardiotoxicity. Hybrid cyclic-linear peptide [R5K]W7A and linear peptide R5KW7A were conjugated with Dox through a glutarate linker to afford [R5K]W7A-Dox and R5KW7A-Dox conjugates to generate Dox derivatives. Alternatively, [R5K]W7C was conjugated with Dox via a disulfide linker to generate [R5K]W7C–S–S-Dox conjugate, where S–S is a disulfide bond. Comparative antiproliferative assays between conjugates [R5K]W7A-Dox, [R5K]W7C–S–S-Dox, linear R5KW7A-Dox, the corresponding physical mixtures of the peptides, …

Ciliary Extracellular Vesicles Are Distinct From The Cytosolic Extracellular Vesicles, Ashraf M. Mohieldin, Rajasekharreddy Pala, Richard Beuttler, James J. Moresco, John R. Yates Iii, Surya M. Nauli

Pharmacy Faculty Articles and Research

Extracellular vesicles (EVs) are cell‐derived membrane vesicles that are released into the extracellular space. EVs encapsulate key proteins and mediate intercellular signalling pathways. Recently, primary cilia have been shown to release EVs under fluid‐shear flow, but many proteins encapsulated in these vesicles have never been identified. Primary cilia are ubiquitous mechanosensory organelles that protrude from the apical surface of almost all human cells. Primary cilia also serve as compartments for signalling pathways, and their defects have been associated with a wide range of human genetic diseases called ciliopathies. To better understand the mechanism of ciliopathies, it is imperative to know …

Structural Characterization And In Vitro Lipid Binding Studies Of Non-Specific Lipid Transfer Protein 1 (Nsltp1) From Fennel (Foeniculum Vulgare) Seeds, Mekdes Megeressa, Bushra Siraj, Shamshad Zarina, Aftab Ahmed

Pharmacy Faculty Articles and Research

Non-specific lipid transfer proteins (nsLTPs) are cationic proteins involved in intracellular lipid shuttling in growth and reproduction, as well as in defense against pathogenic microbes. Even though the primary and spatial structures of some nsLTPs from different plants indicate their similar features, they exhibit distinct lipid-binding specificities signifying their various biological roles that dictate further structural study. The present study determined the complete amino acid sequence, in silico 3D structure modeling, and the antiproliferative activity of nsLTP1 from fennel (Foeniculum vulgare) seeds. Fennel is a member of the family Umbelliferae (Apiaceae) native to southern Europe and the Mediterranean …

Overcoming Barriers For Sirna Therapeutics: From Bench To Bedside, Muhammad Imran Sajid, Muhammad Moazzam, Shun Kato, Kayley Yeseom Cho, Rakesh Kumar Tiwari

Pharmacy Faculty Articles and Research

The RNA interference (RNAi) pathway possesses immense potential in silencing any gene in human cells. Small interfering RNA (siRNA) can efficiently trigger RNAi silencing of specific genes. FDA Approval of siRNA therapeutics in recent years garnered a new hope in siRNA therapeutics. However, their therapeutic use is limited by several challenges. siRNAs, being negatively charged, are membrane-impermeable and highly unstable in the systemic circulation. In this review, we have comprehensively discussed the extracellular barriers, including enzymatic degradation of siRNAs by serum endonucleases and RNAases, rapid renal clearance, membrane impermeability, and activation of the immune system. Besides, we have thoroughly described …

Click-Free Synthesis Of A Multivalent Tricyclic Peptide As A Molecular Transporter, Sumit Kumar, Dindyal Mandal, Shaima Ahmed El-Mowafi, Saghar Mozaffari, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

The cellular delivery of cell-impermeable and water-insoluble molecules remains an ongoing challenge to overcome. Previously, we reported amphipathic cyclic peptides c[WR]₄ and c[WR]₅ consisting of alternate arginine and tryptophan residues as nuclear-targeting molecular transporters. These peptides contain an optimal balance of positive charge and hydrophobicity, which is required for interactions with the phospholipid bilayer to facilitate their application as a drug delivery system. To further optimize them, we synthesized and evaluated a multivalent tricyclic peptide as an efficient molecular transporter. The monomeric cyclic peptide building blocks were synthesized using Fmoc/tBu solid-phase chemistry and cyclization in the …

Comparative Molecular Transporter Properties Of Cyclic Peptides Containing Tryptophan And Arginine Residues Formed Through Disulfide Cyclization, Eman H. M. Mohammed, Dindyal Mandal, Saghar Mozaffari, Magdy Abdel-Hamied Zahran, Amany Mostafa Osman, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

