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Correcting Glucose-6-Phosphate Dehydrogenase Deficiency With A Small-Molecule Activator, Sunhee Hwang, Karen Mruk, Simin Rahighi, Andrew G. Raub, Che-Hong Chen, Lisa E. Dorn, Naoki Horikoshi, Soichi Wakatsuki, James K. Chen, Daria Mochly-Rosen 2018 Stanford University

Correcting Glucose-6-Phosphate Dehydrogenase Deficiency With A Small-Molecule Activator, Sunhee Hwang, Karen Mruk, Simin Rahighi, Andrew G. Raub, Che-Hong Chen, Lisa E. Dorn, Naoki Horikoshi, Soichi Wakatsuki, James K. Chen, Daria Mochly-Rosen

Pharmacy Faculty Articles and Research

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the ...


Oxcarbazepine Overdose In A Polysubstance Related Suicide, Melissa Beals, Robert J. Krumsick, C. Clinton Frazee III, Lindsey J. Haldiman, Uttam Garg 2018 Children's Mercy Hospital

Oxcarbazepine Overdose In A Polysubstance Related Suicide, Melissa Beals, Robert J. Krumsick, C. Clinton Frazee Iii, Lindsey J. Haldiman, Uttam Garg

Posters

Introduction
Oxcarbazepine is a derivative of carbamazepine that is used primarily in the treatment of epilepsy, and experimentally as a mood-stabilizer in adjunctive therapy for the treatment of bipolar disorder. Oxcarbazepine is converted through oxidation to its pharmacologically active metabolite 10-OH-Carbazepine, which is thought to be responsible for most of the anticonvulsant action of the drug. Adverse effects of oxcarbazepine are generally dose-dependent and may include fatigue, somnolence, dizziness, diplopia, nystagmus, and ataxia. Additive sedative effects have been noted when oxcarbazepine is used in combination with other CNS depressionproducing medications. Furthermore, oxcarbazepine and 10-OH-Carbazepine are powerful CYP2C19 inhibitors, potentially increasing ...


Pepducin-Mediated Cardioprotection Via Β-Arrestin-Biased Β2-Adrenergic Receptor-Specific Signaling, Laurel A. Grisanti, Toby P. Thomas, Rhonda L. Carter, Claudio de Lucia, Erhe Gao, Walter J. Koch, Jeffrey L. Benovic, Douglas G. Tilley 2018 University of Missouri

Pepducin-Mediated Cardioprotection Via Β-Arrestin-Biased Β2-Adrenergic Receptor-Specific Signaling, Laurel A. Grisanti, Toby P. Thomas, Rhonda L. Carter, Claudio De Lucia, Erhe Gao, Walter J. Koch, Jeffrey L. Benovic, Douglas G. Tilley

Department of Biochemistry and Molecular Biology Faculty Papers

Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death. β-arrestin (βarr)-biased β-adrenergic receptor (βAR) activation promotes survival signaling responses in vitro; thus, we hypothesize that this pathway can mitigate cardiomyocyte death at the time of reperfusion to better preserve function. However, a lack of efficacious βarr-biased orthosteric small molecules has prevented investigation into whether this pathway relays protection against ischemic injury in vivo. We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from the first intracellular loop of β2AR, allosterically engaged pro-survival signaling cascades in a βarr-dependent manner ...


Recombinant Human Proteoglycan-4 Reduces Phagocytosis Of Urate Crystals And Downstream Nuclear Factor Kappa B And Inflammasome Activation And Production Of Cytokines And Chemokines In Human And Murine Macrophages, Marwa Qadri, Gregory D. Jay, Ling X. Zhang, Wendy Wong, Anthony M. Reginato, Changqi Sun, Tannin A. Schmidt 2018 Chapman University

Recombinant Human Proteoglycan-4 Reduces Phagocytosis Of Urate Crystals And Downstream Nuclear Factor Kappa B And Inflammasome Activation And Production Of Cytokines And Chemokines In Human And Murine Macrophages, Marwa Qadri, Gregory D. Jay, Ling X. Zhang, Wendy Wong, Anthony M. Reginato, Changqi Sun, Tannin A. Schmidt

Pharmacy Faculty Articles and Research

Microbial biofilms are organized communities of cells that are associated with a wide spectrum of resistant and chronic infections that lead to the treatment failure. Accordingly, there is an urgent demand to create novel effective therapeutic drugs that can inhibit biofilm formation with new mechanisms of action to surmount the current escalating resistance. In this study, in silico hybrid model was utilized to develop three novel short linear peptides (4, 5, and 6) with potential biofilm inhibiting activities (scores > 1.0). The peptides were composed of cationic and hydrophobic residues. They were synthesized using solid-phase strategy. Synthesized peptides were purified ...


