Medicine and Health Sciences Commons^™

Role Of Histone Deacetylase (Hdac) In Epithelial To Mesenchymal Transition (Emt) In A Human Cholangiocyte Model Of Ischemic Cholangiopathy, Priyanshi Pragnesh Parikh

Theses and Dissertations

Organ transplants are a vital intervention for many diseases that result in end stage organ failure. Currently, the donation pool is not meeting the demands of the transplant list. Expanding this pool to include donation after cardiac death (DCD) is highly sought-after. However, the use of DCD livers can lead to increased odds of graft failure and ischemic cholangiopathy. The loss of epithelialization and fibrosis that occurs during ischemic cholangiopathy is characteristic of these cells undergoing epithelial-to-mesenchymal transition (EMT). The biological changes the cell experiences enhance migratory capacity, invasiveness, and increased resistance to apoptosis. Our earlier studies have shown differential …

Characterizing The Effects Of Antiandrogens And Senolytics To Enhance The Therapeutic Response To Castration-Resistant Prostate Cancer, Justin M. Silverman

Theses and Dissertations

Prostate cancer is the most frequently diagnosed cancer in males and the second most common cause of cancer deaths. Androgen deprivation therapy, whether through surgical or chemical castration, is the mainstay for treatment of advanced prostate cancer; however, despite an initial response, most patients eventually develop a progressive PSA rise, and castration- sensitive prostate cancer gives rise to castration-resistant prostate cancer. The standard of care therapy includes the antiandrogens such as enzalutamide and abiraterone acetate as well as the microtubule poison, docetaxel, and various immunotherapies; however, while prostate cancer research is progressing, there continues to be a compelling need for …

Sorafenib, Rapamycin, And Venetoclax Attenuate Doxorubicin-Induced Senescence And Promote Apoptosis In Hct116 Cells, Homood M. As Sobeai, Munirah Alohaydib, Ali R. Alhoshani, Khalid Alhazzani, Mashal M. Almutairi, Tareq Saleh, David A. Gewirtz, Moureq R. Alotiabi

Pharmacology and Toxicology Publications

Emerging evidence has shown that the therapy-induced senescent growth arrest in cancer cells is of durable nature whereby a subset of cells can reinstate proliferative capacity. Promising new drugs named senolytics selectively target senescent cells and commit them into apoptosis. Accordingly, senolytics have been proposed as adjuvant cancer treatment to cull senescent tumor cells, and thus, screening for agents that exhibit senolytic properties is highly warranted. Our study aimed to investigate three agents, sorafenib, rapamycin, and venetoclax for their senolytic potential in doxorubicin-induced senescence in HCT116 cells. HCT116 cells were treated with one of the three agents, sorafenib …

Effects Of The Selective Gsk3b Inhibitor, Tideglusib, On Ethanol Consumption, Anxiety-Like Behavior, Taste Preference, And Downstream Proteins, Sam Gottlieb, Douglas Bledsoe, Jessica L. Maltman, Alanna Morgan, Jennifer T. Wolstenholme, Michael F. Miles

Graduate Research Posters

Background: We have shown modulations in glycogen synthase kinase 3 beta (GSK3B) abundance or activity regulate ethanol consumption, suggesting potential as a therapeutic target for alcohol use disorder (AUD). Here we report the GSK3B inhibitor tideglusib’s actions on ethanol consumption, basal behaviors, and modulation of GSK3B targets.

Methods: C57BL/6J males and females received i.g. 200mg/kg tideglusib, except drinking-in-the-dark (males;100mg/kg i.p.). Drinking-in-the-dark (DID): Mice given 20% ethanol 4-hours, 4-days/week x 3 weeks and then i.p. tideglusib or vehicle x 4 days in a Latin Square design with ethanol consumption measured daily. Light/Dark Box: Mice gavaged with tideglusib or vehicle …

Modified Ysk12-Mend-Sirna In Dendritic Cells For Cancer Immunotherapy, Syed S. Alam

