Pharmacy and Pharmaceutical Sciences Commons^™

The Dietary Burden Of Phosphorus And Aluminum In Ready-To-Eat Wheat Flour Tortillas Exceeds That Of Corn Tortillas: Implications For Patients With Chronic Kidney Disease, Kate Chander Chiang, Robert Yokel, Jason M. Unrine, Kamyar Kalantar-Zadeh, Ajay Gupta

Pharmaceutical Sciences Faculty Publications

Background: Ready-to-eat, shelf-stable tortillas contain several phosphorus- and aluminum-containing additives that may increase the risk of adverse events in patients with chronic kidney disease (CKD).

Objective: The present study aimed to measure the dietary aluminum and phosphorus burden in store-bought corn and wheat flour tortillas. Design: This cross-sectional study analyzed the elemental content of commercially available corn and wheat flour tortillas collected from 2019 to 2020.

Setting: Twenty-one elements were quantified by ICP-MS and ICP-OES from 14 corn and 13 wheat flour tortilla brands purchased from local supermarkets in Southern California in 2019–2020.

Statistical analyses performed: Multiple group comparisons were …

Altered Bile Acid Transport In Liver Disease, Sarah Cayton, Lindsay C. Czuba

Pharmaceutical Sciences Faculty Publications

Background/Objectives: Bile acids, synthesized from cholesterol in the liver, are amphipathic molecules that play an integral role in lipid digestion and absorption, while also serving as systemic endocrine hormones. They continuously undergo enterohepatic circulation, where they interact with various transporter proteins. Dysregulated bile acid transport is associated with the pathogenesis of liver disease. This review summarizes the key findings relating to bile acid transport expression and activity in the pathogenesis of liver disease.

Methods: A review of the literature was performed using PubMed and relevant terms including, but not limited to, “bile acid transporters”, “liver disease”, and “bile acid uptake …

Chronic Alcohol Consumption Disrupts The Gut Microbial And Metabolic Landscapes, Madison B. Blanton, Ethan G. Napier, Katelyn E. Keen, Ethan V. Stuart, Isaac R. Cinco, Hami Hemati, Ronald C. Bruntz, Landon Wilson, Stephen Barnes, Rupak Khadka, Kathleen A. Grant, Ilhem Messaoudi

Pharmaceutical Sciences Faculty Publications

Introduction: Alcohol use disorder (AUD) increases incidence of infections, organ damage, and cancers. Aberrant inflammation is likely a driver of these adverse outcomes. Indeed, chronic alcohol consumption (CAC) rewires macrophages/monocytes toward a hyper-inflammatory phenotype. Prior studies showed increased gut permeability and dysbiosis. Translocation of host- and microbial-derived metabolites could trigger the hyper-inflammatory responses generated by macrophages/monocytes. However, the exact changes in these metabolites remain poorly defined due to confounders that complicate clinical studies and the differences between human and rodent gut microbiomes.

Methods: Here, we utilized a non-human primate model of ethanol self-administration to characterize alcohol-induced alterations in gut microbes …

Crystal Structures And Low-Affinity Complex Formation Of Halogenase Ctcp And Fad Reductase Ctcq From The Chlortetracycline Biosynthetic Pathway, Caixia Hou, Sylvie Garneau-Tsodikova, Oleg V. Tsodikov

Pharmaceutical Sciences Faculty Publications

Enzymatic halogenation in natural products has been intensely investigated due to its potential utility as a tool to improve pharmacological and pharmaceutical properties of drug leads. Chlortetracycline (CTC), the first tetracycline (TC) antibiotic discovered nearly eight decades ago, contains a chlorine group. This chlorine is installed enzymatically by the flavin adenine dinucleotide (FAD)-dependent halogenase CtcP. CtcP and the FAD reductase CtcQ, which is also encoded in the CTC biosynthetic gene cluster, function as a two-component system. Structural information on CtcP and CtcQ has been lacking. In this study, we determined crystal structures of CtcP from Kitasatospora aureofaciens in a complex …

Aluminum In Beverages And Foods: A Comprehensive Compilation Of Regulations; Concentrations In Raw, Prepared, And Stored Beverages And Foods; And Intake, Robert Yokel