3d-Printed Fluidic Devices And Incorporated Graphite Electrodes For Electrochemical Immunoassay Of Biomarker Proteins, Abdulhameed Alabdulwaheed 2018 East Tennessee State University

3d-Printed Fluidic Devices And Incorporated Graphite Electrodes For Electrochemical Immunoassay Of Biomarker Proteins, Abdulhameed Alabdulwaheed

Electronic Theses and Dissertations

Biomarkers are measurable indicators of health status or disease state that can be used for diagnosis and may help guide patient treatment strategies. Enzyme-linked immunosorbent assays (ELISA) and other many clinical techniques currently used for measuring biomarker proteins lack sensitivity, demand high analysis cost, are often not well-suited for measuring multiple biomarkers in a single sample, and require long analysis times. Here, we demonstrate simple, low-cost 3D-printed flow-through devices with integrated electrodes modified with gold nanoparticles (AuNPs) for electrochemical immunoassays of S100B, a biomarker protein related to conditions like skin cancer and brain injuries. Flow-through devices are fabricated from photocurable-resin ...


Effects Of Eicosapentaenoic Acid (Epa) On Mouse Endothelial Cell Health, Spencer C. Pageau 2018 Grand Valley State University

Effects Of Eicosapentaenoic Acid (Epa) On Mouse Endothelial Cell Health, Spencer C. Pageau

Masters Theses

Cardiovascular disease is the number one killer of adults in the US (~800,000 lives every year:1 in 3 deaths). Evidence suggests omega-3 fatty acids like eicosapentaenoic acid (EPA), found in fish oils, reduce the risk of developing cardiovascular diseases. Many of these diseases are caused by atherosclerotic plaque development in vessels due to endothelial cell damage initiating inflammatory responses. Recent work argues omega-3 fatty acids stimulate anti-inflammatory responses by binding to Free Fatty Acid (FFA) receptors. Inflammatory responses in endothelial cells alter the expression of many proteins that affect the function of those cells. In particular, gap junction ...


Alpha-Amino Methylation And Acetylation Are Novel Regulators Of Myl9 Function., Christopher David Nevitt 2018 University of Louisville

Alpha-Amino Methylation And Acetylation Are Novel Regulators Of Myl9 Function., Christopher David Nevitt

Electronic Theses and Dissertations

Dysregulation of alpha-amino post-translational modifications (Nα-PTMs) is found in multiple cancers and developmental disorders. However, the exact roles Nα-PTMs play in regulating protein function remain poorly understood. I sought to clarify the role of Nα-methylation and Nα-acetylation in the regulation of Myosin Regulatory Light Chain 9 (MYL9). MYL9 is a key cytoskeletal regulator and transcription factor and is the first protein confirmed to undergo both Nα-methylation and Nα-acetylation. Through this work I revealed novel regulatory features of MYL9, while also presenting a framework by which to understand the coordinated regulation of proteins by Nα-methylation and Nα-acetylation. Nα-PTM selective mutants of ...


Developing Peptide Therapeutics That Inhibit Bacterial Toxins Utilizing A Cholesterol Recognition Amino Acid Consensus (Crac) Motif, Evan Koufos 2018 Lehigh University

Developing Peptide Therapeutics That Inhibit Bacterial Toxins Utilizing A Cholesterol Recognition Amino Acid Consensus (Crac) Motif, Evan Koufos

Theses and Dissertations

Treatment of bacterial illnesses has become increasingly difficult as the development of new antibiotics is being outpaced by the increasing number of antibiotic-resistant organisms. This has led us to search for alternative therapeutic approaches to help combat these illnesses. A viable approach in treating these illnesses is to focus on inhibiting protein toxins, which are one of the many virulence factors that bacteria secrete. Many toxins recognize and bind to cholesterol (Chol) on the host cell membrane as an initial step in their mechanism; however, a viable method of inhibiting this interaction has yet to be uncovered.For our model ...


