Medical Pharmacology Commons^™

Development Of A Course-Based Undergraduate Research Experience To Introduce Drug-Receptor Concepts, Hollie I. Swanson, Ok-Kyong Park-Sarge, Thushani Rodrigo-Peiris, Lin Xiang, Vincent M. Cassone

Pharmacology and Nutritional Sciences Faculty Publications

Course-based research experiences (CUREs) are currently of high interest due to their potential for engaging undergraduate students in authentic research and maintaining their interest in science, technology, engineering, and mathematics (STEM) majors. As part of a campuswide initiative called STEMCats, which is a living learning program offered to freshman STEM majors at the University of Kentucky funded by a grant from Howard Hughes Medical Institute, we have developed a CURE for freshmen interested in pursuing health care careers. Our course, entitled “Drug–Drug Interactions in Breast Cancer,” utilized a semester-long, in-class authentic research project and instructor-led discussions to engage students in …

Network-Driven Plasma Proteomics Expose Molecular Changes In The Alzheimer's Brain, Philipp A. Jaeger, Kurt M. Lucin, Markus Britschgi, Badri Vardarajan, Ruo-Pan Huang, Elizabeth D. Kirby, Rachelle Abbey, Bradley F. Boeve, Adam L. Boxer, Lindsay A. Farrer, Nicole Finch, Neill R. Graff-Radford, Elizabeth Head, Matan Hofree, Ruochun Huang, Hudson Johns, Anna Karydas, David S. Knopman, Andrey Loboda, Eliezer Masliah, Ramya Narasimhan, Ronald C. Petersen, Alexei Podtelezhnikov, Suraj Pradhan, Rosa Rademakers, Chung-Huan Sun, Steven G. Younkin, Bruce L. Miller, Trey Ideker, Tony Wyss-Coray

Pharmacology and Nutritional Sciences Faculty Publications

Background: Biological pathways that significantly contribute to sporadic Alzheimer’s disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.

Results: To access this information we probed relative levels of close to 600 secreted signaling proteins from patients’ blood samples using …

Resveratrol Supplementation Confers Neuroprotection In Cortical Brain Tissue Of Nonhuman Primates Fed A High-Fat/Sucrose Diet, Michel Bernier, Devin Wahl, Ahmed Ali, Joanne Allard, Shakeela Faulkner, Artur Wnorowski, Mitesh Sanghvi, Ruin Moaddel, Irene Alfaras, Julie A. Mattison, Stefano Tarantini, Zsuzsanna Tucsek, Zoltan Ungvari, Anna Csiszar, Kevin J. Pearson, Rafael De Cabo

Pharmacology and Nutritional Sciences Faculty Publications

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the …

Blockade Of Astrocytic Calcineurin/Nfat Signaling Helps To Normalize Hippocampal Synaptic Function And Plasticity In A Rat Model Of Traumatic Brain Injury, Jennifer L. Furman, Pradoldej Sompol, Susan D. Kraner, Melanie M. Pleiss, Esther J. Putman, Jacob Dunkerson, Hafiz Mohmmad Abdul, Kelly N. Roberts, Stephen William Scheff, Christopher M. Norris

Pharmacology and Nutritional Sciences Faculty Publications

Increasing evidence suggests that the calcineurin (CN)-dependent transcription factor NFAT (Nuclear Factor of Activated T cells) mediates deleterious effects of astrocytes in progressive neurodegenerative conditions. However, the impact of astrocytic CN/NFAT signaling on neural function/recovery after acute injury has not been investigated extensively. Using a controlled cortical impact (CCI) procedure in rats, we show that traumatic brain injury is associated with an increase in the activities of NFATs 1 and 4 in the hippocampus at 7 d after injury. NFAT4, but not NFAT1, exhibited extensive labeling in astrocytes and was found throughout the axon/dendrite layers of CA1 and the dentate …

The Role Of Pxr And Ikkβ Signaling In Cardiometabolic Disease, Robert N. Helsley

Theses and Dissertations--Pharmacology and Nutritional Sciences

Cardiovascular disease (CVD) is the leading cause of death worldwide and is partially attributed to perturbations in lipid metabolism. Xenobiotics, such as pharmaceutical drugs and environmental chemicals, have been associated with increased risk of CVD in multiple large-scale human population studies, but the underlying mechanisms remain poorly defined. We and others have identified several xenobiotics as potent agonists for the pregnane X receptor (PXR), a nuclear receptor that can be activated by numerous drugs as well as environmental and dietary chemicals. However, the role of PXR in mediating the pathophysiological effects of xenobiotic exposure in humans and animals remains elusive. …