Pharmaceutical Sciences Faculty Publications

The history and controversy concerning aluminum use in beverage and food preparation and storage are reviewed. This review on aluminum in drinking water, foods, and beverages updates and exceeds prior reviews. Country and international organization regulations that permit incorporation of aluminum containing food additives, their use limit, and purposes are presented. The aluminum concentration in beverages and foods consumed worldwide was gleaned from approximately 2100 sources available to the author. The approximately 17700 values are compiled in 175 tables by beverage or food category that include the analytical method used, sample source, and reference. The tables are posted on the …

A Cocaine Hydrolase Engineered From Human Butyrylcholinesterase As A Medical Countermeasure For Aldicarb Poisoning, Johnathan E. Lesaint, Nellore Bhanu Chandar, Annet Kyomuhangi, Huimei Wei, Fang Zheng, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Publications

Aldicarb is known to be the most toxic carbamate pesticide and could be used easily by terrorists to cause a mass casualty incident. It is highly desired to discover a medical countermeasure for aldicarb poisoning. Based on structural insights from molecular modeling and in vitro experimental validation, CocH3-Fc(M3), a potent cocaine hydrolase engineered from human butyrylcholinesterase (BChE), has a ~4-fold improved binding affinity with aldicarb compared to wild-type human acetylcholinesterase (AChE) and BChE and a 9-28-fold improved bimolecular rate constant for the carbamylation with aldicarb compared to AChE. CocH3-Fc(M3) also has significant catalytic activity for aldicarb hydrolysis and, hence, is …

Development Of A Ghrelin Deacylase To Attenuate Drug Reward And Associated Effects Of Methamphetamine, Madeline J. Stewart, Huimei Wei, Nellore Bhanu Chandar, Fang Zheng, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Publications

All addictive substances directly or indirectly interact with the dopamine reward system to alter the brain’s dopamine receptor activities. It is essential for a truly effective addiction medication to attenuate substance reward and normalize the brain’s physiological functions. Conventional pharmacological intervention approaches to the treatment of substance addiction usually aim to develop and deliver a potential therapeutic agent to the brain to directly block or decrease actions of the substance or its therapeutic target in the brain. However, it is a grand challenge to attenuate the substance reward without affecting the normal physiological functions of brain receptors or transporters. Here, …

Effects Of Biased Analogues Of The Kappa Opioid Receptor Agonist, U50,488, In Preclinical Models Of Pain And Side Effects, Ross Van De Wetering, Loan Y. Vu, Lindsay D. Kornberger, Dan Luo, Brittany Scouller, Sheein Hong, Kelly F. Paton, Thomas E. Prisinzano, Bronwyn M. Kivell

Pharmaceutical Sciences Faculty Publications

Kappa opioid receptor (KOR) agonists have well-established antinociceptive effects. However, many KOR agonists have negative side effects, which limit their therapeutic potential. Some researchers have suggested that the development of biased agonists that preferentially stimulate KOR G-protein pathways over β-arrestin pathways may yield drugs with fewer adverse side effects. This was investigated in the current study. We describe the synthesis and characterization of three U50,488 analogues, 1, 2, and 3. We evaluated the acute and chronic antinociceptive effects of these compounds in mice using the warm-water tail flick assay and in a paclitaxel-induced neuropathic pain model. Side …

Effects Of Fentanyl-Adulterated Methamphetamine On Circulating Ghrelin In Rats, Huimei Wei, Elise C. Maul, Shawn Park, Kaniz Fatema, Daniel J. Peter, Chang-Guo Zhan, Fang Zheng

Pharmaceutical Sciences Faculty Publications

The appetite hormone ghrelin influences biological processes that are responsible for substance use disorder, which is related to alcohol and most abused drugs including cocaine, methamphetamine, nicotine, etc. In general, upregulation of the ghrelin system enhances drug cravings and substance use. Studies reported in the literature consistently demonstrated that the ghrelin system is associated with stimulants. However, research on opioids in combination with methamphetamine has not been reported. In this study, we examined the relationship of circulating ghrelin with the polydrug use of fentanyl and methamphetamine in male Sprague-Dawley rats, demonstrating for the first time that concurrent use of fentanyl …