We have previously reported cyclic cell-penetrating peptides [WR]₅ and [WR]₄ as molecular transporters. To optimize further the utility of our developed peptides for targeted therapy in cancer cells using the redox condition, we designed a new generation of peptides and evaluated their cytotoxicity as well as uptake behavior against different cancer cell lines. Thus, cyclic [C(WR)_xC] and linear counterparts (C(WR)_xC), where x = 4–5, were synthesized using Fmoc/tBu solid-phase peptide synthesis, purified, and characterized. The compounds did not show any significant cytotoxicity (at 25 µM) against ovarian (SK-OV-3), leukemia (CCRF-CEM), gastric adenocarcinoma (CRL-1739), breast …

Recombinant Human Proteoglycan-4 Mediates Interleukin-6 Response In Both Human And Mouse Endothelial Cells Induced Into A Sepsis Phenotype, Holly A. Richendrfer, Mitchell M. Levy, Khaled A. Elsaid, Tannin A. Schmidt, Ling Zhang, Ralph Cabezas, Gregory D. Jay

Pharmacy Faculty Articles and Research

Objectives:

Sepsis is a leading cause of death in the United States. Putative targets to prevent systemic inflammatory response syndrome include antagonism of toll-like receptors 2 and 4 and CD44 receptors in vascular endothelial cells. Proteoglycan-4 is a mucinous glycoprotein that interacts with CD44 and toll-like receptor 4 resulting in a blockade of the NOD-like receptor pyrin domain-containing-3 pathway. We hypothesized that endothelial cells induced into a sepsis phenotype would have less interleukin-6 expression after recombinant human proteoglycan 4 treatment in vitro.

Design:

Enzyme-linked immunosorbent assay and reverse transcriptase-quantitative polymerase chain reaction to measure interleukin-6 protein and gene expression.

Setting: …

Sensory Primary Cilium Is A Responsive Camp Microdomain In Renal Epithelia, Rinzhin T. Sherpa, Ashraf M. Mohieldin, Rajasekharreddy Pala, Dagmar Wachten, Rennolds S. Ostrom, Surya M. Nauli

Pharmacy Faculty Articles and Research

Primary cilia are hair-like cellular extensions that sense microenvironmental signals surrounding cells. The role of adenylyl cyclases in ciliary function has been of interest because the product of adenylyl cyclase activity, cAMP, is relevant to cilia-related diseases. In the present study, we show that vasopressin receptor type-2 (V2R) is localized to cilia in kidney epithelial cells. Pharmacologic inhibition of V2R with tolvaptan increases ciliary length and mechanosensory function. Genetic knockdown of V2R, however, does not have any effect on ciliary length, although the effect of tolvaptan on ciliary length is dampened. Our study reveals that tolvaptan may have a cilia-specific …

Amphiphilic Peptides For Efficient Sirna Delivery, Saghar Mozaffari, Emira Bousoik, Farideh Amirrad, Robert Lamboy, Melissa Coyle, Ryley Hall, Abdulaziz Alasmari, Parvin Mahdipoor, Keykavous Parang, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

A number of amphiphilic cyclic peptides—[FR]4, [WR]5, and [WK]5—containing hydrophobic and positively-charged amino acids were synthesized by Fmoc/tBu solid-phase peptide methods and evaluated for their efficiency in intracellular delivery of siRNA to triple-negative breast cancer cell lines, MDA-MB-231 and MDA-MB-468, in the presence and absence of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Among the peptides, [WR]5, which contains alternate tryptophan (W) and arginine (R) residues, was found to be the most efficient in the delivery of siRNA by improving the delivery by more than 3-fold when compared to other synthesized cyclic peptides that were not efficient. The data also showed that co-formulation of [WR]5 …

Modulation Of Hypoxia-Induced Chemoresistance To Polymeric Micellar Cisplatin: The Effect Of Ligand Modification Of Micellar Carrier Versus Inhibition Of The Mediators Of Drug Resistance, Hoda Soleymani Abyaneh, Amir Hassan Soleimani, Mohammad Reza Vakili, Rania Soudy, Kamaljit Kaur, Francesco Cuda, Ali Tavassoli, Afsaneh Lavasanifar

