Digital Commons Network^™

Targeting Ribonucleotide Reductase For Breast Cancer Treatment, Nahid Sultana

University of the Pacific Theses and Dissertations

Breast cancer is the second most common type of cancer in the world. Hormone receptor (HR) positive breast cancer (BC) is a prevalent disease accounting for approximately 2 million new cases globally. Almost 70-80% of breast cancer patients are women with a positive score for the estrogen receptor (ER). Triple-negative breast cancer (TNBC) which have a negative score for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) is considered an aggressive histological breast cancer subtype with limited treatment options.Frequently, doxorubicin (DOXO)-based chemotherapy is utilized in this patient population due to the lack of …

Role Of Cysteine Redox State In Altering The Epithelial-Mesenchymal Transition In Lung Cancer, Md Anisur Rahman

University of the Pacific Theses and Dissertations

Epithelial-mesenchymal transition is a process by which cancer cells increase their capability for metastasis. EMT involves conversion of epithelial cells into a mesenchymal phenotype which makes cancer cells more invasive and motile. Lung cancer has the highest mortality rate among different types of cancers globally. Lung cancer exists in various types, the most prevalent of which is non-small cell lung cancer (NSCLC). Several factors, including oxidative stress, can induce EMT in cancer cells. However, the mechanism of how reactive oxygen species (ROS)-induced changes in cysteine redox state affect EMT remains elusive. Our studies aim to understand this mechanism by inducing …

The Combinatory Effects Of Pediatric Obesity And Ontogeny On Monocarboxylate Transporter Expression In Tissues Of Drug Disposition, Michael Ng

University of the Pacific Theses and Dissertations

Proton-coupled and sodium-dependent monocarboxylate transporters are encoded by the SLC16A and SLC5A gene family of solute carriers, and are responsible for the transport of essential nutrients such as L-lactate, pyruvate, and ketone bodies. Basigin, or CD147, acts as an ancillary protein for MCT1 and MCT4, and is involved in membrane surface expression of transporters. MCT's are also involved in the shuttling of monocarboxylic xenobiotics across cell membranes, including the drugs valproate and gamma hydroxybutyrate. MCT’s are also important for normal mammalian development, particularly during embryogenesis and early neonatal life. Previous studies have shown that ketogenic diets increase MCT expression in …

Peripherally Restricted Opioid Conjugates And Its Use As Pharmacological Probes And Potential Therapeutics, Md Tariqul Haque Tuhin

University of the Pacific Theses and Dissertations

Opioid-induced constipation (OIC) is one of the major adverse effects of opioid analgesics used by millions of patients each year. While progress has been made, there remains a significant unmet medical need in the treatment of OIC. Major gaps remain in our understanding of the role of the gastrointestinal tract and central nervous system (CNS) in precipitating OIC. For the last four decades, numerous investigations to study the sites of action of opioid analgesics have utilized peripherally acting mu-opioid receptor antagonists (PAMORAs), which have been incorrectly believed to have limited penetration across the blood-brain barrier (BBB). Several preclinical and clinical …

Post-Translational Modification And Degradation Mechanisms Of The Aryl Hydrocarbon Receptor, Yujie Yang

University of the Pacific Theses and Dissertations

The aryl hydrocarbon receptor (AHR) is a transcription factor first discovered to be activated by exogenous ligands, such as dioxins, and helps promote downstream gene (e.g. CYP1A1) transcription to metabolize the toxicants. With the reports of various AHR targets genes, the expression levels and activities of AHR have been implicated in many physiological and pathological situations. Understanding how AHR protein level is regulated would provide more information to target AHR. AHR stays in the cytosol in the absence of ligand in a complex with HSP90, p23 and XAP2. After ligand activation, AHR translocates into the nucleus, fulfilling its transactivation function …

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 …

Intrapulmonary Inoculation Of Multicellular Tumor Spheroids To Construct An Orthotopic Lung Cancer Xenograft Model That Mimics Four Clinical Stages Of Non-Small Cell Lung Cancer, Yingbo Huang

University of the Pacific Theses and Dissertations

Lung cancer leads in mortality among all types of cancer in the US and Non-small cell lung cancer (NSCLC) is the major type of lung cancer. Immuno-compromised mice bearing xenografts of human lung cancer cells represent the most common animal models for studying lung cancer biology and for evaluating potential anticancer agents. However, orthotopic lung cancer models based on intrapulmonary injection of suspended cancer cells feature premature leakage of the cancer cells to both sides of the lung within five days, which generates a quick artifact of metastasis and thus belies the development and progression of lung cancer as seen …