Undergraduate Research Posters

Tumors may induce tolerogenesis through signaling dendritic cells to produce tolerogenic molecules, such as indoleamine 2, 3-dioxygenase 1 (IDO1). Tumor-associated immunosuppression is associated with higher mortality in patients. Small interfering RNA (siRNA) has been shown to silence specific target genes in the target cell. The siRNA associated with these genes could support a gene knockdown of these immunosuppressors and reduce mortality. Delivery of these therapeutic nucleic acids is difficult in vivo because siRNA is easily broken down inside the cell and the bloodstream through present nucleases. Use of liposome polymers has been reviewed extensively in literature. YSK12-C4, a lipid nanoparticle …

Selective Gsk3b Deletion In Camk2a+ Forebrain Neurons Or Inhibition Via Tideglusib, Decreases Ethanol Consumption In C57bl/6j Mice, Sam Gottlieb, Andrew D. Van Der Vaart, Brennen O'Rourke, Michael F. Miles

Graduate Research Posters

Purpose: We previously identified glycogen synthase kinase-3 beta (Gsk3b) as a central member of a gene network highly regulated by acute ethanol in medial prefrontal cortex (mPFC) and associated with risk for alcohol dependence in humans. Further, we have demonstrated modulation of Gsk3b alters ethanol consumption in rodent models. GSK3B could thus represent a potential new therapeutic target for the treatment of alcohol use disorder (AUD). Here, we investigate the mechanisms of Gsk3b action in ethanol consumption and report preclinical evidence for the selective GSK3B inhibitor, tideglusib, as a therapeutic agent for AUD.

Methods: (1) Selective Cre-induced Gsk3b …

The Effect Of The Senolytic Abt-263 On Androgen Deprivation-Induced Senescent Prostate Tumor Cells, So Min Lee

Theses and Dissertations

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men. Although standard treatments such as androgen deprivation therapies (ADT) and antiandrogens have increased survival for many patients, most men placed on these therapies will develop castration-resistant disease (CRPC). Previous studies have shown that these treatments have limited cytotoxicity and instead promote cell growth arrest. Our current work demonstrates that prostate tumor cells grown in the absence of androgens by using charcoal-stripped serum undergo senescence-mediated or senescent-like growth arrest, based on the cellular expression of senescence-associated-beta-galactosidase (SA-β-Gal). Our studies further suggest that this senescence is transient and …

The Effects Of Autophagy And Senescence On Sensitivity To Cisplatin In Head And Neck Cancer, Zara H. Siddiqui

Theses and Dissertations

While current treatments in cancer, such as chemotherapy and radiation, can generally be effective in eliminating disease in patients, there also exists the possibility of recurrence of cancer cells over time. In patients diagnosed with locally advanced head and neck carcinoma, about 50-60% develop a loco-regional recurrence within two years, and 20-30% of patients develop metastatic disease at distant sites in the body [5]. On a cellular level, one mechanism for this survival may be that natural mechanisms such as autophagy and senescence play a role in allowing cells to survive after undergoing treatment. One standard of care chemotherapy for …

In Vivo Effects Of The Cb1 Allosteric Modulator Ldk1258, A Structural Analog Of Org-27569, Mohammed A. Mustafa

Theses and Dissertations

CB1 receptor allosteric modulators are an area of growing interest for their potential novel therapeutic actions. In the present study, we examined LDK1258 in a series of pharmacological in vivo tests sensitive to CB1 receptor stimulation. In the tetrad assay, LDK1258 produced significant decreases in locomotor activity and body temperature measures but did not produce either antinociception as measured in the tail-withdrawal assay or catalepsy as assessed in the bar test. These same effects were observed in both CB1 (-/-) and (+/+) mice. Moreover, LDK1258 failed to shift the dose-response curves of two orthosteric CB1 receptor agonists in the triad …

A Pbpk Model Of Low-Concentration Vitamin D Supplementation In The Absence Of Sunlight, Colton Sawyer

Biology and Medicine Through Mathematics Conference

No abstract provided.