Effects Of Fentanyl-Laced Cocaine On Circulating Ghrelin, Insulin, And Glucose Levels In Rats, Huimei Wei, Elise C. Maul, Annet Kyomuhangi, Shawn Park, Maddilynn L. Mutchler, Chang-Guo Zhan, Fang Zheng

Pharmaceutical Sciences Faculty Publications

Opioid mixed with cocaine has been increasingly implicated in overdose deaths, including both intentional co-use of opioid and cocaine and fentanyl-adulterated drug supply. As ghrelin plays an important role in drug reward and can also influence insulin, this study aimed to assess responses of the circulating ghrelin, insulin, and glucose levels to the combined use of fentanyl and cocaine (a polydrug) in rats by performing combined animal behavioral experiments and biochemical analysis. The experimental data consistently revealed that the fentanyl and cocaine co-use can significantly elevate both the acyl-ghrelin and desacyl-ghrelin levels and significantly decrease the insulin level without significant …

Fluorescence-Guided Resection Of Gl261 Red-Fluc And Trp-Mcherry-Fluc Mouse Glioblastoma Tumors, Louis T. Rodgers, Bryan J. Maloney, Anika M. S. Hartz, Björn Bauer

Pharmaceutical Sciences Faculty Publications

Background: Most preclinical studies on glioblastoma (GBM) fail to provide translational utility in the clinic. Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) improves tumor resection, disease prognosis, and, thus, patient outcomes. Given the critical role of surgery in managing recurrent GBM, it is essential to incorporate surgical elements into preclinical models to accurately reflect clinical scenarios and enhance translational success. However, existing protocols for 5-ALA-guided resection in preclinical models are limited and often lack clinical relevance.

Methods: To address this gap, we developed a novel protocol for the 5-ALA-guided resection in two mouse GBM models: TRP-mCherry-FLuc and GL261 Red-FLuc.

Results: The …

Development Of Zafirlukast Analogues For Improved Antithrombotic Activity Through Thiol Isomerase Inhibition, Justine A. Keovilay, Kaitlind C. Howard, Kirk A. Taylor, Sabeeya Khan, Sienna E. Wurl, Melanie K. Szahaj, Tanya Sage, Nishad Thamban Chandrika, Caixia Hou, Oleg V. Tsodikov, Jonathan M. Gibbins, Sylvie Garneau-Tsodikova, Daniel R. Kennedy

Pharmaceutical Sciences Faculty Publications

Background:   Thiol isomerases play essential and nonredundant roles in platelet activation, aggregation, and thrombus formation. Thiol isomerase inhibitors have the potential to overcome the 2 major drawbacks of current antithrombotic therapies, as they target both arterial and venous thrombosis without enhancing bleeding risks. Recently, a Food and Drug Administration–approved drug, zafirlukast (ZAF), was shown to be a promising pan-thiol isomerase inhibitor. The objective of this study is to develop analogues of ZAF with optimized thiol isomerase inhibition and antithrombotic activity.   Methods:   Thirty-five ZAF analogues were tested in an insulin turbidometric assay for thiol isomerase inhibition. Analogues were tested for platelet …

Functional And Structural Studies On The Esperamicin Thioesterase And Progress Toward Understanding Enediyne Core Biosynthesis, Erome D. Hankore, Mitchell D. Miller, Abigael J. Kosgei, Weijun Xu, Kemin Tan, Michael Endres, Minakshi Bhardwaj, Grazyna Joachimiak, Andrzej Joachimiak, George N. Phillips Jr., Jon S. Thorson, Steven G. Van Lanen

Pharmaceutical Sciences Faculty Publications

Enediynes are among the most potent antitumor and antibacterial natural products. Studies on their biosynthetic pathways have identified a shared, linear polyene precursor generated from an iterative type I polyketide synthase (PKSE) as the source of the enediyne warhead. A key step is the release of this polyene from the PKSE by a discrete thioesterase (TE). Here, we used X-ray crystallography, site-directed mutagenesis, and heterologous coexpression of PKSEs and TEs to elucidate how enediyne TEs mediate the production of the polyene. We solved the structure of wild-type EspE7 from esperamicin producer Actinomodura verrucosospora. The substrate binding pocket was also …