Design, Synthesis, And Evaluation Of Homochiral Peptides Containing Arginine And Histidine As Molecular Transporters, Naglaa Salem El-Sayed, Taryn Miyake, Amir Nasrolahi Shirazi, Shang Eun Park, Jimmy Clark, Stephani Buchholz, Keykavous Parang, Rakesh Tiwari 2018 Chapman University

Design, Synthesis, And Evaluation Of Homochiral Peptides Containing Arginine And Histidine As Molecular Transporters, Naglaa Salem El-Sayed, Taryn Miyake, Amir Nasrolahi Shirazi, Shang Eun Park, Jimmy Clark, Stephani Buchholz, Keykavous Parang, Rakesh Tiwari

Pharmacy Faculty Articles and Research

Linear (HR)n and cyclic [HR]n peptides (n = 4,5) containing alternate arginine and histidine residues were synthesized. The peptides showed 0–15% cytotoxicity at 5–100 μM in human ovarian adenocarcinoma (SK-OV-3) cells while they exhibited 0–12% toxicity in human leukemia cancer cell line (CCRF-CEM). Among all peptides, cyclic [HR]4 peptide was able to improve the delivery of a cell impermeable fluorescence-labeled phosphopeptide by two-fold. Fatty acids of different alkyl chain length were attached at the N-terminal of the linear peptide (HR)4 to improve the molecular transporter property. Addition of fatty acyl chains was expected ...


Increased Heme-Oxygenase 1 Expression In Mesenchymal Stem Cell-Derived Adipocytes Decreases Differentiation And Lipid Accumulation Via Upregulation Of The Canonical Wnt Signaling Cascade, Luca Vanella, Komal Sodhi, Dong Hyun Kim, Nitin Puri, Mani Maheshwari, Terry D . Hinds, Lars Bellner, Dov Goldstein, Stephen J . Peterson, Joseph I. Shapiro M.D., Nader G. Abraham 2018 Marshall University

Increased Heme-Oxygenase 1 Expression In Mesenchymal Stem Cell-Derived Adipocytes Decreases Differentiation And Lipid Accumulation Via Upregulation Of The Canonical Wnt Signaling Cascade, Luca Vanella, Komal Sodhi, Dong Hyun Kim, Nitin Puri, Mani Maheshwari, Terry D . Hinds, Lars Bellner, Dov Goldstein, Stephen J . Peterson, Joseph I. Shapiro M.D., Nader G. Abraham

Mani Maheshwari

Introduction:

Heme oxygenase (HO), a major cytoprotective enzyme, attenuates oxidative stress and obesity. The canonical Wnt signaling cascade plays a pivotal role in the regulation of adipogenesis. The present study examined the interplay between HO-1and the Wnt canonical pathway in the modulation of adipogenesis in mesenchymal stem cell (MSC)-derived adipocytes.

Methods:

To verify the role of HO-1 in generating small healthy adipocytes, cobalt protoporphyrin (CoPP), inducer of HO-1, was used during adipocyte differentiation. Lipid accumulation was measured by Oil red O staining and lipid droplet size was measured by BODIPY staining.

Results:

During adipogenesis in vitro, differentiating pre-adipocytes display ...


Cerium Oxide Nanoparticles Inhibit Lipopolysaccharide Inducedmap Kinase/Nf-Kb Mediated Severe Sepsis, Mani Maheshwari, Nandini Manne PhD, Shinichi Asano, Eric Blough, Kevin M. Rice, Niraj Nepa,, Erin Fankhanel 2018 Marshall University

Cerium Oxide Nanoparticles Inhibit Lipopolysaccharide Inducedmap Kinase/Nf-Kb Mediated Severe Sepsis, Mani Maheshwari, Nandini Manne Phd, Shinichi Asano, Eric Blough, Kevin M. Rice, Niraj Nepa,, Erin Fankhanel

Mani Maheshwari

The life threatening disease of sepsis is associated with high mortality. Septic patient survivability with currently available treatments has failed to improve. The purpose of this study was to evaluate whether lipopolysaccharide (LPS) induced sepsis mortality and associated hepatic dysfunction can be prevented by cerium oxide nanoparticles (CeO2NPs) treatment in male Sprague Dawley rats. Here we provide the information about the methods processing of raw data related to our study published in Biomaterials (Selvaraj et al., Biomaterials, 2015, In press) and Data in Brief (Selvaraj et al., Data in Brief, 2015, In Press). The data present here provides confirmation of ...


Triad3a Induces The Degradation Of Early Necrosome To Limit Ripk1-Dependent Cytokine Production And Necroptosis., Norah A. Alturki, Scott McComb, Ardeshir Ariana, Dikchha Rijal, Robert G. Korneluk, Shao-Cong Sun, Emad S Alnemri, Subash Sad 2018 University of Ottawa; King Saud University

Triad3a Induces The Degradation Of Early Necrosome To Limit Ripk1-Dependent Cytokine Production And Necroptosis., Norah A. Alturki, Scott Mccomb, Ardeshir Ariana, Dikchha Rijal, Robert G. Korneluk, Shao-Cong Sun, Emad S Alnemri, Subash Sad

Department of Biochemistry and Molecular Biology Faculty Papers

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes ...