Diuretic, Natriuretic, And Vasodepressor Activity Of A Lipid Fraction Enhanced In Medium Of Cultured Mouse Medullary Interstitial Cells By A Selective Faah Inhibitor, Zdravka P. Daneva

Theses and Dissertations

The relationship between the endocannabinoid system in the renal medulla and the long-term regulation of blood pressure is not well understood. To investigate the possible role of the endocannabinoid system in renomedullary interstitial cells, mouse medullary interstitial cells (MMICs) were obtained, cultured and characterized for their responses to treatment with a selective inhibitor of fatty acid amide hydrolase (FAAH), PF-3845. Treatment of MMICs with PF-3845 increased cytoplasmic lipid granules detected by Sudan Black B staining and multilamellar bodies identified by transmission electron microscopy. HPLC analyses of lipid extracts of MMIC culture medium revealed a 205nm-absorbing peak that showed responsiveness to …

Effects Of Chemotherapy On Motivated Behavior And Opioid Reward In Rats, Luke P. Legakis

Theses and Dissertations

Paclitaxel, vincristine, oxaliplatin, and bortezomib are cancer chemotherapy drugs with adverse effects that include chemotherapy-induced neuropathic pain (CINP) as well as depression of behavior and mood. In the clinical setting, opioids are often used concurrently with or following chemotherapy to treat pain related to the cancer or CINP, but repeated opioid exposure can also increase the risk of opioid abuse. This dissertation evaluated the effect of chemotherapy treatment on motivated behaviors and opioid reward in rats. The main findings of this evaluation are as follows: (1) Chemotherapy, at doses that produce robust and sustained mechanical hypersensitivity produce only weak or …

Investigating The Role Of Nicotinic Acetylcholine Receptors (Nachrs) In The Development And Maintenance Of Chemotherpy-Induced Peripheral Neuropathy In Mice, Wisam B. Toma

Theses and Dissertations

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a major dose-limiting side effect of several anticancer drugs. The prevalence of CIPN ranges from one-third to two-thirds of cancer patients. CIPN can persist for months to years after completion of chemotherapy. Despite the efficacious use of paclitaxel in the treatment of tumors, it can induce many sensory symptoms, such as paresthesia, numbness, tingling and burning pain, and mechanical and cold allodynia, which typically are present in the hands and feet. Similar to other types of chronic pain, paclitaxel-induced CIPN is comorbid with depression and anxiety in cancer survivors, and paclitaxel induces changes in affect-like …

Novel Insights Into The Contribution Of Cellular Senescence To Cancer Therapy: Reversibility, Dormancy And Senolysis., Tareq Saleh

Theses and Dissertations

Cellular senescence a specialized form of growth arrest that contributes to the pathogenesis of several aging-related disorders including cancer. While by definition tumor cells are considered immortalized, they can undergo senescence when exposed to conventional and targeted cancer therapy. Therapy-Induced Senescence (TIS) represents a fundamental response to therapy and impacts its outcomes. However, TIS has been considered a positive therapeutic goal since senescent tumor cells are expected to enter a state of permanent growth abrogation. In this work we examined the hypothesis that a subpopulation of senescent cells can re-acquire proliferative potential after a state of senescent dormancy, indicating that …

Gastrointestinal Microbiota Modulate Antinociceptive Tolerance Development In Mice With Chronic Morphine Exposure, Ryan A. Mischel

Theses and Dissertations

In October 2017, the United States government declared a state of public health emergency in response to the burgeoning prescription opioid epidemic. Opioid analgesics are the gold standard of therapy for moderate to severe pain, but their clinical utility is greatly limited by analgesic tolerance – a primary driver of diminished pain control and opioid dose escalations. Integral in this process are primary afferent sensory neurons in dorsal root ganglia (DRG), the first-order components of nociceptive sensation. With surmounting evidence that morphine and other narcotics can alter gut microbial composition and promote bacterial translocation to other tissues, a question arises …

Development And Validation Of A Semi-Physiological Pharmacokinetic (Pbpk) Model To Predict Systemic And Pulmonary Exposures After Intravenous, Oral Administration And Pulmonary Inhalation Of Selected Drugs, Budesonide, Tobramycin And Ciprofloxacin, In Humans, Bishoy Hanna