The Role Of Sex Hormones On Monocarboxylate Transporter Expression In Tissues Related To Drug Disposition, Jieyun Cao

University of the Pacific Theses and Dissertations

Proton- and sodium-dependent monocarboxylate transporters (MCTs (SLC16A) and SMCTs (SLC5A)) transport monocarboxylates such as ketone bodies, lactate and pyruvate, as well as drugs such as gamma-hydroxybutyric acid. CD147 acts as an ancillary protein for MCT1 and MCT4, and is involved in membrane trafficking. Previously, it has been shown that MCT expression changes under different sex hormone conditions in skeletal muscle and Sertoli cells. However, it is unknown if MCTs, SMCTs or CD147 demonstrate sex differences in tissues where they play an important role in drug disposition. Monocarboxylate transporter substrates GHB and valproic acid have demonstrated sex differences in pharmacokinetic profiles. …

Investigating The Effect Of Rutaecarpine On The Benzo[A]Pyrene-Induced Dna Damage In Vitro, You Li

University of the Pacific Theses and Dissertations

Benzo[a]pyrene (BaP), is one of the most potent mutagens and carcinogens known. It requires metabolic activation through cytochrome P450 (CYP)1A1 to yield the ultimate carcinogenic metabolite, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE can bind to DNA and form predominantly covalent (+) trans adducts at the N2 position of guanine causing DNA damage. Rutaecarpine (RTC) is an herbal medicine that has been used to treat several diseases such as headache, hypertension, gastrointestinal disorders, amenorrhea, and anti-inflammation. It has also been reported as a potent inducer of CYP enzymes, including CYP1A1, and CYP1A2. The mechanisms underlying up-regulation of CYP1A1 by RTC is dependent on aryl …

The Role Of Aryl Hydrocarbon Receptor (Ahr) In Drug-Drug Interaction And The Expression Of Ahr In Pichia Pastoris, Yujuan Zheng

University of the Pacific Theses and Dissertations

The aryl hydrocarbon receptor is a ligand-activated transcription factor that is involved in many important functions in the body. To study the role and function of AHR, an abundant amount of in vitro expressed and purified protein is needed. A baculovirus insect expression system is commonly employed to express AHR, however, there are several drawbacks with this method, such as mutation potential and high cost. A better in overexpression system is needed and we hypothesize that Pichia pastoris, a yeast expression system, could stably express AHR and ARNT (aryl hydrocarbon receptor nuclear translocator) in sufficient amount with reasonable cost. Codon …

Sexual Dimorphism In Aortic Function Of Uc Davis Type 2 Diabetes Mellitus Rat Model: Estrogen Specific Responses, Farjana Akther

University of the Pacific Theses and Dissertations

Little is known about the interaction between diabetes and sex in vasculature. This study was designed to investigate the effects of estrogen as well as type 2 diabetes (T2D) on aortic function in rats with respect to sex. To test the effects of T2D and sex, UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rat model was used. To study the effects of estrogen, ovariectomized Sprague- Dawley female rats and UCD-T2DM rats at pre-diabetic stage were used and the rats were implanted subcutaneously either with placebo or 17 β-estradiol pellets (60 days release, 1.5mg/pellets). The plasma analytes for metabolic parameters and …

Mechanistic Study Of P23-Mediated Aryl Hydrocarbon Receptor Expression, Beverly Pappas

University of the Pacific Theses and Dissertations

The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule which is involved in diverse biological functions ranging from cancer metastasis to immune regulation. This receptor forms a cytoplasmic complex with Hsp90, p23, and XAP2. We have previously reported that down-regulation of p23 triggers degradation of the AHR protein, uncovering a potentially dynamic event which controls the cellular AHR levels without ligand treatment. Here we investigate the underlying mechanisms for this p23 effect using wild-type HeLa and the p23 knockdown HeLa cells. Reduction of the Hsp90 and XAP2 contents, however, did not affect the AHR protein levels, implying that this …

Polyamine And Acetylpolyamine Levels During Phenylhydrazine-Induced Erythropoiesis In Mouse Spleen, Othman A. Alshabanah

University of the Pacific Theses and Dissertations

The phenylhydrazine-induced erythropoietic mouse spleen is used as a model system to demonstrate the relationship between tissue growth and polyamine metabolism. Phenylhydrazine produced significant changes in spleen weights, hematocrits and reticulocyte counts in Swiss-Webster mice. The average spleen weight went up from a control of 155 mg to 875 mg at 96 hours after phenylhydrazine administration, while a 49% reduction in the value of hematocrit was observed at 72 hours. Reticulocyte counts in peripheral blood went from 0.8 to 58% at 168 hours after treatment with phenylhydrazine. Phenylhydrazine at a dose of 40 mg/kg produced significant increases in the levels …

