Gary Weisman | University of Missouri Columbia (original) (raw)

Papers by Gary Weisman

Frontiers in Bioengineering and Biotechnology, Jul 21, 2021

Annually, >600,000 new cases of head and neck cancer (HNC) are diagnosed worldwide with primary t... more Annually, >600,000 new cases of head and neck cancer (HNC) are diagnosed worldwide with primary treatment being surgery and radiotherapy. During ionizing radiation (IR) treatment of HNC, healthy salivary glands are collaterally damaged, leading to loss of function that severely diminishes the quality of life for patients due to increased health complications, including oral infections and sores, cavities, and malnutrition, among others. Therapies for salivary hypofunction are ineffective and largely palliative, indicating a need for further research to uncover effective approaches to prevent or restore loss of salivary gland function following radiotherapy. Previous work in our lab implicated prostaglandin E 2 (PGE 2) as an inflammatory mediator whose release from radiation-exposed cells promotes salivary gland damage and loss of function. Deletion of the P2X7 purinergic receptor for extracellular ATP reduces PGE 2 secretion in irradiated primary parotid gland cells, and salivary gland function is enhanced in irradiated P2X7R −/− mice compared to wild-type mice. However, the role of PGE 2 signaling in irradiated salivary glands is unclear and understanding the mechanism of PGE 2 action is a goal of this study. Results show that treatment of irradiated mice with the non-steroidal anti-inflammatory drug (NSAID) indomethacin, which reduces PGE 2 production via inhibition of cyclooxygenase-1 (COX-1), improves salivary gland function compared to irradiated vehicle-treated mice. To define the signaling pathway whereby PGE 2 induces salivary gland dysfunction, primary parotid gland cells treated with PGE 2 have increased c-Jun N-terminal Kinase (JNK) activation and cell proliferation and reduced amylase levels and store-operated calcium entry (SOCE). The in vivo effects of blocking PGE 2 production were also examined and irradiated mice receiving indomethacin injections have reduced JNK activity at 8 days post-irradiation and reduced proliferation and increased amylase levels at day 30, as compared to irradiated mice without indomethacin. Combined, these data suggest a mechanism whereby irradiation-induced PGE 2 signaling to JNK blocks critical steps in saliva secretion

Investigative Opthalmology & Visual Science

Journal of Molecular and Cellular Cardiology, 1998

Computational and Structural Biotechnology Journal, 2021

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections remain unmanageable in so... more Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections remain unmanageable in some parts of the world. As with other RNA viruses, mutations in the SARS-CoV-2 gene have been continuously evolving. Recently, four variants have been identified, B.1.1.7, B.1.351, P.1 and CAL.20C. These variants appear to be more infectious and transmissible than the original Wuhan-Hu-1 virus. Using a combination of bioinformatics and structural analyses, we show that the new SARS-CoV-2 variants emerged in the background of an already known Spike protein mutation D614G together with another mutation P323L in the RNA polymerase of SARS-CoV-2. The phylogenetic analysis showed that the CAL.20C and B.1.351 shared one common ancestor, whereas the B.1.1.7 and P.1 shared a different ancestor. Structural comparisons did not show any significant difference between the wild-type and mutant ACE2/Spike complexes. Structural analysis indicated that the N501Y mutation may increase hydrophobic interactions at the ACE2/Spike interface. However, reported greater binding affinity of N501Y Spike with ACE2 does not seem to be entirely due to increased hydrophobic interactions, given that Spike mutation R417T in P.1 or K417N in B.1.351 results in the loss of a salt-bridge interaction between ACE2 and S-RBD. The calculated change in free energy did not provide a clear trend of S protein stability of mutations in the variants. As expected, we show that the CAL.20C generally migrated from the west coast to the east coast of the USA. Taken together, the analyses suggest that the evolution of variants and their infectivity is complex and may depend upon many factors.

ImmunoHorizons, 2018

CD40/CD40L interactions play a critical role in immunity and autoimmunity. In this study, we soug... more CD40/CD40L interactions play a critical role in immunity and autoimmunity. In this study, we sought to understand the requirement for CD40 signaling in the programmed cell death-1 (PD-1) checkpoint and CD28 costimulatory pathways important for maintenance of peripheral tolerance. Blocking either pathway can result in loss of self-tolerance and development of autoimmunity. We found that primary Sjögren’s syndrome (pSS) and autoimmune thyroid diseases (ATDs) that develop spontaneously in CD28-deficient IFN-γ−/− NOD.H-2h4 (CD28−/−) mice required CD40 signaling. Specifically, blockade of CD40L with the anti-CD40L mAb, MR1, inhibited autoantibody production and inflammation in thyroid and salivary gland target tissues. Unexpectedly, however, ATD and pSS in PD-1–deficient IFN-γ−/− NOD.H-2h4 (PD-1−/−) mice developed independently of CD40/CD40L interactions. Treatment with MR1 had no effect and even exacerbated disease development in pSS and ATD, respectively. Most interesting, anti-thyrogl...