A Highly Selective Mpges-1 Inhibitor To Block Abdominal Aortic Aneurysm Progression In The Angiotensin Mouse Model., Lauren M Weaver, Madeline J Stewart, Kai Ding, Charles D. Loftin, Fang Zheng, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Publications

Abdominal aortic aneurysm (AAA) is a deadly, permanent ballooning of the aortic artery. Pharmacological and genetic studies have pointed to multiple proteins, including microsomal prostaglandin E₂ synthase-1 (mPGES-1), as potentially promising targets. However, it remains unknown whether administration of an mPGES-1 inhibitor can effectively attenuate AAA progression in animal models. There are still no FDA-approved pharmacological treatments for AAA. Current research stresses the importance of both anti-inflammatory drug targets and rigor of translatability. Notably, mPGES-1 is an inducible enzyme responsible for overproduction of prostaglandin E₂ (PGE₂)-a well-known principal pro-inflammatory prostanoid. Here we demonstrate for the first …

The Role Of Microglia In Sex- And Region-Specific Blood-Brain Barrier Integrity During Nicotine Withdrawal, Mohit Kumar, Jack V. Keady, Surya P. Aryal, Marissa Hessing, Christopher I. Richards, Jill R. Turner

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Smoking is the largest preventable cause of death and disease in the United States, with ,5% of quit attempts being successful. Microglia activation and proinflammatory neuroimmune signaling in reward neuro- circuitry are implicated in nicotine withdrawal symptomology. Microglia are integral regulators of blood-brain barrier (BBB) functionality as well; however, whether the effects of nicotine withdrawal on microglia function impact BBB integrity is unknown.

METHODS: Mice were treated with chronic nicotine (12 mg/kg/day) and subjected to 48 hours nicotine withdrawal. Regional BBB permeability, together with messenger RNA and protein expression of tight junction proteins, were assessed. PLX5622 chow was used …

Biodegradable Nanoparticles Targeting Circulating Immune Cells Reduce Central And Peripheral Sensitization To Alleviate Neuropathic Pain Following Spinal Cord Injury., Michael N. Saunders, Kate V. Griffin, Irina Kalashnikova, Daniel Kolpek, Dominique R. Smith, Eiji Saito, Brian J. Cummings, Aileen J. Anderson, Lonnie D. Shea, Jonghyuck Park

Pharmaceutical Sciences Faculty Publications

Neuropathic pain is a critical source of comorbidity following spinal cord injury (SCI) that can be exacerbated by immune-mediated pathologies in the central and peripheral nervous systems. In this article, we investigate whether drug-free, biodegradable, poly(lactide- co -glycolide) (PLG) nanoparticle treatment mitigates the development of post-SCI neuropathic pain in female mice. Our results show that acute treatment with PLG nanoparticles following thoracic SCI significantly reduces tactile and cold hypersensitivity scores in a durable fashion. Nanoparticles primarily reduce peripheral immune-mediated mechanisms of neuropathic pain, including neuropathic pain-associated gene transcript frequency, transient receptor potential ankyrin 1 nociceptor expression, and MCP-1 (CCL2) chemokine …

Quantification Of Observable Behaviors Following Oral Administration Of Oxycodone And Nalfurafine In Male Rhesus Monkeys, Sally L. Huskinson, Donna M. Platt, Zachary R. Smith, William S. Doyle, C. Austin Zamarripa, Kristen Dunaway, Thomas E. Prisinzano, Kevin B. Freeman

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Recent preclinical studies have investigated the atypical kappa-opioid receptor (KOR) agonist, nalfurafine, as a co-formulary with mu-opioid receptor (MOR) agonists as a potential deterrent for misuse. However, no study has investigated effects of nalfurafine combined with a MOR agonist using an oral route of administration. The objective of the current study was to measure behavioral effects of orally administered oxycodone and nalfurafine, alone and combined, in rhesus monkeys using a quantitative behavioral observation procedure.