Protein Kinase A And Epac Mediate Chronic Pain After Injury: Prolonged Inhibition By Endogenous Y1 Receptors In Dorsal Horn, Weisi Fu

Theses and Dissertations--Physiology

Inflammation or nerve injury sensitizes several populations of nociceptive neurons in the dorsal horn of the spinal cord, including those that express the neuropeptide Y (NPY) Y1 receptor (Y1R). Our overall hypothesis is that after tissue or nerve injury, these Y1R-expressing neurons enter a state of latent sensitization (LS) that contributes to vulnerability to the development of chronic pain; furthermore, LS is under the tonic inhibitory control of endogenous Y1R signaling. First, we evaluated the intracellular signaling pathways that become activated in Y1R-expressing neurons and participate in LS. To do this, we established behavioral models of inflammatory or neuropathic pain, …

Chronic Ethanol Exposure Enhances The Aggressiveness Of Breast Cancer: The Role Of P38Γ, Mei Xu, Siying Wang, Zhenhua Ren, Jacqueline A. Frank, Xiuwei H. Yang, Zhuo Zhang, Zun-Ji Ke, Xianglin Shi, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Both epidemiological and experimental studies suggest that ethanol may enhance aggressiveness of breast cancer. We have previously demonstrated that short term exposure to ethanol (12–48 hours) increased migration/invasion in breast cancer cells overexpressing ErbB2, but not in breast cancer cells with low expression of ErbB2, such as MCF7, BT20 and T47D breast cancer cells. In this study, we showed that chronic ethanol exposure transformed breast cancer cells that were not responsive to short term ethanol treatment to a more aggressive phenotype. Chronic ethanol exposure (10 days - 2 months) at 100 (22 mM) or 200 mg/dl (44 mM) caused the …

Endoplasmic Reticulum Stress And Ethanol Neurotoxicity, Fanmuyi Yang, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Ethanol abuse affects virtually all organ systems and the central nervous system (CNS) is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD) which is associated with mental retardation and other behavioral deficits. A number of potential mechanisms have been proposed for ethanol-induced brain damage; these include the promotion of neuroinflammation, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, and thiamine deficiency. The endoplasmic reticulum (ER) regulates posttranslational protein processing and transport. The accumulation of …

Cd151-Α3Β1 Integrin Complexes Are Prognostic Markers Of Glioblastoma And Cooperate With Egfr To Drive Tumor Cell Motility And Invasion, Pengcheng Zhou, Sonia Erfani, Zeyi Liu, Changhe Jia, Yecang Chen, Bingwei Xu, Xinyu Deng, Jose E. Alfáro, Li Chen, Dana L. Napier, Michael Lu, Jian-An Huang, Chunming Liu, Olivier Thibault, Rosalind Segal, Binhua P. Zhou, Natasha Kyprianou, Craig Horbinski, Xiuwei H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Glioblastoma, one of the most aggressive forms of brain cancer, is featured by high tumor cell motility and invasiveness, which not only fuel tumor infiltration, but also enable escape from surgical or other clinical interventions. Thus, better understanding of how these malignant traits are controlled will be key to the discovery of novel biomarkers and therapies against this deadly disease. Tetraspanin CD151 and its associated α3β1 integrin have been implicated in facilitating tumor progression across multiple cancer types. How these adhesion molecules are involved in the progression of glioblastoma, however, remains largely unclear. Here, we examined an in-house tissue microarray-based …

Intracellular Na+ Concentration ([Na+]I) Is Elevated In Diabetic Hearts Due To Enhanced Na+–Glucose Cotransport, Rebekah Lambert, Sarah Srodulski, Xiaoli Peng, Kenneth B. Margulies, Florin Despa, Sanda Despa

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Intracellular Na⁺ concentration ([Na⁺]i) regulates Ca²⁺ cycling, contractility, metabolism, and electrical stability of the heart. [Na⁺]i is elevated in heart failure, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na⁺]i is also increased in type 2 diabetes (T2D) due to enhanced activity of the Na⁺-glucose cotransporter.

