Pharmacy and Pharmaceutical Sciences Commons^™

Differential Modulation Of Sk Channel Subtypes By Phosphorylation, Young-Woo Nam, Dezhi Kong, Dong Wang, Razan Orfali, Rinzhin T. Sherpa, Jennifer Totonchy, Surya M. Nauli, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca²⁺-activated K⁺ (SK) channels are voltage-independent and are activated by Ca²⁺ binding to the calmodulin constitutively associated with the channels. Both the pore-forming subunits and the associated calmodulin are subject to phosphorylation. Here, we investigated the modulation of different SK channel subtypes by phosphorylation, using the cultured endothelial cells as a tool. We report that casein kinase 2 (CK2) negatively modulates the apparent Ca²⁺ sensitivity of SK1 and IK channel subtypes by more than 5-fold, whereas the apparent Ca²⁺ sensitivity of the SK3 and SK2 subtypes is only reduced by ∼2-fold, when heterologously …

Drug Delivery Systems: Exploring Rheological Properties And Therapeutic Effect Of 5-Fu Chitosan Gel For Topical Wound Healing, Samuel Tetteh-Quarshie

Theses, Dissertations and Capstones

Diabetic skin wound is a common complication of diabetes that occurs in about 15% of diabetic patients and often requires prolonged hospitalization for its management and treatment. Natural polymers are used for wound dressing due to their biological adhesiveness, non-toxicity, and biodegradable nature. 5-Fluorouracil (FU) has been shown to alter adipokine expression which is implicated in cutaneous wound repair. Thus, our overall objective was to investigate the utility of chitosan (CS) gel for topical delivery of 5-FU to treat diabetic wounds. We prepared chitosan gel (2% w/w) in serial dilutions of 5-FU (25μg/mL, 2.5μg/mL, 0.25μg/mL, and 0.025μg/mL) and evaluated their …

Mechanisms Of Apoptosis Induced By Actinomycin D In Aerodigestive Tract Cancers, Adeoluwa Ayodeji Adeluola

Theses, Dissertations and Capstones

Upper aerodigestive tract cancers including cancers of the oral cavity, pharynx, larynx, esophagus, and lungs are the most prevalent cancers and leading causes of cancer-related deaths. Collectively, over 300,000 new cases and 146,500 deaths are projected within the US in the year 2021. Drug-associated toxicities, as well as resistance to therapy (intrinsic and acquired), are big challenges for successfully treating these cancers. Recent studies have shown that combining low-dose actinomycin D with existing therapies is a promising strategy to reduce toxicity (cyclotherapy) and to overcome resistance. The development of these treatment strategies however requires an understanding of the molecular mechanisms …

The Development Of A Cancer-Targeting Peptide-Drug Conjugate For The Treatment Of Melanoma, Cassandra Dill

Pharmaceutical Sciences (MS) Theses

Cancer is an ongoing global pandemic which has caused a dramatic shift in research priorities. One of the most aggressive and difficult to treat has invariably remained metastatic melanoma. Although encompassing only 4% of overall skin cancer diagnoses, chances for recovery were slim until recent revolutionary development of immunotherapy adding to its regimen spectrum. This is due to its resistance to many standard-of-care treatment methods, along with its relatively high-metastatic potential. Within the past decade, eight new targeted and immune checkpoint inhibitors have gained FDA approval. The median life survival has increased significantly from 9 months to over 2 years …

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Tools And Antimicrobial Agents, David Salehi

Pharmaceutical Sciences (MS) Theses

Cell-penetrating peptides containing arginine as positively charged residues and tryptophan or diphenylalanine as hydrophobic residues were synthesized. The synthesis was accomplished through the Fmoc solid-phase peptide synthesis in the presence of HBTU and DIPEA. The side-chain protected linear peptides were cleaved from the resin and cyclized in the presence of DIC and HOAt in the solution phase overnight. MALDI-TOF mass spectrometry was used to characterize the peptides.