Purinergic Signalling, 2015

Journal of Biological Chemistry, 1998

The FASEB Journal

Extracellular nucleotides exert various effects in the cardiovascular system. Uridine 5′‐triphosp... more Extracellular nucleotides exert various effects in the cardiovascular system. Uridine 5′‐triphosphate (UTP) regulates G‐protein‐coupled P2Y2 receptor (P2Y2R) activation which causes actin cytoskeletal reorganization. We isolated aortic smooth muscle cells (SMC) from wild‐type (WT) and P2Y2R−/− mice to investigate whether UTP and the P2Y2R modulate expression of low density lipoprotein receptor‐related protein 1 (LRP1) and low density lipoprotein receptor (LDLR). For LRP1 expression, cells were stimulated in the presence or absence of 100 μM UTP overnight. For LDLR mRNA expression, cells were transiently transfected for 24 h with cDNA encoding a hemagglutinin‐tagged WT P2Y2R or a mutant P2Y2R that does not bind filamin‐A (FLN‐A) and treated with 100 μM UTP overnight. Total RNA was isolated, reversed transcribed to cDNA, and mRNA abundance determined by RT‐PCR using the ΔCt method with GAPDH as a control gene. Results show SMC expressing the P2Y2R that lacks the FLN‐A binding domain e...

Extracellular nucleotides exert a large num- ber of physiological effects through activation of P... more Extracellular nucleotides exert a large num- ber of physiological effects through activation of P2Y re- ceptors. We expressed rat P2Y2 (rP2Y2) receptor, tagged with green fluorescent protein (GFP) in HEK-293 cells and visualized receptor translocation in live cells by confocal microscopy. Functional receptor expression was confirmed by determining (Ca 2+ )i responses. Agonist stimulation caused a time-dependent translocation of the receptor from the plasma membrane to the cytoplasm. Rearrangement of the actin cytoskeleton was observed during agonist-mediated rP2Y2-GFP receptor internal-

IUPHAR/BPS guide to pharmacology CITE, Sep 16, 2019

P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5]) are ... more P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned receptors to endogenously expressed receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y receptor' or 'P2Y 1-like', etc., until further, as yet undefined, corroborative criteria can be applied [46, 109, 187, 375, 388]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y 2 receptor subtype, approved in Japan for the management of dry eye disease [ 236], and the P2Y 12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [ 52, 316]. Contents This is a citation summary for P2Y receptors in the Guide to Pharmacology database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analyzers. Readers will almost certainly want to visit the relevant sections of the database which are given here under database links. GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

IUPHAR/BPS guide to pharmacology CITE, Apr 26, 2023

P2Y receptors (nomenclature as agreed by the nomenclature as agreed by the NC-IUPHAR NC-IUPHAR Su... more P2Y receptors (nomenclature as agreed by the nomenclature as agreed by the NC-IUPHAR NC-IUPHAR Subcommittee on P2Y Receptors [ Subcommittee on P2Y Receptors [3 3, , 5 5, , 189 189] ]) are activated by the endogenous ligands ATP, ADP, UTP, UDP, UDP-glucose and adenosine. The eight mammalian P2Y receptors are activated by distinct nucleotides: P2Y 1 , P2Y 11 , P2Y 12 and P2Y 13 are activated by adenosine-nucleotides; P2Y 2 , P2Y 4 can be activated by both adenosine and uridine nucleotides, with some species-specific differences; P2Y 6 is mainly activated by UDP; P2Y 14 is preferentially activated by sugaruracil nucleotides. The missing numbers in the receptor nomenclature refer either to non-mammalian orthologs or receptors having some sequence homology to P2Y receptors but for which there is no functional evidence of responsiveness to nucleotides [380]. Based on their G protein coupling P2Y receptors can be divided into two subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 and P2Y 11 receptors couple via Gq proteins to stimulate phospholipase C followed by increases in inositol phosphates and mobilization of Ca 2+ from intracellular stores. P2Y 11 receptors couple in addition to Gs proteins followed by increased adenylate cyclase activity. In contrast, P2Y 12 , P2Y 13 , and P2Y 14 receptors signal primarily through activation of Gi proteins and inhibition of adenylate cyclase activity or control of ion channel activity [380]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y 2 receptor subtype, approved in Japan and South Korea for the management of dry eye disease [238], and the P2Y 12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 320]. Contents Contents This is a citation summary for P2Y receptors in the Guide to Pharmacology database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analyzers. Readers will almost certainly want to visit the relevant sections of the database which are given here under database links. GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [44]. Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version.