Pharmacy Faculty Articles and Research

Hypoxia can induce chemoresistance, which is a significant clinical obstacle in cancer therapy. Here, we assessed development of hypoxia-induced chemoresistance (HICR) against free versus polymeric cisplatin micelles in a triple negative breast cancer cell line, MDA-MB-231. We then explored two strategies for the modulation of HICR against cisplatin micelles: a) the development of actively targeted micelles; and b) combination therapy with modulators of HICR in MDA-MB-231 cells. Actively targeted cisplatin micelles were prepared through surface modification of acetal-poly(ethylene oxide)-poly(-carboxyl-"-caprolactone) (acetal-PEO-PCCL) micelles with epidermal growth factor receptor (EGFR)-targeting peptide, GE11 (YHWYGYTPQNVI). Our results showed that hypoxia induced resistance against free and …

Uplc-Ms/Ms Analysis Of Dextromethorphan-O-Demethylation Kinetics In Rat Brain Microsomes, Barent N. Dubois, Reza Mehvar

Pharmacy Faculty Articles and Research

Formation of dextrorphan (DXT) from dextromethorphan (DXM) has been widely used to assess cytochrome P450 2D (CYP2D) activity. Additionally, the kinetics of CYP2D activity have been well characterized in the liver microsomes. However, studies in brain microsomes are limited due to the lower microsomal content and abundance of CYP2D in the brain relative to the liver. In the present study, we developed a micro-scale enzymatic incubation method, coupled with a sensitive UPLC-MS/MS assay for the quantitation of the rate of DXT formation from DXM in brain microsomes. Rat brain microsomes were incubated with different concentrations of DXM for various times. …

Astromimetics: The Dawn Of A New Era For (Bio)Materials Science?, Vuk Uskoković, Victoria M. Wu

Pharmacy Faculty Articles and Research

Composite, multifunctional fine particles are likely to be at the frontier of materials science in the foreseeable future. Here we present a submicron composite particle that mimics the stratified structure of the Earth by having a zero-valent iron core, a silicate/silicide mantle, and a thin carbonaceous crust resembling the biosphere and its biotic deposits. Particles were formulated in a stable colloidal form and made to interact with various types of healthy and cancer cells in vitro. A selective anticancer activity was observed, promising from the point of view of the intended use of the particles for tumor targeting across the …

A V-To-F Substitution In Sk2 Channels Causes Ca2+ Hypersensitivity And Improves Locomotion In A C. Elegans Als Model, Young-Woo Nam, Sabia N. Baskoylu, Dimitris Gazgalis, Razan Orfali, Meng Cui, Anne C. Hart, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca2+-activated K+ (SK) channels mediate medium afterhyperpolarization in the neurons and play a key role in the regulation of neuronal excitability. SK channels are potential drug targets for ataxia and Amyotrophic Lateral Sclerosis (ALS). SK channels are activated exclusively by the Ca2+-bound calmodulin. Previously, we identified an intrinsically disordered fragment that is essential for the mechanical coupling between Ca2+/calmodulin binding and channel opening. Here, we report that substitution of a valine to phenylalanine (V407F) in the intrinsically disordered fragment caused a ~6 fold increase in the Ca2+ sensitivity of SK2-a channels. This substitution resulted in a novel interaction between …

Pde8 Is Expressed In Human Airway Smooth Muscle And Selectively Regulates Camp Signaling By Β 2 Ar-Ac6, Timothy B. Johnstone, Kaitlyn H. Smith, Cynthia J. Koziol-White, Fengying Li, Austin G. Kazarian, Maia L. Corpuz, Maya Shumyachter, Frederick J. Ehlert, Bianca E. Himes, Reynold A. Pannettieri Jr., Rennolds S. Ostrom

Pharmacy Faculty Articles and Research

Two cAMP signaling compartments centering around adenylyl cyclase (AC) exist in human airway smooth muscle (HASM) cells, one containing ß2AR-AC6 and another containing E prostanoid receptors (EPR)-AC2. We hypothesized that different phosphodiesterase (PDE) isozymes selectively regulate cAMP signaling in each compartment. According to RNA-seq data, 18 of 24 PDE genes were expressed in primary HASM cells derived from age- and gender-matched donors with and without asthma. PDE8A was the third most abundant of the cAMP-degrading PDE genes, after PDE4A and PDE1A. Knockdown of PDE8A using shRNA evoked 2-fold greater cAMP responses to 1 DM forskolin in the presence of IBMX. …

