Molecular Biology Commons^™

Modeling Biphasic, Non-Sigmoidal Dose-Response Relationships: Comparison Of Brain- Cousens And Cedergreen Models For A Biochemical Dataset, Venkat D. Abbaraju, Tamaraty L. Robinson, Brian P. Weiser

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Biphasic, non-sigmoidal dose-response relationships are frequently observed in biochemistry and pharmacology, but they are not always analyzed with appropriate statistical methods. Here, we examine curve fitting methods for “hormetic” dose-response relationships where low and high doses of an effector produce opposite responses. We provide the full dataset used for modeling, and we provide the code for analyzing the dataset in SAS using two established mathematical models of hormesis, the Brain-Cousens model and the Cedergreen model. We show how to obtain and interpret curve parameters such as the ED50 that arise from modeling, and we discuss how curve parameters might change …

A Conserved Mechanism For Hormesis In Molecular Systems, Sharon N. Greenwood, Regina G. Belz, Brian P. Weiser

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Hormesis refers to dose-response phenomena where low dose treatments elicit a response that is opposite the response observed at higher doses. Hormetic dose-response relationships have been observed throughout all of biology, but the underlying determinants of many reported hormetic dose-responses have not been identified. In this report, we describe a conserved mechanism for hormesis on the molecular level where low dose treatments enhance a response that becomes reduced at higher doses. The hormetic mechanism relies on the ability of protein homo-multimers to simultaneously interact with a substrate and a competitor on different subunits at low doses of competitor. In this …

Investigating The Efficacy Of Tazemetosttat For In Vitro Treatment Of Human Triple Negative Breast Cancer Cells, Harshita Indukuri

Honors Scholars Collaborative Projects

Cancer is a formidable, genetic disease that affects many people, either directly or indirectly. Breast cancer is the most commonly diagnosed cancer worldwide (31). Triple-negative breast cancer (TNBC) is a type of breast cancer that has a higher lethality compared to other breast cancers and has a poor prognosis due to its highly invasive nature and limited treatment options. Finding safe, effective, and accessible treatment for TNBC is integral to treating TNBC patients. Tazemetostat is an EZH2-inhibitor that has recently been approved for use in epithelioid sarcoma (23). EZH2 is an overexpressed protein in many cancers, including TNBC (11). However, …

The Development Of Inhibitors For Sars-Cov-2 Orf8, My Thanh Thao Nguyen

CSB/SJU Distinguished Thesis

An unexpected outbreak of SARS-CoV-2 caused a worldwide pandemic in 2020. Many repurposed drugs were tested, but there are currently only three FDA approved antivirals (Merck’s antiviral Molnupiravir, Pfizer’s antiviral Paxlovid, and Remdisivir).1 Most of the antiviral drugs tested SARS-CoV-2 main protease and RNA-dependent RNA polymerase. However, it is important to explore different drug targets of SARS-CoV-2 to prepare for the virus mutations of the future. This research looks at an alternative approach in which SARSCoV- 2 Open Reading Frame 8 (ORF8), which has been shown to be a rapidly evolving hypervariable gene, was chosen to be the protein of …

Neuroprotective Effect Of Liraglutide In An Experimental Mouse Model Of Multiple Sclerosis: Role Of Ampk/Sirt1 Signaling And Nlrp3 Inflammasome, Reham A. Ammar, Ahmed F. Mohamed, Mohamed M. Kamal, Marwa M. Safar, Noha F. Abdelkader

Pharmacy

The heterogeneous nature of multiple sclerosis (MS) and the unavailability of treatments addressing its intricate network and reversing the disease state is yet an area that needs to be elucidated. Liraglutide, a glucagon-like peptide-1 analogue, recently exhibited intriguing potential neuroprotective effects. The currents study investigated its potential effect against mouse model of MS and the possible underlying mechanisms. Demyelination was induced in C57Bl/6 mice by cuprizone (400 mg/kg/day p.o.) for 5 weeks. Animals received either liraglutide (25 nmol/kg/day i.p.) or dorsomorphin, an AMPK inhibitor, (2.5 mg/ Kg i.p.) 30 min before the liraglutide dose, for 4 weeks (starting from the …

Investigation Of Oncogenic Ras And Endoplasmic Reticulum-Mitochondria Calcium Flux And Their Relationship In The Context Of Tumorigenesis, Emma Anderson