Opioid Receptor Effects Of Two Aminotetralin Derivatives In Guinea Pig Ileum Longitudinal Muscle And Mouse Vas Deferens Preparations, Francisca Fatima Matos

University of the Pacific Theses and Dissertations

Two substituted analogs of 3-amino-2,2-dimethyltetralin, namely 3-dimethylamino-7-hydroxy-2,2-dimethyl-1-tetralone HBr (J) and 3-dimethylamino-7-hydroxy-2,2-dimethyl-1-tetralol (MRSAL) were evaluated for opioid agonist and antagonist activity using the electrically-stimulated guinea pig ileum longitudinal muscle and mouse vas deferens preparations. The effects of these compounds in these tissues were compared to those induced by several opioid prototype agonists at mu, kappa and delta sites (normorphine, dihydromorphine, ethylketocyclazocine, U-50,488H, beta -endorphin, dynorphin 1-13, leu-enkephalin and DADLE) and one opioid antagonist (naloxone). The results of these experiments demonstrated that compound J inhibited contractions in a concentration-dependent manner as an opioid agonist and its effects were antagonized by naloxone in …

Synthesis And Opioid-Related Activities Of Some Cis - And Trans -3-(Mono- Or Dialkylamino)-7-(Methoxy Or Hydroxy)-1-Phenyl-1,2,3,4-Tetrahydronaphthalenes, Herbert Ebiom Essien

University of the Pacific Theses and Dissertations

Cis and trans isomers of 3-(mono- or dialkylamino)-7-(methoxy or hydroxy)-1-phenyl-1,2,3,4-tetrahydronapthalenes were synthesized. Compounds HC- 11 (cis) and HT- 11 (trans) with 3- (dimethylamino) and 7-methoxy substituents and compounds HC- 13 and HT- 13 with 3- ((cyclopropylmethyl)methylamino) and 7-methoxy substituents were synthesized from their corresponding 3-(methylamino) and 7-methoxy derivatives (HC- 10 and HT- 10). HC- 10 and HT- 10 were previously prepared by reductive amination of the 3-tetralone and separated by fractional recrystallization. HC- 10 was obtained predominantly in a 9:1 ratio. Analysis of proton NMR spectral data supports the fact that both the phenyl group at C-1 and nitrogen substituents …

In Vitro Percutaneous Penetration Of Methotrexate, Rajaram Vaidyanathan

University of the Pacific Theses and Dissertations

This research project was designed to investigate the effects of various physical and chemical parameters on percutaneous penetration of methotrexate. The potential of propylene glycol in water as a vehicle for topical delivery of methotrexate has been examined. A detailed examination of solubility, partition coefficient and pH parameters in the range of 2 to 6 pH units has been conducted with the goal of correlating their effects on skin penetration of methotrexate. The importance of physiochemical parameters such as solubility and partition coefficient and their aid in the development of a suitable delivery system for topical application has been explained. …

Brunfelsia Hopeana - Pharmacologic Screening: Isolation And Characterization Of Hopeanine, Radhakrishnan Parameswaran Iyer

University of the Pacific Theses and Dissertations

The genus Brunfelsia (Fam. Solannceae) comprises some 40 species of shrubs native to South Africa and West Indies. Brunfelsia hopeana (common name: Manaca root) and related species are recognized in folk medicine in South America as being useful as diuretic, antirheumatic, antisyphilitic agents and as narcotic hallucinogens. In view of the interesting folkloric uses and a paucity of chemical and pharmacological investigation of B. hopeana, a systematic phytochemical and pharmacological investigation on B. hopeana was undertaken in our laboratory.

Hippocratic screening of the whole root powder and extracts of B. hopeana administered intrapcritonially to rats, indicated that the whole root …

The Biochemistry Of Vascular Smooth Muscle In The Spontaneously Hypertensive Rat, John Edward Taylor

University of the Pacific Theses and Dissertations

Cyclic adenosine 3’,5’-monophosphate (cAMP) was first described as the mediator of the glycogenolytic effect of epinephrine and glucagon in the liver almost two decades ago. It has since been found that cAMP may mediate the effects of a number of hormones and neurohormones, and this observation has led to the development of the second messenger hypothesis of hormone action. According to the second messenger theory, the hormone or first messenger brings information to the cell, whereas, the second messenger (cAMP) transfers this information into intracellular events. More recent evidence has described the existence of an additional second messenger, cyclic guanosine …

Sensory Nerve Activity In The Rat Following Induced Swelling And Inflammation., Jeffrey Stephen Bohrman

University of the Pacific Theses and Dissertations

Pain is one of the cardinal signs of inflammation, but its production during the inflammatory process has been poorly delineated. While analgesic and antiedema activities have been well studied in the literature, neurogram studies of nerves directly involved with local inflammation have not been reported to date.