Theses and Dissertations

Using a semi-PBPK modeling/quantitative meta-analysis approach, this project investigated what factors affect pulmonary and systemic exposures of Budesonide (BUD), Tobramycin (TOB), and Ciprofloxacin (CIP) after inhalation:

Three structurally different pulmonary disposition models were developed for each drug, including pulmonary absorption (all three), excretion (TOB and CIP) and sequestration (TOB) in a peripheral and central lung compartment. Systemic disposition parameters were estimated using available human mean plasma (c_p(t)) and sputum (c_s(t)) concentration profiles after IV administration, and GI absorption parameters were estimated from these profiles after oral administration. Pulmonary disposition parameters were estimated from c_p(t) …

Investigating The Role Of Nicotinic Acetylcholine Receptor Agonists In Lung Cancer Progression And Chemosensitivity In The Context Of Treating Chemotherapy-Induced Peripheral Neuropathy, Sarah L. Kyte

Theses and Dissertations

While cancer chemotherapy continues to significantly contribute to the number of cancer survivors, exposure to these drugs can often result in chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms in the hands and feet, such as numbness, burning, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a microtubule poison that is commonly used to treat breast, lung, and ovarian cancers, has been found to cause CIPN in 59-78% of cancer patients. There is currently no effective preventative or therapeutic treatment for this side effect, …

Multiple Blood-Brain Barrier Transport Mechanisms Limit Bumetanide Accumulation, And Therapeutic Potential, In The Mammalian Brain, Kerstin Römermann, Maren Fedrowitz, Philip Hampel, Edith Kaczmarek, Kathrin Töllner, Thomas Erker, Douglas H. Sweet, Wolfgang Löscher

Pharmacology and Toxicology Publications

There is accumulating evidence that bumetanide, which has been used over decades as a potent loop diuretic, also exerts effects on brain disorders, including autism, neonatal seizures, and epilepsy, which are not related to its effects on the kidney but rather mediated by inhibition of the neuronal Na-K-C1 cotransporter isoform NKCC1. However, following systemic administration, brain levels of bumetanide are typically below those needed to inhibit NKCC1, which critically limits its clinical use for treating brain disorders. Recently, active efflux transport at the blood-brain barrier (BBB) has been suggested as a process involved in the low brain:plasma ratio of bumetanide, …

A Topological Analysis Of Targeted In-111 Up- Take In Spect Images Of Murine Tumors., David Damiano

Biology and Medicine Through Mathematics Conference

No abstract provided.

Development Of A Translational Model To Screen Medications For Cocaine Use Disorder I: Choice Between Cocaine And Food In Rhesus Monkeys, Amy R. Johnson

Pharmacology and Toxicology Publications

Background

Homologous cocaine self-administration procedures in laboratory animals and humans may facilitate translational research for medications development to treat cocaine dependence. This study, therefore, sought to establish choice between cocaine and an alternative reinforcer in rhesus monkeys responding under a procedure back-translated from previous human studies and homologous to a human laboratory procedure described in a companion paper.

Methods

Four rhesus monkeys with chronic indwelling intravenous catheters had access to cocaine injections (0, 0.043, 0.14, or 0.43 mg/kg/injection) and food (0, 1, 3, or 10 1 g banana-flavored food pellets). During daily 5 h sessions, a single cocaine dose and …

Effects Of 7-Day Repeated Treatment With The 5-Ht2a Inverse Agonist/Antagonist Pimavanserin On Methamphetamine Vs. Food Choice In Male Rhesus Monkeys, Matthew L. Banks L. Banks

Pharmacology and Toxicology Publications

Background

Preclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)_2A receptors modulate mesolimbic dopamine function, such that 5-HT_2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT_2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT_2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys.