Senior Honors Theses

Intracellular calcium as a signaling molecule is a pervasive feature of cellular pathways, especially those that manage internal homeostasis and transitions through the cell cycle, so much so that regulated, responsive calcium flux between the endoplasmic reticulum (ER) and the mitochondria has been suggested to play a major role in cancer development. Another factor commonly implicated in tumorigenesis is RAS, an oncogene that controls signaling for many pathways that are also regulated by calcium. While both calcium and oncogenic RAS signaling are implicated in cancer development, possible links between them have yet to be determined. The identification of these links …

High And Low Toxin Producing Strains Of Karenia Brevis Differ Significantly In The Redox Proteome, Lipid Profiles, And Xanthophyll Cycle Pigments, Ricardo Colon

FIU Electronic Theses and Dissertations

The dinoflagellate Karenia brevis, blooms annually in the Gulf of Mexico, producing a suite of neurotoxins known as the brevetoxins. The cellular toxin content of K. brevis, however, is highly variable between or even within strains. I investigated biochemical differences between high (KbHT) and low (KbLT) toxin producing cultures both derived from the Wilson strain, related to energy-dependent quenching (qE) by photosystem II, and the content of reduced thiols of the proteome. By characterizing the xanthophyll content of the two strains I was able to determine that KbLT performs qE inconsistently. To investigate the …

Type I Topoisomerases As Potential Targets For Therapeutics, Ahmed Seddek

FIU Electronic Theses and Dissertations

DNA topoisomerases are universal enzymes that control the topological features of DNA in all forms of life. This study aims to find potential inhibitors of some of the DNA topoisomerases in bacteria and humans that can be developed into potential therapeutics.

The first aim of this study is to find potential inhibitors of bacterial topoisomerase I that can be developed into antibiotics. There is an urgent need to develop novel antibiotics to overcome the world-wide health crisis of antimicrobial resistance. Virtual screening and biochemical assays were combined to screen thousands of compounds for potential inhibitors of bacterial topoisomerase I. NSC76027 …

An Investigation Into The Adverse Effects Of Oxidative Stress From Exposure To Bisphenol A And Its Analogues, Rachel Nas

Senior Honors Theses

Oxidative stress is a physiological event caused by an overaccumulation of reactive oxygen species (ROS) within the body. While ROS are a natural by-product of oxygen metabolism, too many can lead to cell and tissue damage and contribute to many etiologies. Bisphenol A (BPA), a component of many plastic products, has been shown to induce oxidative stress. While the industrial usage of BPA usage has lessened, the safety of its replacements is unknown. This paper will primarily discuss ROS and mechanisms of oxidative stress, the usage of BPA and its analogues, etiologies associated with oxidative stress resulting from exposure to …

Cloning And Characterization Of A Pyrethroid Pesticide Decomposing Esterase Gene, Est3385, From Rhodopseudomonas Palustris Psb-S, Xiangwen Luo, Deyong Zhang, Xuguo Zhou, Jiao Du, Songbai Zhang, Yong Liu

Entomology Faculty Publications

Full length open reading frame of pyrethroid detoxification gene, Est3385, contains 963 nucleotides. This gene was identified and cloned based on the genome sequence of Rhodopseudomonas palustris PSB-S available at the GneBank. The predicted amino acid sequence of Est3385 shared moderate identities (30–46%) with the known homologous esterases. Phylogenetic analysis revealed that Est3385 was a member in the esterase family I. Recombinant Est3385 was heterologous expressed in E. coli, purified and characterized for its substrate specificity, kinetics and stability under various conditions. The optimal temperature and pH for Est3385 were 35 °C and 6.0, respectively. This enzyme could …

Contractile Response Of Bovine Lateral Saphenous Vein To Ergotamine Tartrate Exposed To Different Concentrations Of Molecularly Imprinted Polymer, Manoj B. Kudupoje, James L. Klotz, Alexandros Yiannikouris, Karl A. Dawson, Kyle R. Mcleod, Eric S. Vanzant

Animal and Food Sciences Faculty Publications

Ergot alkaloids, in their active isomeric form, affect animal health and performance, and adsorbents are used to mitigate toxicities by reducing bioavailability. Adsorbents with high specificity (molecularly imprinted polymers: MIP) adsorb ergot alkaloids in vitro, but require evaluation for biological implications. Using ex vivo myography, synthetic polymers were evaluated for effects on the bioactivity of ergotamine tartrate (ETA). Polymers were first evaluated using isotherms. Lateral saphenous veins were collected from 17 steers for four independent studies: dose response of ETA, adsorbent dose response, validation of pre-myograph incubation conditions and MIP/ non-molecularly imprinted polymer (NIP) comparison. Norepinephrine normalized percent contractile response …