IUPHAR/BPS guide to pharmacology CITE, Sep 2, 2021

P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5, 192])... more P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5, 192]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned receptors to endogenously expressed receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y receptor' or 'P2Y 1-like', etc., until further, as yet undefined, corroborative criteria can be applied [47, 110, 190, 383, 396]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y 2 receptor subtype, approved in Japan for the management of dry eye disease [241], and the P2Y 12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [53, 323]. Contents This is a citation summary for P2Y receptors in the Guide to Pharmacology database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analyzers. Readers will almost certainly want to visit the relevant sections of the database which are given here under database links. GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [44]. Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

The FASEB Journal, Apr 1, 2015

Global spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has triggered unpre... more Global spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has triggered unprecedented scientific efforts, as well as containment and treatment measures. Despite these efforts, SARS-CoV-2 infections remain unmanageable in some parts of the world. Due to inherent mutability of RNA viruses, it is not surprising that the SARS-CoV-2 genome has been continuously evolving since its emergence. Recently, four functionally distinct variants, B.1.1.7, B.1.351, P.1 and CAL.20C, have been identified, and they appear to more infectious and transmissible than the original (Wuhan-Hu-1) virus. Here we provide evidence based upon a combination of bioinformatics and structural approaches that can explain the higher infectivity of the new variants. Our results show that the greater infectivity of SARS-CoV-2 than SARS-CoV can be attributed to a combination of several factors, including alternate receptors. Additionally, we show that new SARS-CoV-2 variants emerged in the background o...

Oral Oncology, 2020

To assess functional expression of the P2Y 2 nucleotide receptor (P2Y 2 R) in head and neck squam... more To assess functional expression of the P2Y 2 nucleotide receptor (P2Y 2 R) in head and neck squamous cell carcinoma (HNSCC) cell lines and define its role in nucleotide-induced epidermal growth factor receptor (EGFR) transactivation. The use of anti-EGFR therapeutics to treat HNSCC is hindered by intrinsic and acquired drug resistance. Defining novel pathways that modulate EGFR signaling could identify additional targets to treat HNSCC. Materials and Methods: In human HNSCC cell lines CAL27 and FaDu and the mouse oral cancer cell line MOC2, P2Y 2 R contributions to extracellular nucleotide-induced changes in intracellular free Ca 2+ concentration and EGFR and extracellular signal-regulated kinase (ERK1/2) phosphorylation were determined using the ratiometric Ca 2+ indicator fura-2 and immunoblot analysis, respectively. Genetic knockout of P2Y 2 Rs using CRISPR technology or pharmacological inhibition with P2Y 2 R-selective antagonist AR-C118925 defined P2Y 2 R contributions to in vivo tumor growth. Results: P2Y 2 R agonists UTP and ATP increased intracellular Ca 2+ levels and ERK1/2 and EGFR phosphorylation in CAL27 and FaDu cells, responses that were inhibited by AR-C118925 or P2Y 2 R knockout. P2Y 2 R-mediated EGFR phosphorylation was also attenuated by inhibition of the adamalysin family of metalloproteases or Src family kinases. P2Y 2 R knockout reduced UTP-induced CAL27 cell proliferation in vitro and significantly reduced CAL27 and FaDu tumor xenograft volume in vivo. In a syngeneic mouse model of oral cancer, AR-C118925 administration reduced MOC2 tumor volume. Conclusion: P2Y 2 Rs mediate HNSCC cell responses to extracellular nucleotides and genetic or pharmacological blockade of P2Y 2 R signaling attenuates tumor cell proliferation and tumorigenesis, suggesting that the P2Y 2 R represents a novel therapeutic target in HNSCC.

Biochemical Pharmacology, 2021

Purinergic receptors for extracellular nucleotides and nucleosides contribute to a vast array of ... more Purinergic receptors for extracellular nucleotides and nucleosides contribute to a vast array of cellular and tissue functions, including cell proliferation, intracellular and transmembrane ion flux, immunomodulation and thrombosis. In mammals, the purinergic receptor system is composed of G protein-coupled P1 receptors A1, A2A, A2B and A3 for extracellular adenosine, P2X1-7 receptors that are ATP-gated ion channels and G protein-coupled P2Y1,2,4,6,11,12,13 and 14 receptors for extracellular ATP, ADP, UTP, UDP and/or UDP-glucose. Recent studies have implicated specific P2Y receptor subtypes in numerous oncogenic processes, including cancer tumorigenesis, metastasis and chemotherapeutic drug resistance, where G protein-mediated signaling cascades modulate intracellular ion concentrations and activate downstream protein kinases, Src family kinases as well as numerous mitogen-activated protein kinases. We are honored to contribute to this special issue dedicated to the founder of the field of purinergic signaling, Dr. Geoffrey Burnstock, by reviewing the diverse roles of P2Y receptors in the initiation, progression and metastasis of specific cancers with an emphasis on pharmacological and genetic strategies employed to delineate cell-specific and P2Y receptor subtype-specific responses that have been investigated using in vitro and in vivo cancer models. We further highlight bioinformatic and empirical evidence on P2Y receptor expression in human clinical specimens and cover clinical perspectives where P2Y receptor-targeting interventions may have therapeutic relevance to cancer treatment.