METHODS: Adult male rhesus monkeys (N=5) were orally administered vehicle, oxycodone (0.56-1.8mg/kg), nalfurafine (0.001-0.0056mg/kg), or mixtures (1.0mg/kg oxycodone/0.001-0.0056mg/kg nalfurafine) in a Jell-O vehicle at multiple …

Discovery Of A Potent Highly Biased Mor Partial Agonist Among Diastereomeric C9-Hydroxyalkyl-5-Phenylmorphans., Joshua A. Lutz, Agnieszka Sulima, Eugene S. Gutman, Eric W. Bow, Dan Luo, Sophia Kaska, Thomas E. Prisinzano, Carol A. Paronis, Jack Bergman, Gregory H. Imler, Andrew T. Kerr, Arthur E. Jacobson, Kenner C. Rice

Pharmaceutical Sciences Faculty Publications

All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space around the C9 substituent in our search for potent MOR partial agonists. These compounds were designed to lessen the lipophilicity observed with their C9-alkenyl substituted relatives. Many of the 12 diastereomers that were obtained were found to have nanomolar or subnanomolar potency in the forskolin-induced cAMP accumulation assay. Almost all these potent compounds were fully efficacious, and three of those chosen for in vivo evaluation, 15, 21, and 36, were all extremely G-protein biased; none of the three compounds recruited beta-arrestin2. Only one of the …

Oxidative Stress And Micrornas In Endothelial Cells Under Metabolic Disorders, Morgan Minjares, Wendy Wu, Jie-Mei Wang

Pharmaceutical Sciences Faculty Publications

Reactive oxygen species (ROS) are radical oxygen intermediates that serve as important second messengers in signal transduction. However, when the accumulation of these molecules exceeds the buffering capacity of antioxidant enzymes, oxidative stress and endothelial cell (EC) dysfunction occur. EC dysfunction shifts the vascular system into a pro-coagulative, proinflammatory state, thereby increasing the risk of developing cardiovascular (CV) diseases and metabolic disorders. Studies have turned to the investigation of microRNA treatment for CV risk factors, as these post-transcription regulators are known to co-regulate ROS. In this review, we will discuss ROS pathways and generation, normal endothelial cell physiology and ROS-induced …

A Mor Antagonist With High Potency And Antagonist Efficacy Among Diastereomeric C9-Alkyl-Substituted N-Phenethyl-5-(3-Hydroxy)Phenylmorphans, Dana R. Chambers, Agnieszka Sulima, Dan Luo, Thomas E. Prisinzano, Arthur E. Jacobson, Kenner C. Rice

Pharmaceutical Sciences Faculty Publications

The 5-(3-hydroxy)phenylmorphan structural class of compounds are unlike the classical morphinans, 4,5-epoxymorphinans, and 6,7-benzomorphans, in that they have an equatorially oriented aromatic ring rather than the axial orientation of that ring found in the classical opioids. This modified and simplified opioid-like structure has been shown to retain antinociceptive activity, depending on its stereochemistry and substituents, and some of them have been found to be much more potent than morphine. A simple C9-hydroxy-5-(3-hydroxy)phenylmorphan enantiomer was found to be about 500 times more potent than morphine in vivo. We have previously examined C9-alkenyl and hydroxyalkyl substituents in the N-phenethyl-5-(3-hydroxy)phenylmorphan class of compounds. …

Potent Mor Agonists From 2′-Hydroxy-5,9-Dimethyl-N-Phenethyl Substituted-6,7-Benzomorphans And From C8-Hydroxy, Methylene And Methyl Derivatives Of N-Phenethylnormetazocine, Madhurima Das, George W. Ward, Agnieszka Sulima, Dan Luo, Thomas E. Prisinzano, Gregory H. Imler, Andrew T. Kerr, Arthur E. Jacobson, Kenner C. Rice

Pharmaceutical Sciences Faculty Publications

(−)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a para-OH or ortho-F substituent in the aromatic ring of the N-phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1R,5R,9R)-6,11-dimethyl-3-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol and (1R,5R,9R)-6,11-dimethyl-3-(4-hydroxyphenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d] azocin-8-ol, were more potent than the unsubstituted compound N-phenethylnormetazocine and about 30 or 40 times more potent than morphine, respectively. A variety of substituents in the ortho, meta, or para position in the aromatic ring of the N-phenethyl moiety were synthesized, 25 of these compounds, and found to have varying effects on potency and efficacy as determined by the forskolin-induced …

Cerium Dioxide, A Jekyll And Hyde Nanomaterial, Can Increase Basal And Decrease Elevated Inflammation And Oxidative Stress, Robert Yokel, Marsha L. Ensor, Hemendra J. Vekaria, Patrick G. Sullivan, David J. Feola, Arnold Stromberg, Michael T. Tseng, Douglas A. Harrison

Pharmaceutical Sciences Faculty Publications

It was hypothesized that the catalyst nanoceria can increase oxidative

stress/inflammation from the basal state and reduce it from the elevated state .