9-Aminoacridine Inhibits Ribosome Biogenesis And Synergizes With Cytotoxic Drugs To Induce Selective Killing Of P53-Deficient Cells, Leonid Anikin, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Common cancer treatments target rapidly dividing cells and do not discriminate between cancer and normal host cells. One approach to mitigating negative side‐effects of cancer treatment is to temporarily arrest cell cycle progression and thus protect normal cells during cytotoxic treatments, a concept called cyclotherapy. We recently proposed that transient inhibition of post‐transcriptional steps of ribosome biogenesis (RBG) can be used to selectively arrest p53‐positive host cells and not p53‐null cancer cells. In this study, we investigated whether cytoprotective RBG inhibition can be achieved through small molecule treatment.

The Effect Of Target-Specific Biomolecules In Breast Cancer, Mohannad Garoub

FIU Electronic Theses and Dissertations

Cancer is the second leading cause of mortality in the United States and the World, therefore, early effective prevention, diagnosis, and therapy is needed. Estrogens play a major role in the initiation and progression of breast cancer. Elevated lifetime exposure to estrogens is associated with an increased risk of developing breast cancer. Estrogens through influencing mitochondria contribute to estrogen induced breast carcinogenesis; however, the exact mitochondrial mechanisms underlying the estrogen carcinogenic effect in breast tissue are not clearly understood. For this dissertation, the mitotoxic and cytotoxic effects of triphenylphosphonium cation (TPP) and Origanum majorana organic extract (OME) as well as …

Survival Model Of Intrahepatic Cholangiocarcinoma; Sex As A Biological Variable, Mary A. Phillippi, Justin L. Mott, Cody J. Wehrkamp, Ying Xie, David Oupicky, Ashley M. Mohr, Bailey A. Stringham

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

4,4’-Dichlorodiphenyltrichloroethane (Ddt) And 4,4’-Dichlorodiphenyldichloroethylene (Dde) Promote Adipogenesis In 3tl1 Adipocyte Cell Culture, J Kim, Q Sun, Y Yue, Kyong-Sup Yoon, K -Y Whang, J M. Clark, Y Park

SIUE Faculty Research, Scholarship, and Creative Activity

4,4’-Dichlorodiphenyltrichloroethane (DDT), a chlorinated hydrocarbon insecticide, was extensively used in the 1940s and 1950s. DDT is mainly metabolically converted into 4,4’- dichlorodiphenyldichloroethylene (DDE). Even though most countries banned DDT in the 1970s, due to the highly lipophilic nature and very stable characteristics, DDT and its metabolites are present ubiquitously in the environment, including food. Recently, there are publications on relationships between exposure to insecticides, including DDT and DDE, and weight gain and altered glucose homeostasis. However, there are limited reports regarding DDT or DDE and adipogenesis, thus we investigated effects of DDT and DDE on adipogenesis using 3T3-L1 preadipocytes. Treatment …

Hiv Vaccines: Progress, Limitations And A Crispr/Cas9 Vaccine, Omar A. Garcia Martinez

Biology: Student Scholarship & Creative Works

ABSTRACT: The HIV-1 pandemic continues to thrive due to ineffective HIV-1 vaccines. Historically, the world’s most infectious diseases, such as polio and smallpox, have been eradicated or have come close to eradication due to the advent of effective vaccines. Highly active antiretroviral therapy is able to delay the onset of AIDS but can neither rid the body of HIV-1 proviral DNA nor prevent further transmission. A prophylactic vaccine that prevents the various mechanisms HIV-1 has to evade and attack our immune system is needed to end the HIV-1 pandemic. Recent advances in engineered nuclease systems, like the CRISPR/Cas9 system, have …

Fipronil Promotes Adipogenesis Via Ampkα-Mediated Pathway In 3t3-L1 Adipocytes, Quancai Sun, Jeremy Yang, Kyong-Sup Yoon, John M. Clark, Yeonhwa Park

