Medicine and Health Sciences Commons^™

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

Pharmaceutical Sciences Faculty Publications

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

A Computational Analysis Of Selective Metabolism Of Bupropion By Cytochrome P450 2b6, Alyssa Santos

Honors Scholar Theses

Bupropion is an antidepressant and smoking cessation aid that is extensively metabolized by cytochrome P450 (CYP) 2B6. It is a highly lipophilic chiral drug that undergoes stereoselective metabolism with preference for the (S)-enantiomer. Despite chemical reasons for why bupropion can be metabolized by other CYP isozymes, clinically, bupropion is preferentially metabolized by CYP2B6, and at certain concentrations, CYP2E1, CYP2C19, and CYP3A4. A computational analysis with simulated molecular docking was performed using two different scoring algorithms to analyze the specific amino acid interactions between bupropion and various CYP isozymes. Trials were run using one stereoisomer of bupropion (R …

Hypoglycemic, Hypolipidemic And Antioxidant Effects Of Iridoid Glycosides Extracted From: Corni Fructus: Possible Involvement Of The Pi3k-Akt/Pkb Signaling Pathway, Jiefang Kang, Chen Guo, Rodolfo Thome, Ning Yang, Yuan Zhang, Xing Li, Xiaoyan Cao

Department of Neurology Faculty Papers

Iridoid glycosides (CIG) are the major component of Corni fructus. In this work, we researched the antioxidative, hypoglycemic and lowering blood lipids effects of CIG on diabetic mice induced by a high-fat diet (HFD) and streptozotocin (STZ). Furthermore, to investigate the molecular mechanism of action, the phosphorylation and protein expression of phosphoinositide 3-kinase (PI3K) and its downstream proteins, such as insulin receptor (INSR), protein kinase B (Akt/PKB) and glucose transporter 4 (GLUT4) have been detected. The results showed that CIG significantly improved oral glucose tolerance in diabetic mice. Biochemical indices also revealed that CIG had a positive effect on lipid …

Loss Of Fructose-1,6-Bisphosphatase Induces Glycolysis And Promotes Apoptosis Resistance Of Cancer Stem-Like Cells: An Important Role In Hexavalent Chromium-Induced Carcinogenesis, Jin Dai, Yanli Ji, Wei Wang, Donghern Kim, Leonard Yenwong Fai, Lei Wang, Jia Luo, Zhuo Zhang

Toxicology and Cancer Biology Faculty Publications

Hexavalent chromium (Cr(VI)) compounds are confirmed human carcinogens for lung cancer. Our previous studies has demonstrated that chronic exposure of human bronchial epithelial BEAS-2B cells to low dose of Cr(VI) causes malignant cell transformation. The acquisition of cancer stem cell-like properties is involved in the initiation of cancers. The present study has observed that a small population of cancer stem-like cells (BEAS-2B-Cr-CSC) exists in the Cr(VI)-transformed cells (BEAS-2B-Cr). Those BEAS-2B-Cr-CSC exhibit extremely reduced capability of generating reactive oxygen species (ROS) and apoptosis resistance. BEAS-2B-Cr-CSC are metabolic inactive as evidenced by reductions in oxygen consumption, glucose uptake, ATP production, and lactate …

Treatment Of A Chemoresistant Neuroblastoma Cell Line With The Antimalarial Ozonide Oz513., Don W. Coulter, Timothy R. Mcguire, J. Graham Sharp, Erin M. Mcintyre, Yuxiang Dong, Xiaofang Wang, Shawn Gray, Gracey R. Alexander, Nagendra K. Chatuverdi, Shantaram Joshi, Xiaoyu Chen, Jonathan L. Vennerstrom

Journal Articles: Pharmacy Practice

BACKGROUND: Evaluate the anti-tumor activity of ozonide antimalarials using a chemoresistant neuroblastoma cell line, BE (2)-c.

METHODS: The activity of 12 ozonides, artemisinin, and two semisynthetic artemisinins were tested for activity against two neuroblastoma cell-lines (BE (2)-c and IMR-32) and the Ewing's Sarcoma cell line A673 in an MTT viability assay. Time course data indicated that peak effect was seen 18 h after the start of treatment thus 18 h pre-treatment was used for all subsequent experiments. The most active ozonide (OZ513) was assessed in a propidium iodide cell cycle flow cytometry analysis which measured cell cycle transit and apoptosis. …

A Branch Point Of Streptomyces Sulfur Amino Acid Metabolism Controls The Production Of Albomycin, Aditya Kulkarni, Yu Zeng, Wei Zhou, Steven Van Lanen, Weiwen Zhang, Shawn Chen

Pharmaceutical Sciences Faculty Publications

Albomycin (ABM), also known as grisein, is a sulfur-containing metabolite produced by Streptomyces griseus ATCC 700974. Genes predicted to be involved in the biosynthesis of ABM and ABM-like molecules are found in the genomes of other actinomycetes. ABM has potent antibacterial activity, and as a result, many attempts have been made to develop ABM into a drug since the last century. Although the productivity of S. griseus can be increased with random mutagenesis methods, understanding of Streptomyces sulfur amino acid (SAA) metabolism, which supplies a precursor for ABM biosynthesis, could lead to improved and stable production. We previously characterized the …

Haemophilus Influenzae Responds To Glucocorticoids Used In Asthma Therapy By Modulation Of Biofilm Formation And Antibiotic Resistance, Chris S. Earl, Tee Wooi Keong, Shi-Qi An, Sarah Murdoch, Yvonne Mccarthy, Junkal Garmendia, Joseph Ward, J Maxwell Dow, Liang Yang, George A. O'Toole, Robert P. Ryan