One purpose of this investigation was to determine if differences in neurogram patterns were apparent using different phlogistic agents and electrophysical recording of the inflammation-induced “pain.”

Comparative Phytochemistry Of Saururaceae Essential Oils., Lohit Venkateswara Tutupalli

University of the Pacific Theses and Dissertations

In view of their native medicinal uses, a systematic investigation of the phytochemistry and Hippocratic screening of three members of the Saururaceac namely, Anemopsis californica, Saururus cernuus and Houttuynia cordata was undertaken.

Antibradykinin Evaluation Of Cryogenine And Selected Other Agents, Ralph William Trottier Jr.

University of the Pacific Theses and Dissertations

One intent of this study was to detect and to define any antibradykinin capacity that cryogenine may have using both in vivo and in vitro pharmacological models. The activity of cryogenine in these tests was compared to a variety of clinically-proven anti-inflammatory compounds as well as to other agents known to possess anti-inflammatory activity in certain experimentally-induced inflammations. Cryogenine is an unusual anti-inflammatory agent since it is an alkaloid - all of the commonly used anti-inflammatories (aspirin, phenylbutazone, indomethacin, etc.) are organic acids.

A Pharmacologic Investigation Of The Antiinflammatory Activity Of Cryogenine, Donald Saadia Kosersky

University of the Pacific Theses and Dissertations

This study was conducted in an attempt to define the anti inflammatory efficacy of cryogenine, the major alkaloid of Heimia salicifolia Link and Otto. The anti inflammatory effects produced by cryogenine, phenylbutazone, indomethacin, mefenamic acid, paramethasone, hydrocortisone and 6-mercaptopurine were compared considering the sequential changes in various motameters during the course of adjuvant-induced polyarthritis in rats. Polyarthritis was induced by the subplantar injection of a suspension of heat-killed Mycobacterium butyricus in mineral oil into the right hind paw of Sprague-Dawley rats. The manifestations of the diseases were monitored in terms of hind paw swelling, subjective appearance of secondary lesions, impairment …

Observations Related To The Mechanisms Of Tetracycline-Induced Lipid Accumulation In A Strain Of Mouse Fibroblasts Cultivated In Vitro, Dale William James

University of the Pacific Theses and Dissertations

Intravenous administration of tetracycline has been known to result in fatty degeneration of the liver. This study was undertaken in order to elucidate some of the actions of tetracycline on mammalian cells in culture and to attempt to relate these findings to the clinical condition of fatty degeneration of the liver mentioned above.

It is suggested that lipid accumulation occurring after tetracycline administration is possible the result of a decrease in B-lipoprotein synthesis and enzyme inhibition. These factors could result from the high blood levels of tetracycline seen after large and rapid intravenous injections of the drugs into normal patients …

The Effects Of Indomethacin On A Strain Of Fibroblasts Cultivated In Vitro, John Thomas Mccloskey

University of the Pacific Theses and Dissertations

Man has always searched for greater understanding of himself and his environment. As a result, much scientific investigation has been directed towards the understanding of the life process. In recent years, such scientific inquiry has become increasingly focused on the fundamental biochemical events taking place at the cellular, subcellular, and molecular levels. In the course of investigation into the nature of living things, research has often necessitated the development of new techniques and investigational tools to serve as experimental systems. Very often such new methods have made possible the discovery of previously unknown processes. One very interesting and useful investigational …

A Study Of Several Factors Incident To The Absorption Of Choline From The Small Intestine Of The Albino Rat, Ralph E. Purdy

University of the Pacific Theses and Dissertations

The substance choline, one of the quaternary nitrogen bases, has been the subject of a number of reviews and investigations. It has been described as a cholinergic agent, an inotropic agent, a vitamin, and perhaps in other ways. In spite of the interest shown in its action and uses, there is as yet very little information available as to the mechanism by which it is absorbed by the intestinal mucosa.

The studies referred to thus far leave the field open for additional investigation. No mention was found in the literature of studies on selective areas of absorption of choline in …