SIUE Faculty Research, Scholarship, and Creative Activity

Emerging evidence suggests that organochlorine, organophosphorus and neonicotinoid insecticide exposure may be linked to the development of obesity and type 2 diabetes. However, there is no knowledge of the potential influence of fipronil, which belongs to the phenylpyrazole chemical family, on obesity. Thus, the goal of this study was to determine the role of fipronil in adipogenesis using 3T3-L1 adipocytes. Fipronil treatment, at 10 mM, increased fat accumulation in 3T3-L1 adipocytes as well as promoted key regulators of adipocyte differentiation (CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor gamma-γ), and key regulators of lipogenesis (acetyl-CoA carboxylase and fatty acid synthase). The …

Numerical Simulations Of In Vitro Nanoparticle Toxicity – The Case Of Poly(Amido Amine) Dendrimers., Marcus Maher, Pratap Naha, Sourav Prasanna Mukherjee, Hugh Byrne

Articles

A phenomenological rate equation model is constructed to numerically simulate nanoparticle uptake and subsequent cellular response. Polyamidoamine dendrimers (generations 4-6) are modelled and the temporal evolution of the intracellular cascade of; increased levels of reactive oxygen species, intracellular antioxidant species, caspase activation, mitochondrial membrane potential decay, tumour necrosis factor and interleukin generation is simulated, based on experimental observations.

The dose and generation dependence of several of these response factors are seen to well represent experimental observations at a range of time points. The model indicates that variations between responses of different cell-lines, including murine macrophages, human keratinocytes and colon cells, …

Mitochondrial Dna Instability In Cells Lacking Aconitase Correlates With Iron Citrate Toxicity, Muhammad A. Farooq, Tammy M. Pracheil, Zhejun Dong, Fei Xiao, Zhengchang Liu

Biological Sciences Faculty Publications

Aconitase, the second enzyme of the tricarboxylic acid cycle encoded by ACO1 in the budding yeast Saccharomyces cerevisiae, catalyzes the conversion of citrate to isocitrate. aco1 Delta results in mitochondrial DNA (mtDNA) instability. It has been proposed that Aco1 binds to mtDNA and mediates its maintenance. Here we propose an alternative mechanism to account for mtDNA loss in aco1 Delta mutant cells. We found that aco1 Delta activated the RTG pathway, resulting in increased expression of genes encoding citrate synthase. By deleting RTG1, RTG3, or genes encoding citrate synthase, mtDNA instability was prevented in aco1 Delta mutant …

Novel Cis-Restricted Β-Lactam Combretastatin A-4 Analogues Display Anti-Vascular And Anti-Metastatic Properties In Vitro, Seema M. Nathwani, Lisa M. Greene, Linda Hughes, Miriam Carr, Niamh O'Boyle, Susan Mcdonnell, Mary J. Meegan, Daniela M. Zisterer

Articles

No abstract provided.

Combretazet-3 A Novel Synthetic Cis-Stable Combretastatin-A4-Azetidinone Hybrid With Enhanced Stabilityand Therapeutic Efficacy In Colon Cancer, Lisa M. Greene, Shu Wang, Niamh O'Boyle, Sandra A. Bright, Jane E. Reid, Patrick Kelly, Mary J. Meegan, Daniela M. Zisterer

Articles

In recent years an extensive series of synthetic combretastatin A-4 (CA-4)-azetidinone (β-lactam) hybrids were designed and synthesised with a view to improve the stability, therapeutic efficacy and aqueous solubility of CA-4. Lead compounds containing a 3,4,5-trimethoxy aromatic ring at position 1 and a variety of substitution patterns at positions 3 and 4 of the β-lactam ring were screened in three adenocarcinoma-derived colon cancer cell lines (CT-26, Caco-2 and the CA-4 resistant cell line, HT-29). In both CT-26 and Caco-2 cells all β-lactam analogues analysed displayed potent therapeutic efficacy within the nanomolar range. Substitution of the ethylene bridge of CA-4 with …

Ppar Agonists Down-Regulate The Expression Of Atp10c Mrna During Adipogenesis, A Peretich, Maria Cekanova Ms, Rndr, Phd, S Hurst, Sj Baek, Madhu Dahr

Faculty Publications and Other Works -- Biochemistry, Cellular and Molecular Biology

No abstract provided.