The cytotoxicity of the synthesized peptides was determined in CCRF-CEM (human, lymphoblast peripheral blood), and HEK-293 (human, embryonic epithelial kidney healthy) cells using the MTS assay. A concentration of 10 µM was found …

Pharmacogenomics And Ssris Appropriateness In Older Community Dwelling African Americans, Wint War Phyo, Lana Sargent, Elvin T. Price

Graduate Research Posters

Background: Depressive and anxiety disorders are among the most common illnesses experienced by older adults (age > 60). The selective serotonin reuptake inhibitors (SSRIs) are preferred class of antidepressants for these disorders due to their high efficacy and safety profiles among older adults. However, SSRIs are metabolized by highly polymorphic cytochrome P450 enzymes, specifically CYP2D6 and CYP2C19. This can lead to variable dose-response outcomes, especially among older African American population.

Objective: Analyze the frequency of CYP2D6 and CYP2C19 polymorphisms in African American older adults who are taking SSRIs and identify potential inappropriate use of SSRIs in these older adults using the …

Science-Based Regulation Of Pharmacological Substances In Competition Horses, Jacob Machin

Theses and Dissertations--Toxicology and Cancer Biology

Current testing methodologies within equine forensic toxicology focus on arbitrary thresholds and zero-tolerance policy. Modern analytical chemistry’s limits of detection are low enough that oftentimes femtogram-per-milliliter amounts of a substance can readily be identified in both blood and urine of a horse. For most pharmacologically relevant compounds, these concentrations have no relevance to pharmacological effect. It is therefore crucial that testing methodologies to determine appropriate thresholds and cut-offs be developed that are driven by biological activity rather than arbitrary limits of detection. This dissertation looks to address this by suggesting a system of calculated Effective Plasma Concentrations by which a …

Standardization Of E-Cigarette Research: Addressing The Analysis Of Total Nicotine And Free Base Nicotine In E-Cigarettes, Vinit Gholap

Theses and Dissertations

Electronic cigarettes (e-cigarettes) are one of the major sources of exposure to nicotine, an addictive chemical. Since 2016, the Food and Drug Administration (FDA) has started regulating these products under the Tobacco Control Act yet, specifications about the nicotine content in these products have not been established. In e-cigarettes, nicotine concentration ranges from 0 to >50mg/mL. Additionally, several e-cigarette related parameters have been identified which can affect nicotine delivery to users. Of these factors, nicotine forms (protonated and free base) have been found to play a significant role in nicotine absorption profiles yet, a limited and contradictory research is available …

Delineating The Biosynthesis Of Capuramycin-Type Antibiotics, Ashley L. Biecker

Theses and Dissertations--Pharmacy

New antibiotic scaffolds with novel drug targets are needed to combat the rise of drug-resistant, infectious microorganisms. The bacterial translocase I is a ubiquitous enzyme in the peptidoglycan biosynthetic pathway that has yet to be targeted by clinically used antibiotics. It catalyzes the transfer of N-acetylmuramoyl-pentapeptide to undecaprenylphosphate in order to generate lipid I during cell wall biosynthesis. A screening of bacterial translocase I inhibitors led to the discovery of the novel compound capuramycin and its analogues: A-500359s, A-503083s, and A-102395, produced by various species of actinomycetes. The capuramycins show potent activity against the bacterial translocase I with IC50s …

Investigating The Effect Of Khat (Catha Edulis) On Selected Obesity Markers And Pathways In C57bl/6j Male Mice, Mustafa Ahmed Al-Shagga

Student Works (2020-2029)

In East African and South Western Arabian populations, Catha edulis (khat) is believed to suppress appetite and reduce body weight. First, this study conducted a systematic review of the literature on the effects of khat and its active alkaloid cathinone on body weight and appetite regulation. Second, this study investigated the effect of khat and cathinone on selected metabolic and histopathologic parameters and their influence on the expression of obesity-related genes in high-fat diet-induced obese mice. Forty-two male C57BL/6J mice were divided into seven groups (n= 6); normal diet control treated with vehicle (NDC), normal diet treated with 200 mg/kg …