The Mitochondrial Protease Htra2 Restricts The Nlrp3 And Aim2 Inflammasomes., Ian Gaël Rodrigue-Gervais, Karine Doiron, Claudia Champagne, Lindsey Mayes, Gabriel André Leiva-Torres, Paulin Vanié, Todd Douglas, Silvia M. Vidal, Emad S. Alnemri, Maya Saleh 2018 McGill University; INRS-Institut Armand Frappier

The Mitochondrial Protease Htra2 Restricts The Nlrp3 And Aim2 Inflammasomes., Ian Gaël Rodrigue-Gervais, Karine Doiron, Claudia Champagne, Lindsey Mayes, Gabriel André Leiva-Torres, Paulin Vanié, Todd Douglas, Silvia M. Vidal, Emad S. Alnemri, Maya Saleh

Department of Biochemistry and Molecular Biology Faculty Papers

Activation of the inflammasome pathway is crucial for effective intracellular host defense. The mitochondrial network plays an important role in inflammasome regulation but the mechanisms linking mitochondrial homeostasis to attenuation of inflammasome activation are not fully understood. Here, we report that the Parkinson's disease-associated mitochondrial serine protease HtrA2 restricts the activation of ASC-dependent NLRP3 and AIM2 inflammasomes, in a protease activity-dependent manner. Consistently, disruption of the protease activity of HtrA2 results in exacerbated NLRP3 and AIM2 inflammasome responses in macrophages ex vivo and systemically in vivo. Mechanistically, we show that the HtrA2 protease activity regulates autophagy and controls the ...


30-Day Oral Acetaminophen Tolerance In Adult Horses, Sarah E. Foreman 2018 Augustana College, Rock Island Illinois

30-Day Oral Acetaminophen Tolerance In Adult Horses, Sarah E. Foreman

Celebration of Learning

There are no controlled studies of acetaminophen toxicity in horses. The objective was to test the hypotheses that oral acetaminophen administered at a dosage 25% higher than that sometimes used in horses would result in measurable hepatic toxicity as seen in humans and other species. Six healthy adult horses were administered 25 mg/kg acetaminophen powder in corn syrup twice daily for 30 days. Three other horses served as negative controls receiving only corn syrup. Jugular venous blood samples were obtained on days 7 and 1 before treatment; on treatment days 1, 2, 5, 8, 12, 15, 19, 22, 26 ...


Novel Determinants That Influence Azole Susceptibility In Candida Glabrata And Candida Albicans, Sarah Garland Whaley 2018 University of Tennessee Health Science Center

Novel Determinants That Influence Azole Susceptibility In Candida Glabrata And Candida Albicans, Sarah Garland Whaley

Theses and Dissertations (ETD)

Despite the scientific and medical communities’ best efforts, the incidence of fungal infections in susceptible populations continues to rise. The most common cause of these opportunistic fungal infections is Candida. In fact, Candida is the fourth most common pathogen associated with nosocomial blood stream infections. Reported mortality rates for patients with candidemia vary, but have not decreased in the past fifteen years and are reported to be as high as 50%. Candida glabrata, second only to Candida albicans among Candida infections, expresses high rates of resistance to treatment with arguably the best class of currently available antifungals - the azoles.

Other ...


Linear Ubiquitin Chain-Binding Domains, Lilian Fennell, Simin Rahighi, Fumiyo Ikeda 2018 Vienna BioCenter

Linear Ubiquitin Chain-Binding Domains, Lilian Fennell, Simin Rahighi, Fumiyo Ikeda

Pharmacy Faculty Articles and Research

Ubiquitin modification (ubiquitination) of target proteins can vary with respect to chain lengths, linkage type, and chain forms, such as homologous, mixed, and branched ubiquitin chains. Thus, ubiquitination can generate multiple unique surfaces on a target protein substrate. Ubiquitin‐binding domains (UBDs) recognize ubiquitinated substrates, by specifically binding to these unique surfaces, modulate the formation of cellular signaling complexes and regulate downstream signaling cascades. Among the eight different homotypic chain types, Met1‐linked (also termed linear) chains are the only chains in which linkage occurs on a non‐Lys residue of ubiquitin. Linear ubiquitin chains have been implicated in immune ...