Nanoceria are cleared by macrophages. To test the hypothesis, M0 (non-polarized),

M1- (classically activated, pro-inflammatory), and M2-like (alternatively activated,

regulatory phenotype) RAW 264.7 macrophages were nanoceria exposed. Responses

were quantified by arginase activity, IL-1ß level, cell oxygen consumption rate (OCR),

the glycolysis stress test (GST), morphology determined by light microscopy,

macrophage phenotype marker expression and morphology using a novel three

dimensional immunohistochemical method, and RT-qPCR. Nanoceria blocked

arginase and IL-1ß effects, increased M0 cell OCR and GST …

Sex Differences In Kappa Opioid Receptor Agonist Mediated Attenuation Of Chemotherapy-Induced Neuropathic Pain In Mice, Kelly F. Paton, Dan Luo, Anne C. La Flamme, Thomas E. Prisinzano, Bronwyn M. Kivell

Pharmaceutical Sciences Faculty Publications

Chemotherapy-induced neuropathic pain is a common side effect for cancer patients which has limited effective treatment options. Kappa opioid receptor (KOR) agonists are a promising alternative to currently available opioid drugs due to their low abuse potential. In the current study, we have investigated the effects of Salvinorin A (SalA) analogues, 16-Ethynyl SalA, 16-Bromo SalA and ethyoxymethyl ether (EOM) SalB, and in a preclinical model of paclitaxel-induced neuropathic pain in male and female C57BL/6J mice. Using an acute dose-response procedure, we showed that compared to morphine, 16-Ethynyl SalA was more potent at reducing mechanical allodynia; and SalA, 16-Ethynyl SalA, and …

Similarly Efficacious Anti-Malarial Drugs Sj733 And Pyronaridine Differ In Their Ability To Remove Circulating Parasites In Mice, Arya Sheelanair, Aleksandra S. Romanczuk, Rosemary A. Aogo, Rohit Nemai Haldar, Lianne I. M. Lansink, Deborah Cromer, Yandira G. Salinas, R. Kiplin Guy, James S. Mccarthy, Miles P. Davenport, Ashraful Haque, David S. Khoury

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the "parasite clearance curve", has been critical for assessing drug efficacy; yet underlying mechanisms remain partly unresolved. The clearance curve may be shaped both by the rate at which drugs kill parasites, and the rate at which drug-affected parasites are removed from circulation.

METHODS: In this context, two anti-malarials, SJ733, and an ACT partner drug, pyronaridine …

Direct Nose To The Brain Nanomedicine Delivery Presents A Formidable Challenge, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

This advanced review describes the anatomical and physiological barriers and mechanisms impacting nanomedicine translocation from the nasal cavity directly to the brain. There are significant physiological and anatomical differences in the nasal cavity, olfactory area, and airflow reaching the olfactory epithelium between humans and experimentally studied species that should be considered when extrapolating experimental results to humans. Mucus, transporters, and tight junction proteins present barriers to material translocation across the olfactory epithelium. Uptake of nanoparticles through the olfactory mucosa and translocation to the brain can be intracellular via cranial nerves (intraneuronal) or other cells of the olfactory epithelium, or extracellular …

Total Synthesis Of Decahydroquinoline Poison Frog Alkaloids Ent-Cis-195a And Cis-211a, Takuya Okada, Naizhen Wu, Katsuki Takashima, Jungoh Ishimura, Hiroyuki Morita, Takuya Ito, Takeshi Kodama, Yuhei Yamasaki, Shin-Ichi Akanuma, Yoshiyuki Kubo, Ken-Ichi Hosoya, Hiroshi Tsuneki, Tsutomu Wada, Toshiyasu Sasaoka, Takahiro Shimizu, Hideki Sakai, Linda P. Dwoskin, Syed R. Hussaini, Ralph A. Saporito, Naoki Toyooka