Cyclic Peptide Conjugate Of Curcumin And Doxorubicin As An Anticancer Agent, Shaban Darwish, Saghar Mozaffari, Keykavous Parang, Rakesh Tiwari

Pharmacy Faculty Articles and Research

The hydrophobicity of curcumin creates hurdle towards its use in the anticancer therapy. Herein, we synthesized a curcumin-doxorubicin conjugated cyclic peptide scaffold to improve the solubility of curcumin and create a conjugate containing two anticancer agents. A solid-phase Fmoc/tBu solid phase methodology was used to synthesize a cell-penetrating nuclear targeting peptide with free thiol and amine groups, which was coupled with the activated doxorubicin (Dox) and curcumin, affording Dox-peptide-curcumin conjugate (DPCC) (10). The antiproliferative activity of the conjugate was evaluated in human leukemia carcinoma cell (CCRF-CEM), human ovarian carcinoma cell (SKOV-3), and normal kidney cell line (LLCPK). Cyclic peptide-doxorubicin conjugate …

Identification Of Potential Drug Targets In Cancer Signaling Pathways Using Stochastic Logical Models, Peican Zhu, Hamidreza Montazeri Aliabadi, Hasan Uludag, Jie Han

Pharmacy Faculty Articles and Research

The investigation of vulnerable components in a signaling pathway can contribute to development of drug therapy addressing aberrations in that pathway. Here, an original signaling pathway is derived from the published literature on breast cancer models. New stochastic logical models are then developed to analyze the vulnerability of the components in multiple signalling sub-pathways involved in this signaling cascade. The computational results are consistent with the experimental results, where the selected proteins were silenced using specific siRNAs and the viability of the cells were analyzed 72 hours after silencing. The genes elF4E and NFkB are found to have nearly no …

Menthol Binding And Inhibition Of A7-Nicotinic Acetylcholine Receptors, Abrar Ashoor, Jacob C. Nordman, Daniel Veltri, Keun-Hang Susan Yang, Lina T. Al Kury, Yaroslav M. Shuba, Mohamed Magoub, Frank Christopher Howarth, Bassem Sadek, Amarda Shehu, Nadine Kabbani, Murat Oz

Mathematics, Physics, and Computer Science Faculty Articles and Research

Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the α7 subunit of the nicotinic acetylcholine (nACh) receptor function. Using a two-electrode voltage-clamp technique, menthol was found to reversibly inhibit α7-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca2+-dependent Cl− channels, since menthol inhibition remained unchanged by intracellular injection of the Ca2+ chelator BAPTA and perfusion with Ca2+-free bathing solution containing …

Plant Lectin Can Target Receptors Containing Sialic Acid, Exemplified By Podoplanin, To Inhibit Transformed Cell Growth And Migration, Jhon Ochoa-Alvarez, Harini Krishnan, Yongquan Shen, Nimish Acharya, Min Han, Dean Mcnulty, Hitoki Hasegawa

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Cancer is a leading cause of death of men and women worldwide. Tumor cell motility contributes to metastatic invasion that causes the vast majority of cancer deaths. Extracellular receptors modified by α2,3-sialic acids that promote this motility can serve as ideal chemotherapeutic targets. For example, the extracellular domain of the mucin receptor podoplanin (PDPN) is highly O-glycosylated with α2,3-sialic acid linked to galactose. PDPN is activated by endogenous ligands to induce tumor cell motility and metastasis. Dietary lectins that target proteins containing α2,3-sialic acid inhibit tumor cell growth. However, anti-cancer lectins that have been examined thus far target receptors …

Different Requirements Of The Swi/Snf Complex For Robust Nucleosome Displacement At Promoters Of Heat Shock Factor And Msn2- And Msn4-Regulated Heat Shock Genes, Tamara Y. Erkina, P. A. Tschetter, Alexander M. Erkine

Scholarship and Professional Work – COPHS

The stress response in yeast cells is regulated by at least two classes of transcription activators—HSF and Msn2/4, which differentially affect promoter chromatin remodeling. We demonstrate that the deletion of SNF2, an ATPase activity-containing subunit of the chromatin remodeling SWI/SNF complex, eliminates histone displacement, RNA polymerase II recruitment, and heat shock factor (HSF) binding at the HSP12 promoter while delaying these processes at the HSP82 and SSA4 promoters. Out of the three promoters, the double deletion of MSN2 and MSN4 eliminates both chromatin remodeling and HSF binding only at the HSP12 promoter, suggesting that Msn2/4 activators are primary determinants of …