METHODS AND RESULTS: To test this hypothesis, we used myocardial tissue from humans with T2D and a rat model of late-onset T2D (HIP rat). Western blot analysis showed increased Na⁺-glucose cotransporter expression in failing hearts from T2D patients compared …

Reversal Of Aging-Related Neuronal Ca2+ Dysregulation And Cognitive Impairment By Delivery Of A Transgene Encoding Fk506-Binding Protein 12.6/1b To The Hippocampus, John C. Gant, Kuey-Chu Chen, Inga Kadish, Eric M. Blalock, Olivier Thibault, Nada M. Porter, Philip W. Landfield

Pharmacology and Nutritional Sciences Faculty Publications

Brain Ca(2+) regulatory processes are altered during aging, disrupting neuronal, and cognitive functions. In hippocampal pyramidal neurons, the Ca(2+)-dependent slow afterhyperpolarization (sAHP) exhibits an increase with aging, which correlates with memory impairment. The increased sAHP results from elevated L-type Ca(2+) channel activity and ryanodine receptor (RyR)-mediated Ca(2+) release, but underlying molecular mechanisms are poorly understood. Previously, we found that expression of the gene encoding FK506-binding protein 12.6/1b (FKBP1b), a small immunophilin that stabilizes RyR-mediated Ca(2+) release in cardiomyocytes, declines in hippocampus of aged rats and Alzheimer's disease subjects. Additionally, knockdown/disruption of hippocampal FKBP1b in young rats augments neuronal Ca(2+) responses. …

D-Tagatose-Based Compositions And Methods For Preventing And Treating Atherosclerosis, Metabolic Syndrome, And Symptoms Thereof, Robert A. Lodder, Lisa A. Cassis

Pharmacology and Nutritional Sciences Faculty Patents

Pharmaceutical compositions including D-tagatose along with a stilbene or stilbenoid component, or a salt or derivative thereof. Methods of prophylaxis and therapy by administering to a mammal a pharmaceutically effective amount of D-tagatose, optionally in combination with a stilbene or stilbenoid component, or a salt or derivative thereof to prevent or treat atherosclerosis, the metabolic syndrome, obesity, or diabetes.

Angiotensin Ii Is Required To Induce Exaggerated Salt Sensitivity In Dahl Rats Exposed To Maternal Separation, Analia S. Loria, David M. Pollock, Jennifer S. Pollock

Pharmacology and Nutritional Sciences Faculty Publications

We previously reported that maternal separation, rat model of early life stress, enhances pressor responses to acute and chronic stressors. The aims of this study were to determine whether Dahl salt-sensitive (DS) rats subjected to maternal separation (MatSep-DS) as compared to normally reared DS (Ctl-DS) rats show exaggerated blood pressure responses to acute behavioral stressors, such as restraint stress or air jet stress (AJS), or, hypertensive stimuli including chronic high-salt diet (4% NaCl) and angiotensin II (AngII) infusion (200 ng/Kg/min) during 1 week. MatSep was performed in male DS rats for 3 h/day from postnatal days 2-14. At 8 weeks …

Thrombospondin1 Deficiency Attenuates Obesity-Associated Microvascular Complications In Apoe-/- Mice, Hasiyeti Maimaitiyiming, Kate Clemons, Qi Zhou, Heather Norman, Shuxia Wang

Pharmacology and Nutritional Sciences Faculty Publications

Obesity is associated with insulin resistance and the increased development of vascular complications. Previously, we have demonstrated that thrombospondin1 (TSP1) regulates macrophage function and contributes to obesity associated inflammation and insulin resistance. However, the role of TSP1 in the development of obesity associated vascular complications is not clear. Therefore, in the current study, we investigated whether TSP1 deficiency protects mice from obesity associated micro as well as macro-vascular complications in ApoE-/- mice. In this study, male ApoE-/- mice and ApoE-/-TSP1-/- mice were fed with a low-fat (LF) or a high-fat (HF) diet for 16 weeks. We found that body weight …

Cd47 Deficiency Protects Mice From Diet-Induced Obesity And Improves Whole Body Glucose Tolerance And Insulin Sensitivity, Hasiyeti Maimaitiyiming, Heather Norman, Qi Zhou, Shuxia Wang

Pharmacology and Nutritional Sciences Faculty Publications

CD47 is a transmembrane protein with several functions including self-recognition, immune cell communication, and cell signaling. Although it has been extensively studied in cancer and ischemia, CD47 function in obesity has never been explored. In this study, we utilized CD47 deficient mice in a high-fat diet induced obesity model to study for the first time whether CD47 plays a role in the development of obesity and metabolic complications. Male CD47 deficient and wild type (WT) control mice were fed with either low fat (LF) or high fat (HF) diets for 16 weeks. Interestingly, we found that CD47 deficient mice were …