Methods …

Identification Of The Metabolic Enzyme Involved Morusin Metabolism And Characterization Of Its Metabolites By Ultraperformance Liquid Chromatogaphy Quadrupole Time-Of-Flight Mass Spectrometry (Uplc/Q-Tof-Ms/Ms), Xianbao Shi, Brianna Mackie, Gang Zhang, Shuman Yang, Yonggui Song, Dan Su, Yali Liu, Lina Shan

Pharmacology and Toxicology Publications

Morusin, the important active component of a traditional Chinese medicine, Morus alba L., has been shown to exhibit many vital pharmacological activities. In this study, six recombinant CYP450 supersomes and liver microsomes were used to perform metabolic studies. Chemical inhibition studies and screening assays with recombinant human cytochrome P450s were also used to characterize the CYP450 isoforms involved in morusin metabolism. The morusin metabolites identified varied greatly among different species. Eight metabolites of morusin were detected in the liver microsomes from pigs (PLMs), rats (RLMs), and monkeys (MLMs) by LC-MS/MS and six metabolites were detected in the liver microsomes from …

Time-Course Analysis Of Brain Regional Expression Network Responses To Chronic Intermittent Ethanol And Withdrawal: Implications For Mechanisms Underlying Excessive Ethanol Consumption, Maren L. Smith, Marcelo F. Lopez, Kellie Archer, Aaron R. Wolen, Howard C. Becker, Michael F. Miles

Pharmacology and Toxicology Publications

Long lasting abusive consumption, dependence, and withdrawal are characteristic features of alcohol use disorders (AUD). Mechanistically, persistent changes in gene expression are hypothesized to contribute to brain adaptations leading to ethanol toxicity and AUD. We employed repeated chronic intermittent ethanol (CIE) exposure by vapor chamber as a mouse model to simulate the cycles of ethanol exposure and withdrawal commonly seen with AUD. This model has been shown to induce progressive ethanol consumption in rodents. Brain CIE-responsive expression networks were identified by microarray analysis across five regions of the mesolimbic dopamine system and extended amygdala with tissue harvested from 0-hours to …

Effects Of Traumatic Brain Injury On Oxycodone Reinstatement And Physical Dependence, Neil B. Varshneya

Theses and Dissertations

Epidemiological data indicate that patients who experience a traumatic brain injury (TBI) have an elevated risk of developing a substance use disorder (SUD), but the underlying neurobiological connections remain unclear. To further understand the relationship between TBI and SUD, we investigated the effects of TBI on the abuse-related effects of oxycodone in preclinical models. Our evaluation utilized a lateral fluid percussion injury of moderate severity in adult male Sprague-Dawley rats. In the first aim, we tested the hypothesis that moderate TBI increases the risk for relapse to an opioid use disorder as measured by reinstatement of lever-pressing behavior following extinction …

Redox Regulation Of Nlrp3 Inflammasomes: Ros As Trigger Or Effector?, Justine M. Abais, Min Xia, Yang Zhang, Krishna M. Boini, Pin-Lan Li

Pharmacology and Toxicology Publications

Significance: Inflammasomes are multiprotein complexes localized within the cytoplasm of the cell that are responsible for the maturation of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, and the activation of a highly inflammatory form of cell death, pyroptosis. In response to infection or cellular stress, inflammasomes are assembled, activated, and involved in host defense and pathophysiology of diseases. Clarification of the molecular mechanisms leading to the activation of this intracellular inflammatory machinery may provide new insights into the concept of inflammation as the root of and route to human diseases. Recent Advances: The activation of inflammasomes, specifically the most …

Adipose-Derived Mesenchymal Stem Cells Improve Glucose Homeostasis In High-Fat Diet-Induced Obese Mice, Mingjun Cao, Qingjie Pan, Huanshen Dong, Xinxu Yuan, Yang Li, Zhen Sun, Xiao Dong, Hongjun Wang

Pharmacology and Toxicology Publications

Introduction

Effective therapies for obesity and diabetes are still lacking. The aim of this study was to evaluate whether a single intravenous infusion of syngeneic adipose-derived mesenchymal stem cells (ASCs) can reduce obesity, lower insulin resistance, and improve glucose homeostasis in a high-fat diet-induced obese (DIO) mouse model.