Bisphosohoglycertae Mutase: A Potential Target For Sickle Cell Disease, Anfal S. Aljahdali

Theses and Dissertations

Bisphosphoglycerate mutase (BPGM) is a part of the erythrocyte glycolysis system. Specifically, it is a central enzyme in the Rapoport-Leubering pathway, a side glycolytic pathway involved in the regulation of the concentration of the natural allosteric effector of hemoglobin (Hb), 2,3-bisphosphoglycerate (2,3-BPG). BPGM catalyses the synthesis and hydrolysis of 2,3-BPG through its synthase and phosphatase activities. The synthase activity is the main role of BPGM, while the phosphatase activity is low and is activated by the physiological effector, 2-phosphoglycolate (2-PG) with the latter mechanism poorly understood.

BPGM activity and 2,3-BPG levels in red blood cells (RBCs) have a significant role …

Glycosaminoglycan Modulation Of Key Proteins In Alzheimer's Disease, Tamim Chiba

Theses and Dissertations

Glycosaminoglycans (GAGs) are linear polysaccharides whose disaccharide building blocks consist of an amino sugar (D-glucosamine) and either uronic acid (D-glucuronic acid or L-iduronic acid) or galactose. Nearly all GAGs (with the exception of hyaluronic acid) are covalently attached to proteins, forming proteoglycans, and are ubiquitous in nature. The monomeric units, chain length, degree and pattern of sulfation, and epimerization are important properties that determine the influence of these molecules. Through Coulombic forces, hydrogen bonds and hydrophobic interactions, they regulate many physiological and pathophysiological processes such as blood coagulation, cell growth and differentiation, inflammatory processes, host defense and viral infection mechanisms. …

Investigations On Novel Cyp26a1/B1 Inhibitor, Dx308: Using Atra Response As A Theraputic Target For Traumatic Brain Injury And Parkinson’S Disease, Jacob Morgan Leatherwood

Graduate Student Theses, Dissertations, & Professional Papers

Neurodegenerative diseases (NDs) take a wide spectrum of pathologies and have a tendency to present themselves later in life. Neurodegenerative diseases affect 6 million Americans annually with ~1 million currently living with Parkinson’s disease (PD). One of the greatest contributors to the pathogenesis of neurodegenerative diseases is the occurrence of a traumatic brain injury (TBI) during life.

All-trans-retinoic acid (atRA) is the active metabolite of Vitamin A. The retinoic acid pathway is known to be activated following TBI and is reduced in PD patients. Previous studies found a decrease in inflammation and behavioral deficits following administration of Vitamin …

Bayesian-Derived Vancomycin Auc24h Threshold For Nephrotoxicity In Special Populations, Dan Ho

University of the Pacific Theses and Dissertations

A Bayesian-derived 24-hour area under the concentration-time curve over minimum inhibitory concentration from broth microdilution (AUC24h/MICBMD) ratio of 400 to 600 is recommended as the new monitoring parameter for vancomycin to optimize efficacy and minimize nephrotoxicity. The AUC24h threshold of 600 mg*h/L for nephrotoxicity was extrapolated from studies that assessed the general population. It is unclear if this upper threshold is consistent or varies when used in special populations such as critically ill patients, obese patients, patients with preexisting renal disease, and patients on concomitant nephrotoxins.The purpose of this study is to investigate the generalizability of the proposed vancomycin AUC24h …

Development Of Miriplatin-Loaded Nanoparticles Against Non-Small Cell Lung Cancer, Zhongyue Yuan

University of the Pacific Theses and Dissertations

Lung cancer claims the highest mortality and the second-most estimated new cases among all oncological diseases [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all newly diagnosed lung cancers [2]. Approximately 40% of newly diagnosed lung cancer patients are stage IV. For stage IIIB/IV NSCLC, cytotoxic combination chemotherapy is standard first-line chemotherapy. A regimen of platinum (cisplatin or carboplatin) plus paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, or pemetrexed is the recommended clinical treatment [3].