Breaking Symmetry In Viral Icosahedral Capsids As Seen Through The Lenses Of X-Ray Crystallography And Cryo-Electron Microscopy., Kristin N. Parent, Jason R. Schrad, Gino Cingolani 2018 Michigan State University

Breaking Symmetry In Viral Icosahedral Capsids As Seen Through The Lenses Of X-Ray Crystallography And Cryo-Electron Microscopy., Kristin N. Parent, Jason R. Schrad, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

The majority of viruses on Earth form capsids built by multiple copies of one or more types of a coat protein arranged with 532 symmetry, generating an icosahedral shell. This highly repetitive structure is ideal to closely pack identical protein subunits and to enclose the nucleic acid genomes. However, the icosahedral capsid is not merely a passive cage but undergoes dynamic events to promote packaging, maturation and the transfer of the viral genome into the host. These essential processes are often mediated by proteinaceous complexes that interrupt the shell's icosahedral symmetry, providing a gateway through the capsid. In this ...


Novel Combination Bmp7 And Hgf Gene Therapy Instigates Selective Myofibroblast Apoptosis And Reduces Corneal Haze In Vivo, Suneel Gupta, Michael K. Fink, Arkasubhra Ghosh, Ratnakar Tripathi, Prashant R. Sinha, Ajay Sharma, Nathan P. Hesemann, Shyam S. Chaurasia, Elizabeth A. Giuliano, Rajiv R. Mohan 2018 Harry S. Truman Memorial Veterans’ Hospital

Novel Combination Bmp7 And Hgf Gene Therapy Instigates Selective Myofibroblast Apoptosis And Reduces Corneal Haze In Vivo, Suneel Gupta, Michael K. Fink, Arkasubhra Ghosh, Ratnakar Tripathi, Prashant R. Sinha, Ajay Sharma, Nathan P. Hesemann, Shyam S. Chaurasia, Elizabeth A. Giuliano, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

PURPOSE. We tested the potential of bone morphogenic protein 7 (BMP7) and hepatocyte growth factor (HGF) combination gene therapy to treat preformed corneal fibrosis using established rabbit in vivo and human in vitro models.

METHODS. Eighteen New Zealand White rabbits were used. Corneal fibrosis was produced by alkali injury. Twenty-four hours after scar formation, cornea received topically either balanced salt solution (BSS; n ¼ 6), polyethylenimine-conjugated gold nanoparticle (PEI2-GNP)-naked plasmid (n ¼ 6) or PEI2-GNP plasmids expressing BMP7 and HGF genes (n ¼ 6). Donor human corneas were used to obtain primary human corneal fibroblasts and myofibroblasts for mechanistic ...


Arylquinoline And Analog Compounds And Use Thereof To Treat Cancer, David S. Watt, Chunming Liu, Vivek M. Rangnekar, Vitaliy M. Sviripa, Ravshan Burikhanov, Wen Zhang 2018 University of Kentucky

Arylquinoline And Analog Compounds And Use Thereof To Treat Cancer, David S. Watt, Chunming Liu, Vivek M. Rangnekar, Vitaliy M. Sviripa, Ravshan Burikhanov, Wen Zhang

Molecular and Cellular Biochemistry Faculty Patents

The subject technology relates to arylquinoline compounds and their use for treating cancer or cancer metastasis. The compounds of the subject technology promote cells to secrete a pro-apoptotic tumor suppressor, i.e., prostate apoptosis response-4 (Par-4), which in turn promote apoptosis in cancer cells or metastatic cells.


Sphingomyelin And Gm1 Influence Huntingtin Binding To, Disruption Of, And Aggregation On Lipid Membranes, Maxmore Chaibva, Xiang Gao, Pranav Jain, Warren A. Campbell, Shelli L. Frey, Justin Legleiter 2018 West Virginia University

Sphingomyelin And Gm1 Influence Huntingtin Binding To, Disruption Of, And Aggregation On Lipid Membranes, Maxmore Chaibva, Xiang Gao, Pranav Jain, Warren A. Campbell, Shelli L. Frey, Justin Legleiter

Chemistry Faculty Publications

Huntington disease (HD) is an inherited neurodegenerative disease caused by the expansion beyond a critical threshold of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin (htt) protein. Expanded polyQ promotes the formation of a variety of oligomeric and fibrillar aggregates of htt that accumulate into the hallmark proteinaceous inclusion bodies associated with HD. htt is also highly associated with numerous cellular and subcellular membranes that contain a variety of lipids. As lipid homeostasis and metabolism abnormalities are observed in HD patients, we investigated how varying both the sphingomyelin (SM) and ganglioside (GM1) contents modifies the interactions between htt ...


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