Pharmaceutical Sciences Faculty Publications

The total synthesis of two decahydroquinoline poison frog alkaloids ent-cis-195A and cis-211A were achieved in 16 steps (38% overall yield) and 19 steps (31% overall yield), respectively, starting from known compound 1. Both alkaloids were synthesized from the common key intermediate 11 in a divergent fashion, and the absolute stereochemistry of natural cis-211A was determined to be 2R, 4aR, 5R, 6S, and 8aS. Interestingly, the absolute configuration of the parent decahydroquinoline nuclei of cis-211A was the mirror image of that …

Landomycins As Glutathione-Depleting Agents And Natural Fluorescent Probes For Cellular Michael Adduct-Dependent Quinone Metabolism, Alessio Terenzi, Mery La Franca, Sushilla Van Schoonhoven, Rostyslav Panchuk, Álvaro Martínez, Petra Heffeter, Redding Gober, Christine Pirker, Petra Vician, Christian R. Kowol, Rostyslav Stoika, Luca Salassa, Jürgen Rohr, Walter Berger

Pharmaceutical Sciences Faculty Publications

Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. The aglycone landomycinone is the distinctive core, while the oligosaccharide chain differs within derivatives. Herein, we report that landomycins spontaneously form Michael adducts with biothiols, including reduced cysteine and glutathione, both cell-free or intracellularly involving the benz[a]anthraquinone moiety of landomycinone. While landomycins generally do not display emissive properties, the respective Michael adducts exerted intense blue fluorescence in a glycosidic chain-dependent manner. This allowed label-free tracking of the short-lived nature of the mono-SH-adduct followed by oxygen-dependent evolution with addition of another SH-group. Accordingly, hypoxia distinctly stabilized the fluorescent mono-adduct. While …

Rapid-Onset Anti-Stress Effects Of A Kappa-Opioid Receptor Antagonist, Ly2795050, Against Immobility In An Open Space Swim Paradigm In Male And Female Mice, Caroline Baynard, Thomas E. Prisinzano, Eduardo R. Butelman

Pharmaceutical Sciences Faculty Publications

The kappa-opioid receptor (KOR) / dynorphin system is implicated with behavioral and neurobiological effects of stress exposure (including heavy exposure to drugs of abuse) in translational animal models. Thus some KOR-antagonists can decrease the aversive, depressant-like and anxiety-like effects caused by stress exposure. The first generation of selective KOR-antagonists have slow onsets (hours) and extremely long durations of action (days-weeks), in vivo. A new generation of KOR antagonists with rapid onset and shorter duration of action can potentially decrease the effects of stress exposure in translational models, and may be of interest for medication development. This study examined the …

Autoradiographic Localization Of [3h]-Nisoxetine Binding Sites In The Cns Of Male And Female Japanese Quail, Shannon E. Eaton, James R. Pauly, Deann M. Hopkins, Chana K. Akins

Pharmaceutical Sciences Faculty Publications

Background

In the central nervous system of mammals, transporters localized on the presynaptic nerve terminals regulate the reuptake of neurotransmitters. These transporters are selective for a specific neurotransmitter such as dopamine (DA) and norepinephrine (NE). Specifically in the synapse, the dopamine transporter (DAT) reuptakes DA and the norepinephrine transporter (NET) reuptakes NE. However previous research has found that avian species do not have a gene for DAT, and therefore, birds may be using the NET to clear both NE and DA from the synapse. The current study aimed to extend this finding by localizing NET expression in male and female …

Neuron-Derived Extracellular Vesicles Modulate Microglia Activation And Function, Hui Peng, Brock T. Harvey, Christopher I. Richards, Kimberly Nixon

Pharmaceutical Sciences Faculty Publications

Microglia act as the immune cells of the central nervous system (CNS). They play an important role in maintaining brain homeostasis but also in mediating neuroimmune responses to insult. The interactions between neurons and microglia represent a key process for neuroimmune regulation and subsequent effects on CNS integrity. However, the molecular mechanisms of neuron-glia communication in regulating microglia function are not fully understood. One recently described means of this intercellular communication is via nano-sized extracellular vesicles (EVs) that transfer a large diversity of molecules between neurons and microglia, such as proteins, lipids, and nucleic acids. To determine the effects of …