Methods

Seven-week-old C57BL/6 mice were fed a high-fat diet for 20 weeks to generate the DIO mouse model. Mice were given a single intravenous infusion of ex vivo expanded syngeneic ASCs at 2 × 10 ⁶ cells per mouse. DIO or CHOW mice injected with saline were used as controls. Body weights, …

Metabolic Interplay Between Astrocytes And Neurons Regulates Endocannabinoid Action, Andreu Viader, Jacqueline L. Blankman, Peng Zhong, Xiaojie Liu, Joel E. Scholsburg, Christopher M. Joslyn, Qing-Song Liu, Aaron J. Tomarchio, Aron H. Lichtman, Dana E. Selley, Laura J. Sim-Selley, Benjamin F. Cravatt

Pharmacology and Toxicology Publications

The endocannabinoid 2-arachidonoylglycerol (2-AG) is a retrograde lipid messenger that modulates synaptic function, neurophysiology, and behavior. 2-AG signaling is terminated by enzymatic hydrolysis—a reaction that is principally performed by monoacylglycerol lipase (MAGL). MAGL is broadly expressed throughout the nervous system, and the contributions of different brain cell types to the regulation of 2-AG activityin vivo remain poorly understood. Here, we genetically dissect the cellular anatomy of MAGL-mediated 2-AG metabolism in the brain and show that neurons and astrocytescoordinately regulate 2-AG content and endocannabinoid-dependent forms of synaptic plasticity and behavior. We also find that astrocytic MAGL is mainly responsible …

Stem Cell Conditioned Culture Media Attenuated Albumin-Induced Epithelial– Mesenchymal Transition In Renal Tubular Cells, Junping Hu, Qing Zhu, Pin-Lan Li, Weili Wang, Fan Yi, Ningjun Li

Pharmacology and Toxicology Publications

Background: Proteinuria-induced epithelial-mesenchymal transition (EMT) plays an important role in progressive renal tubulointerstitial fibrosis in chronic renal disease. Stem cell therapy has been used for different diseases. Stem cell conditioned culture media (SCM) exhibits similar beneficial effects as stem cell therapy. The present study tested the hypothesis that SCM inhibits albumin-induced EMT in cultured renal tubular cells. Methods: Rat renal tubular cells were treated with/without albumin (20 µmg/ml) plus SCM or control cell media (CCM). EMT markers and inflammatory factors were measured by Western blot and fluorescent images. Results: Albumin induced EMT as shown by significant decreases in levels of …

Differing Roles Of Autophagy In Hiv-Associated Neurocognitive Impairment And Encephalitis With Implications For Morphine Co-Exposure, Seth M. Dever, Myosotys Rodriguez, Jessica Lapierre, Blair N. Costin, Nazira El-Hage

Pharmacology and Toxicology Publications

We investigated the role of autophagy in HIV-infected subjects with neurocognitive impairment (NCI) ± HIV encephalitis (HIVE), many of which had a history of polysubstance abuse/dependence, using post-mortem brain tissues to determine whether differences in autophagy related factors may be more associated with NCI or NCI-encephalitis. Using qRT-PCR, we detected significant differences in gene expression levels with SQSTM1, LAMP1 higher in HIV-infected subjects without NCI while ATG5, SQSTM1 were then lower in HIV infection/NCI and ATG7, SQSTM1 being higher in NCI-HIVE. Immunohistochemical labeling of these autophagy associated proteins (also including Beclin 1 and LC3B) in Iba1-positive microglial cells showed generally …

Contribution Of Nrf2 To Atherogenic Phenotype Switching Of Coronary Arterial Smooth Muscle Cells Lacking Cd38 Gene, Ming Xu, Xiao-Xue Li, Lei Wang, Mi Wang, Yang Zhang, Pin-Lan Li

Pharmacology and Toxicology Publications

Background/Aims: Recent studies have indicated that CD38 gene deficiency results in dedifferentiation or transdifferentiation of arterial smooth muscle cells upon atherogenic stimulations. However, the molecular mechanisms mediating this vascular smooth muscle (SMC) phenotypic switching remain unknown. Methods & Results: In the present study, we first characterized the phenotypic change in the primary cultures of coronary arterial myocytes (CAMs) from CD38-/- mice. It was shown that CD38 deficiency decreased the expression of contractile marker calponin, SM22α and α-SMA but increased the expression of SMC dedifferentiation marker, vimentin, which was accompanied by enhanced cell proliferation. This phenotypic change in CD38-/- CAMs was …