Cisplatin is the first-generation platinum-based anti-cancer drug. Although cisplatin is much more effective than other platinum drugs at the same dosage [4], accumulating reports …

Impact Of 17-Beta Estradiol And Moderate-Intensity Exercise On Mesenteric Arterial Function Of Uc Davis Type-2 Diabetes Mellitus Rats, Md Rahatullah Razan

University of the Pacific Theses and Dissertations

The studies in this dissertation were designed to investigate the impacts of estrogen (17-β estradiol/E2) and moderate-intensity exercise (MIE) on the mesenteric arterial (MA) function of the University of California Davis type-2 diabetes mellitus (UCD-T2DM) Rat model. Our recent report suggests that diabetes impairs MA vasorelaxation in both sexes of the UCD-T2DM model. Particularly, we reported that MA from prediabetic male rats showed a greater impairment compared to that in prediabetic females. However, when females become diabetic, they exhibit a greater vascular dysfunction than males. Therefore, the aim of the first study was to investigate whether female sex hormone, specifically …

Mechanistic Insights Of Mitochondrial Reactive Oxygen Species In Alzheimer's Disease Models, Jakob C. Green

Theses and Dissertations

Alzheimer’s disease (AD) is a neurodegenerative disease that results in impaired cognition, disorientation, confusion, poor judgement, and behavioral changes. The mitochondrial cascade hypothesis (MCH), which postulates that accumulating oxidative stress and mitochondrial dysfunction plays an integral role in the development of the disease, potentially upstream, in conjunction with or independent of Aβ and tau. The literature supports the critical role of mitochondrial dysfunction in the progression and development of AD, but is inconclusive about what precise role, as initiator or delegate, it performs. Regardless, the impact that oxidative stress and mitochondrial dysfunction have on AD deserves further study and investigation. …

Investigating Cannabinoid Type-1 Receptor (Cb1r) Positive Allosteric Modulators (Pams) In Mouse Models Of Overt Cannabimimetic Activity, Subjective Drug Effects, And Neuropathic Pain, Jayden Elmer

Theses and Dissertations

Chronic pain affects between 20 and 30 percent of the adult population in western countries and represents a wide array of specific etiologies (Berge, 2011). Neuropathic pain secondary to traumatic nerve injury, chemotherapeutic toxicity, or diseases (e.g., diabetes mellitus) is often refractory to conventional analgesics, with patients receiving less than 50% pain relief compared to placebo (Finnerup et al. 2010). The endocannabinoid system has shown potential as a therapeutic target for neuropathic pain wherein CB1 agonism via administration of exogenous agonists or pharmacological blockade of endocannabinoid catabolic enzymes exhibits efficacy in reversing allodynia in the chronic constriction injury (CCI) model …

Exploring The Dopamine Transporter Utilizing A Two-Pronged Approach With Novel Cathinone Analogs And Mutant Dopamine Transporters, Charles B. Jones Iii

Theses and Dissertations

The dopamine transporter (DAT) is responsible for the removal of the neurotransmitter from the synaptic gap and a therapeutic target for a multitude of drugs. While the ortholog Drosophila melanogaster dopamine transporter (dDAT) and human serotonin transporter (hSERT) have resolved structures, the human dopamine transporter (hDAT) does not. A 3-D computational homology model of hDAT was constructed for the study of molecular interactions with agents within the central binding site (S1) of the transporter.

Synthetic cathiones are a class of abused stimulant drugs that primarily target DAT. Greater than 150 cathinones have been identified on the clandestine market but there …

Development Of Sam-Based Chemical Probes For Methyltransferases, Daniel V. Mongeluzi

Theses and Dissertations

Fig.1. SAM analog for the profiling of MTase activity. A. Chemical structure of probe 1; B. General scheme of the labeling and capture strategy.