Activation Of The Nf-Κb Pathway As A Mechanism Of Alcohol Enhanced Progression And Metastasis Of Human Hepatocellular Carcinoma, Fei Wang, Jin-Lian Yang, Ke-Ke Yu, Mei Xu, You-Zhi Xu, Li Chen, Yan-Min Lu, Hao-Shu Fang, Xin-Yi Wang, Zhong-Qian Hu, Fei-Fei Li, Lixin Kan, Jia Luo, Si-Ying Wang

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is the third leading cause of cancer-related death in human. Alcohol is a known risk factor for HCC. However it is still unclear whether and how alcohol enhances the progression and metastasis of existing HCC.

METHODS AND RESULTS: We first retrospectively investigated 52 HCC patients (24 alcohol-drinkers and 28 non-drinkers), and found a positive correlation between alcohol consumption and advanced Tumor-Node-Metastasis (TNM) stages, higher vessel invasion and poorer prognosis. In vitro and in vivo experiments further indicated that alcohol promoted the progression and migration/invasion of HCC. Specifically, in …

Pact/Rax Regulates The Migration Of Cerebellar Granule Neurons In The Developing Cerebellum, Yue Yong, Ya Meng, Hanqing Ding, Zhiqin Fan, Yifen Tang, Chenghua Zhou, Jia Luo, Zun-Ji Ke

Pharmacology and Nutritional Sciences Faculty Publications

PACT and its murine ortholog RAX were originally identified as a protein activator for the dsRNA-dependent, interferon-inducible protein kinase PKR. Recent studies indicated that RAX played a role in embryogenesis and neuronal development. In this study, we investigated the expression of RAX during the postnatal development of the mouse cerebellum and its role in the migration of cerebellar granule neurons (CGNs). High expression of RAX was observed in the cerebellum from postnatal day (PD) 4 to PD9, a period when the CGNs migrate from the external granule layer (EGL) to the internal granule layer (IGL). The migration of the EGL …

Mitochondrial And Neuroprotective Effects Of Phenelzine Related To Scavenging Of Neurotoxic Lipid Peroxidation Products, John Cebak

Theses and Dissertations--Neuroscience

Lipid peroxidation is a key contributor to the pathophysiology of traumatic brain injury (TBI). Traditional antioxidant therapies are intended to scavenge the free radicals responsible for either the initiation or propagation of lipid peroxidation (LP). However, targeting free radicals after TBI is difficult as they rapidly react with other cellular macromolecules, and thus has a limited post-injury time window in which they may be intercepted by a radical scavenging agent. In contrast, our laboratory has begun testing an antioxidant approach that scavenges the final stages of LP i.e. formation of carbonyl-containing breakdown products. By scavenging breakdown products such as the …

Cd151-Α3Β1 Integrin Complexes Suppress Ovarian Tumor Growth By Repressing Slug-Mediated Emt And Canonical Wnt Signaling, Lauren A. Baldwin, John T. Hoff, Jason Lefringhouse, Michael Zhang, Changhe Jia, Zeyi Liu, Sonia Erfani, Hongyan Jin, Mei Xu, Qing-Bai She, John R. Van Nagell Jr., Chi Wang, Li Chen, Rina Plattner, David M. Kaetzel, Jia Luo, Michael Lu, Dava West, Chunming Liu, Fred R. Ueland, Ronny Drapkin, Binhua P. Zhou, Xiuwei H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3β1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by …

A Pilot Study On The Use Of Lecture Tools To Enhance The Teaching Of Pharmacokinetics And Pharmacodynamics, Hollie I. Swanson, Michael T. Piascik

Pharmacology and Nutritional Sciences Faculty Publications

Pharmacokinetics and pharmacodynamics are essential topics contained within the medical curriculum and are highly amenable to active-learning approaches. In this pilot study, we incorporated Lecture Tools, a cloud-based audience response system, into a lecture-based graduate course. Lecture Tools was used by both the instructors and the students during peer presentations. Advantages noted by the instructors include the versatility of the questions that can be presented and the ease with which student assessment can be conducted. Student surveys revealed that, overall, the use of Lecture Tools enhanced student attentiveness and engagement and facilitated student participation in questions and answers. Some disadvantages …