Dartmouth Scholarship

Glucocorticosteroids are used as a main treatment to reduce airway inflammation in people with asthma who suffer from neutrophilic airway inflammation, a condition frequently associ- ated with Haemophilus influenzae colonization. Here we show that glucocorticosteroids have a direct influence on the behavior of H. influenzae that may account for associated difficulties with therapy. Using a mouse model of infection, we show that cortico- steroid treatment promotes H. influenzae persistence. Transcrip- tomic analysis of bacteria either isolated from infected mouse airway or grown in laboratory medium identified a number of genes encoding regulatory factors whose expression responded to the presence of …

Analyzation Of Metabolic Reprogramming In Drug-Resistant Mcf-7 Cells, Derick Han, Ho Leung, Andrew Vo

Student Scholar Symposium Abstracts and Posters

The Warburg effect states that cancer cells mainly receive their energy from anaerobic glycolysis. Thus, mitochondria play a different role in the metabolism of cancer cells as opposed to normal, healthy cells. In chemotherapy, there is always a chance of the cancer regressing. Making drug-resistant cancer cells to analyze their metabolism may change how cancer is treated. This study aimed to create drug-resistant MCF-7 cell lines with doxorubicin in order to determine the metabolic changes that have occurred in the process of becoming resistant to drug treatments.

Influence Networks Based On Coexpression Improve Drug Target Discovery For The Development Of Novel Cancer Therapeutics, Nadia M. Penrod, Jason H. Moore

Dartmouth Scholarship

Background: Thedemandfornovelmolecularlytargeteddrugswillcontinuetoriseaswemoveforwardtowardthe goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. …

Nutrition Support Therapy In Acute Kidney Injury: Distinguishing Dogma From Good Practice, Jane M. Gervasio, Ann B. Cotton

Scholarship and Professional Work – COPHS

Acute kidney injury (AKI) is a frequently observed complication in critically ill patients. Its presentation may range from the early risk of renal dysfunction to complete renal failure. Morbidity and mortality in the AKI patient increase with the decline of renal function. Appropriate nutrition therapy is essential in the medical management of the AKI patient. Assessment of nutritional requirements should take into account the patient’s underlying complication, comorbid medical conditions, and severity of the renal dysfunction. Various stages of AKI determine the direction of nutrition therapy. Additionally, understanding the macro- and micronutrient modifications and electrolyte and vitamin alterations that should …

Hepatic Disposition Of Cyclosporine A In Isolated Perfused Rat Livers, Reza Mehvar, Anjaneya Chimalakonda

Pharmacy Faculty Articles and Research

PURPOSE. To develop an isolated perfused rat liver model to study the hepatic disposition of cyclosporine A (CyA) in both sexes.

METHODS. Livers were isolated from male (n = 6) and female (n = 7) rats and perfused with a physiological buffer in a single-pass manner. A bolus 1-mg dose of CyA was injected into the inlet catheter and periodical samples (0-15 min) were collected from the outlet perfusate. The concentrations of CyA in the outlet perfusate, collected bile (0-15 min), and liver tissue (at the end of perfusion) were quantitated by HPLC and subjected to statistical moment analysis. …

Measured Energy Expenditure Of Tube-Fed Patients With Severe Neurodevelopment Disabilities, Roland N. Dickerson, Rex O. Brown, Jane M. Gervasio, Emily B. Hak, Lawrence J. Hak, John E. Williams

Scholarship and Professional Work – COPHS

Objective: To determine measured resting energy expenditure (REE) of nonambulatory tube-fed patients with severe neurological neurodevelopmental disabilities.

Methods: Twenty patients were prospectively studied. Only steady state indirect calorimetry measurements were taken. All measurements were conducted using a canopy system. Nutritional needs were met entirely by enteral feedings via a permanent ostomy.

Results: REE was widely distributed from 16 kcals/kg/day to 39 kcals/kg/day. The mean REE (888 ±176 kcals/day) of the patients was significantly (p < 0.01) lower than predicted as estimated by the Harris-Benedict equations (1081 ± 155 kcals/day) and World Health Organization equations (1194 ± 167 kcals/day). Fat-free mass (FFM) was the best parameter for predicting REE. Two predictive equations were developed that are not significantly biased and more precise (≤ 15% error) than conventional predictive formulas.

Conclusion: Conventional formulas for estimating energy expenditure are inaccurate and generally overestimate measured energy expenditure of nonambulatory patients with severe developmental …

Chronic Hypothermia And Energy Expenditure In A Neurodevelopmentally Disabled Patient: A Case Study, Jane M. Gervasio, Roland N. Dickerson, Rex O. Brown, J. Barret Matthews

Scholarship and Professional Work – COPHS

Hypothermia is defined as a core body temperature of <35°C and results in a decrease in measured resting energy expenditure. A 51-year-old mentally disabled patient experienced chronic hypothermia from neurologic sequelae. Because of her continued weight gain and increased body fat in the presence of presumed hypocaloric nutrition, indirect calorimetry measurements were performed twice in a 3-month period. The resting energy expenditure measurements prompted a reduction of her daily caloric intake to prevent further overfeeding. Hypothermia reduces oxygen consumption and, as a consequence, decreases resting energy expenditure. In patients for whom chronic hypothermia is a problem, nutritional intake must be adjusted to prevent overfeeding, excessive weight gain, and the long-term complications of an excess of total calories.