A

B

Methylation is a fundamental mechanism used in the biological system to modify the structure and function of biomolecules such as proteins, DNA, RNA, and metabolites.¹ Methyl groups are installed by a large and diverse class of S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTases), which transfer the sulfonium methyl group of SAM to either carbon, nitrogen, oxygen, or other heteroatoms on biomolecules.² Dysregulated MTase activity contributes to numerous diseases, including cancer, metabolic disorders, neurodegenerative diseases. …

Systematic Structure-Activity Relationship Studies Of Nalfurafine, Mengchu Li

Theses and Dissertations

Today’s opioid crisis is one of the most challenging public health emergency. Two million Americans suffer opioid addiction. Over 20 million adults are affected by daily pain without non-addictive analgesics.

Kappa opioid receptor (KOR) is one of the most studied new pain targets void of abuse liability. KOR agonists have shown potent analgesia and also potential in alleviating opioid addiction. The only approved KOR agonist in clinic is nalfurafine (NFU). Though not leading to addiction, the analgesic effects of NFU are accompanied by sedative side effects. Therefore, we designed a systematical structure-activity relationship study of NFU for developing non-addictive analgesics. …

Peptidomimetic And Non- Peptidomimetic Derivatives As Possible Sars-Cov-2 Main Protease (Mpro) Inhibitors, Mohammed A. Al Awadh, Mohini S. Ghatge Ph.D, Mona A. Al Khairi, Faik N. Musayev, Akua K. Donkor, Mohammed H. Al Mughram, Abdelsattar M. Omar Ph.D, Moustafa M. El-Araby Ph.D, Martin K. Safo Ph.D

Graduate Research Posters

To design novel inhibitors of the SARS-CoV-2 main protease (Mpro), we investigated the binding mode of the recently reported α-ketoamide inhibitors of this enzyme. Following, we utilized in-silico screening to identify 168 peptidomimetic and non-peptidomimetic compounds that are high probability Mpro binding candidates. The compounds were synthesized in 5 to 10 mg for initial screening for their potential inhibition of Mpro using Fluorescence Resonance Energy Transfer (FRET) assay. The study was conducted using the main protease, MBP-tagged (SARS-CoV-2) Assay Kit (BPS Bioscience, #79955-2), and the fluorescence due to enzymatic cleavage of substrate measured using BMG LABTECH CLARIOstar™, a fluorescent microplate …

Evaluation Of Antipsychotic Activity Of Ethanolic Bark Extract Of Myrica Esculenta In Rats, Biswash Sapkota, Ankit Acharya, Bishal Dangi, Annegowda Hv

Pharmaceutical Sciences and Research

The antipsychotic properties of Myrica esculenta stem bark were evaluated. The stem bark was collected, shade dried, and pulverized. Extraction was carried out with 70% ethanol by occasional shaking. Preliminary phytochemical screening of the extract was investigated in this study. Antipsychotic activity was evaluated against apomorphine-induced stereotypy using cook’s pole climbing apparatus and haloperidol-induced catalepsy models. Bioamine determination of noradrenaline and dopamine was also performed. The extract contains phytochemicals, including glycosides, flavonoids, volatile oils, proteins, saponins, phenolics, and tannins. The result showed decreased apomorphine-induced stereotyped behavior. This study reported significant dose-dependent potentiation of haloperidol-induced catalepsy in rats and a longer …

Design And Synthesis Of Pyrimidine Based Fused Heterocyclics In The Potential Treatment Of Cancer And Opportunistic Infection, Farhana Islam

Electronic Theses and Dissertations

Dose-limiting toxicities of clinically used agents and development of resistance are two significant limitations in cancer chemotherapy. Microtubule targeting agents (MTAs) are a structurally diverse set of compounds that disrupt microtubule dynamics and exert their anticancer effect. Combination chemotherapy with antiangiogenic agents and microtubule targeting agents has shown an advantage against both these drawbacks. Single agents with dual antiangiogenic activity and cytotoxicity would afford a therapy that circumvents pharmacokinetic problems of multiple agents, avoid drug-drug interactions, lower the drug dose, decrease overlapping toxicities, and delay or prevent tumor cell resistance. The work in this dissertation reflects the progress of fused …

Pharmacological Characterization Of Novel Serotonin Transporter Inhibitors Identified Through Computational Structure-Based Virtual Screening, Michael Wasko