Sex-Specific Alterations In Nos Regulation Of Vascular Function In Aorta And Mesenteric Arteries From Spontaneously Hypertensive Rats Compared To Wistar Kyoto Rats, Analia S. Loria, Krystal N. Brinson, Brandon M. Fox, Jennifer C. Sullivan

Pharmacology and Nutritional Sciences Faculty Publications

The present study tested the hypothesis that spontaneously hypertensive rats (SHR) have impaired nitric oxide synthase (NOS)-mediated regulation of vascular function versus Wistar-Kyoto rats (WKY). Aorta and small mesenteric arteries were studied from male and female SHR (M SHR and F SHR) and WKY (M WKY and F WKY). Phenylephrine (PE)-induced vasoconstriction was greater in aorta of M SHR versus all others (P < 0.05); there were neither sex nor strain differences in PE contraction in mesenteric arteries. The NOS inhibitor l-Nitro-Arginine Methyl Ester (l-NAME) increased PE-induced vasoconstriction in all rats, although the increase was the least in male SHR (P < 0.05), revealing a blunted vasoconstrictor buffering capacity of NOS. l-NAME increased sensitivity to PE-induced constriction only in mesenteric arteries of SHR, although, the maximal percent increase in contraction was comparable among groups. ACh-induced relaxation was also less in aorta from M SHR versus all others (P < 0.05). ACh relaxation was comparable among groups in mesenteric arteries, although SHR exhibited a greater NOS component to ACh-induced relaxation than WKY. To gain mechanistic insight into sex and strain differences in vascular function, NOS activity and NOS3 protein expression were measured. Aortic NOS activity was comparable between groups and M SHR had greater NOS3 expression than M WKY. In contrast, although vascular function was largely maintained in mesenteric arteries of SHR, NOS activity was less in SHR versus WKY. In conclusion, M SHR exhibit a decrease in NOS regulation of vascular function compared to F SHR and WKY, although this is not mediated by decreases in NOS activity and/or expression.

Neuroinflammation And Neurologic Deficits In Diabetes Linked To Brain Accumulation Of Amylin, Sarah Srodulski, Savita Sharma, Adam B. Bachstetter, Jennifer M. Brelsfoard, Conrado Pascual, Xinmin Simon Xie, Kathryn E. Saatman, Linda J. Van Eldik, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: We recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment contains deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells. Amylin deposition is promoted by chronic hypersecretion of amylin (hyperamylinemia), which is common in humans with obesity or pre-diabetic insulin resistance. Human amylin oligomerizes quickly when oversecreted, which is toxic, induces inflammation in pancreatic islets and contributes to the development of T2D. Here, we tested the hypothesis that accumulation of oligomerized amylin affects brain function.

METHODS: In contrast to amylin from humans, rodent amylin is neither amyloidogenic nor cytotoxic. …

Cardioprotection By Controlling Hyperamylinemia In A "Humanized" Diabetic Rat Model, Sanda Despa, Savita Sharma, Todd R. Harris, Hua Dong, Ning Li, Nipavan Chiamvimonvat, Heinrich Taegtmeyer, Kenneth B. Margulies, Bruce D. Hammock, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Chronic hypersecretion of the pancreatic hormone amylin is common in humans with obesity or prediabetic insulin resistance and induces amylin aggregation and proteotoxicity in the pancreas. We recently showed that hyperamylinemia also affects the cardiovascular system. Here, we investigated whether amylin aggregates interact directly with cardiac myocytes and whether controlling hyperamylinemia protects the heart.

METHODS AND RESULTS: By Western blot, we found abundant amylin aggregates in lysates of cardiac myocytes from obese patients, but not in controls. Aggregated amylin was elevated in failing hearts, suggesting a role in myocyte injury. Using rats overexpressing human amylin in the pancreas (HIP …

Method For Treating Hair Growth Disorders, Such As Female Pattern Alopecia, And Compositions Useful Therefore, Elaine L. Jacobson, Myron K. Jacobson, Hyuntae Kim, Donna L. Coyle, William R. Coyle

Pharmacology and Nutritional Sciences Faculty Patents

The invention relates to formulations useful in treating hair disorders, improving the health of hair, increasing hair growth, and in increasing the niacin content of hair follicles. Nicotinic acid alkyl esters having a straight chain alkyl group of from 1 to 22 methylene units, preferably from 6 to 16 methylene units, and most preferably from 8 to 14 methyl units, may be used, alone or in combinations for treating these conditions.