Electronic Theses and Dissertations

Depression is a mental health disorder affecting greater than 350 million people worldwide with roughly 7% of the United States population diagnosed as of 2017. The selective serotonin reuptake inhibitors (SSRIs) have been the mainstay of pharmacotherapies for depression for the last 40 years. The SSRIs target the serotonin transporter (SERT), a monoamine transporter (MAT) responsible for terminating serotonergic neurotransmission. The SSRIs are not perfect therapeutics and suffer from delayed response times, inconsistent efficacy among patients, and often produce intolerable side effects. Therefore, a strong need exists to develop new antidepressants that are more efficacious and have fewer adverse effects. …

Long-Acting Nanoformulated Antivirals For The Treatment And Prevention Of Hiv-1 And Hbv Infections, Dhruvkumar M. Soni Dr.

Theses & Dissertations

While antiretroviral therapy (ART) has revolutionized treatment and prevention of human immunodeficiency virus type one (HIV-1) infection, regimen adherence, viral mutations, drug toxicities, stigma and pill fatigue are limitations. These have led to the development of long acting (LA) ART. These include, but are not limited to, implantable devices, new chemical entities, prodrug modifications and nanoformulations. To these ends, this thesis focues on the transformation of nucleoside reverse transcriptase inhibitors (NRTIs) into LA parenterals, While elusive, data from our laboratories demonstrated that modifications to the PROdrug and nucleoTide technology (ProTide) enables improvements in drug apparent half-life and tissue and cell …

Cd47 Differentially Regulates White And Brown Fat Function, Heather Norman-Burgdolf, Dong Li, Patrick G. Sullivan, Shuxia Wang

Pharmacology and Nutritional Sciences Faculty Publications

Mechanisms that enhance energy expenditure are attractive therapeutic targets for obesity. Previously we have demonstrated that mice lacking cd47 are leaner, exhibit increased energy expenditure, and are protected against diet-induced obesity. In this study, we further defined the physiological role of cd47 deficiency in regulating mitochondrial function and energy expenditure in both white and brown adipose tissue. We observed that cd47 deficient mice (under normal chow diet) had comparable amount of white fat mass but reduced white adipocyte size as compared to wild-type mice. Subsequent ex vivo and in vitro studies suggest enhanced lipolysis, and not impaired lipogenesis or energy …

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 …

An Update Of The Virion Proteome Of Kaposi Sarcoma-Associated Herpesvirus, Ramina Nabiee, Basir Syed, Jesus Ramirez Castano, Rukhsana Lalani, Jennifer Totonchy

Pharmacy Faculty Articles and Research

The virion proteins of Kaposi sarcoma-associated herpesvirus (KSHV) were initially characterized in 2005 in two separate studies that combined the detection of 24 viral proteins and a few cellular components via LC-MS/MS or MALDI-TOF. Despite considerable advances in the sensitivity and specificity of mass spectrometry instrumentation in recent years, leading to significantly higher yields in detections, the KSHV virion proteome has not been revisited. In this study, we have re-examined the protein composition of purified KSHV virions via ultra-high resolution Qq time-of-flight mass spectrometry (UHR-QqTOF). Our results confirm the detection of all previously reported virion proteins, in addition to 17 …

Rational Design Of 2,4-Disubstituted Quinazoline Small Molecules To Inhibit The Inflammatory Cytokine Oncostatin M, Riley Olsen

Boise State University Theses and Dissertations

Inflammation is one of the body's most important natural defense mechanisms involved in wound healing. It is usually triggered by a harmful event, such as physical trauma or exposure to external stimuli including bacteria, fungi, viruses, harmful chemicals, or environmental particulates. The inflammatory process brings blood containing inflammatory mediators consisting of leukocytes, hormones, and cytokines to the site of trauma to begin healing. However, the lack of a proper inflammatory response or an overactive response can lead to further progressive tissue damage resulting in chronic inflammatory conditions or death. The cytokine oncostatin M (OSM) is of particular interest due to …