Frontal White Matter Integrity In Adults With Down Syndrome With And Without Dementia, David K. Powell, Allison Caban-Holt, Greg A. Jicha, William C. Robertson, Roberta Davis, Brian T. Gold, Frederick A. Schmitt, Elizabeth Head

Magnetic Resonance Imaging and Spectroscopy Center Faculty Publications

Adults with Down syndrome (DS) are at high risk for developing Alzheimer's disease after the age of 40 years. To detect white matter (WM) changes in the brain linked to dementia, fractional anisotropy (FA) from diffusion tensor imaging was used. We hypothesized that adults with DS without dementia (DS n = 10), DS with dementia (DSAD n = 10) and age matched non-DS subjects (CTL n = 10) would show differential levels of FA and an association with scores from the Brief Praxis Test and the Severe Impairment Battery. WM integrity differences in DS compared with CTL were found predominantly …

Spatiotemporal Expression Of Manf In The Developing Rat Brain, Haiping Wang, Zunji Ke, Alexander Alimov, Mei Xu, Jacqueline A. Frank, Shengyun Fang, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved neurotrophic factor which exhibited neuroprotective properties. Recent studies suggested that MANF may play a role in the neural development of Drosophila and zebra fishes. In this study, we investigated the spatiotemporal expression of MANF in the brain of postnatal and adult rats. MANF expression appeared wide spread and mainly localized in neurons. In the cerebral cortex, neurons in layer IV and VI displayed particularly strong MANF immunoreactivity. In the hippocampus, intensive MANF expression was observed throughout the subfields of Cornu Amonis (CA1, CA2, and CA3) and the granular layer of the …

Aged Rats Are Hypo-Responsive To Acute Restraint: Implications For Psychosocial Stress In Aging, Heather M. Buechel, Jelena Popovic, Kendra Staggs, Katie L. Anderson, Olivier Thibault, Eric M. Blalock

Pharmacology and Nutritional Sciences Faculty Publications

Cognitive processes associated with prefrontal cortex and hippocampus decline with age and are vulnerable to disruption by stress. The stress/stress hormone/allostatic load hypotheses of brain aging posit that brain aging, at least in part, is the manifestation of life-long stress exposure. In addition, as humans age, there is a profound increase in the incidence of new onset stressors, many of which are psychosocial (e.g., loss of job, death of spouse, social isolation), and aged humans are well-understood to be more vulnerable to the negative consequences of such new-onset chronic psychosocial stress events. However, the mechanistic underpinnings of this age-related shift …

The Rak/Frk Tyrosine Kinase Associates With And Internalizes The Epidermal Growth Factor Receptor, Ling Jin, Rolf J. Craven

Pharmacology and Nutritional Sciences Faculty Publications

Src is the founding member of a diverse family of intracellular tyrosine kinases, and Src has a key role in promoting cancer growth, in part, through its association with receptor tyrosine kinases. However, some Src-related proteins have widely divergent physiological roles, and these proteins include the Rak/Frk tyrosine kinase (Frk stands for Fyn-related kinase), which inhibits cancer cell growth and suppresses tumorigenesis. Rak/Frk phosphorylates and stabilizes the Pten tumor suppressor, protecting it from degradation, and Rak/Frk associates with the retinoblastoma (Rb) tumor suppressor. However, the role of Rak/Frk in receptor-mediated signaling is largely unknown. Here, we demonstrate that Rak/Frk associates …

Phosphatidylinositol 3-Kinase (Pi3k) As A Therapeutic Target In Nsclc, Christopher W. Stamatkin

Theses and Dissertations--Pharmacy

Deregulated activation of phosphatidylinositol 3-kinase (PI3K) pathway is central to many human malignancies. The functions of this pathway are critical for normal cell metabolism, proliferation, and survival. In lung cancers, the PI3K pathway activity is often aberrantly driven by multiple mutations, including EGFR, KRAS, and PIK3CA. Molecules targeting the PI3K pathway are intensely investigated as potential anti-cancer agents. Although inhibitors of the pathway are currently in clinical trials, rational and targeted use of these compounds, alone or in combination, requires an understanding of isoform-specific activity in context. We sought to identify class IA PI3K enzyme (p110a/PIK3CA, p110b/PIK3CB, p110d/PIK3CD) activities using …

Biochemical Pathways In Cancer, Eun-Kyoung Yim Breuer, Mandi M. Murph, Rolf J. Craven

Pharmacology and Nutritional Sciences Faculty Publications

No abstract.