Gene Alterations By Peroxisome Proliferator-Activated Receptor Gamma Agonists In Human Colorectal Cancer Cells, Maria Cekanova, X Li, J Yuan, K B. Kim, Seung J. Baek

Faculty Publications and Other Works -- Biochemistry, Cellular and Molecular Biology

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear transcription factor that controls the genes involved in metabolism and carcinogenesis. In the present study, we examined the alteration of gene expression in HCT-116 human colorectal cancer cells by PPARgamma agonists: MCC-555 (5 microM), rosiglitazone (5 microM), and 15-deoxy-Delta12,14-prostaglandin J2 (1 microM). The long-oligo microarray data revealed a list of target genes commonly induced (307 genes) and repressed (32 genes) by tested PPARgamma agonists. These genes were analyzed by Onto-Express software and KEGG pathway analysis and revealed that PPARgamma agonists are involved in cell proliferation, focal adhesion, and several signaling pathways. …

2-Aminoethoxydiphenyl Borate As A Prototype Drug For A Group Of Structurally Related Calcium Channel Blockers In Human Platelets, Yuliya Dobrydneva, Christopher J. Abelt, Beth Dovel, Celina M. Thadigiri, Roy L. Williams, Peter F. Blackmore

Chemistry & Biochemistry Faculty Publications

We have synthesized a series of 2-aminoethoxydiphenyl borate (2-APB, 2,2-diphenyl-1,3,2-oxazaborolidine) analogs and tested their ability to inhibit thrombin-induced Ca²⁺ influx in human platelets. The analogs were either synthesized by adding various substituents to the oxazaborolidine ring (methyl, dimethyl, tert-butyl, phenyl, methyl phenyl, and pyridyl) or increasing the size of the oxazaborolidine ring to seven- and nine-membered rings. NMR analysis of the boron-containing analogs suggests that each of them exist as a ring structure through the formation of an N -> B coordinate bond (except for the hexyl analog). The possibility that these boron-containing compounds formed dimers was also …

Expression Of G-Protein Inwardly Rectifying Potassium Channels (Girks) In Lung Cancer Cell Lines, Howard Plummer 3rd, Madhu Dhar, Maria Cekanova Ms, Rndr, Phd, Hildegard Schuller

Faculty Publications and Other Works -- Biochemistry, Cellular and Molecular Biology

BACKGROUND: Previous data from our laboratory has indicated that there is a functional link between the beta-adrenergic receptor signaling pathway and the G-protein inwardly rectifying potassium channel (GIRK1) in human breast cancer cell lines. We wanted to determine if GIRK channels were expressed in lung cancers and if a similar link exists in lung cancer. METHODS: GIRK1-4 expression and levels were determined by reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR. GIRK protein levels were determined by western blots and cell proliferation was determined by a 5-bromo-2'-deoxyuridine (BrdU) assay. RESULTS: GIRK1 mRNA was expressed in three of six small …

Expression And Localization Of Estrogen Receptor-Alpha Protein In Normal And Abnormal Term Placentae And Stimulation Of Trophoblast Differentiation By Estradiol, A Bukovsky, Maria Cekanova Ms, Rndr, Phd, Mr Caudle, J Wimalasena, Js Foster, Dc Henley, Rf Elder

Faculty Publications and Other Works -- Biochemistry, Cellular and Molecular Biology

Estrogens play an important role in the regulation of placental function, and 17-beta-estradiol (E2) production rises eighty fold during human pregnancy. Although term placenta has been found to specifically bind estrogens, cellular localization of estrogen receptor alpha (ER-alpha) in trophoblast remains unclear. We used western blot analysis and immunohistochemistry with h-151 and ID5 monoclonal antibodies to determine the expression and cellular localization of ER-alpha protein in human placentae and cultured trophoblast cells. Western blot analysis revealed a ~65 kDa ER-alpha band in MCF-7 breast carcinoma cells (positive control). A similar band was detected in five normal term placentae exhibiting strong …

Placental Expression Of Estrogen Receptor Beta And Its Hormone Binding Variant – Comparison With Estrogen Receptor Alpha And A Role For Estrogen Receptors In Asymmetric Division And Differentiation Of Estrogen-Dependent Cells, Antonin Bukovsky, Michael R. Caudle, Maria Cekanova Ms, Rndr, Phd, Romaine I. Fernando, Jay Wimalasena, James S. Foster, Donald C. Henley, Robert F. Elder

Faculty Publications and Other Works -- Biochemistry, Cellular and Molecular Biology

During human pregnancy, the production of 17-beta-estradiol (E2) rises steadily to eighty fold at term, and placenta has been found to specifically bind estrogens. We have recently demonstrated the expression of estrogen receptor alpha (ER-alpha) protein in human placenta and its localization in villous cytotrophoblast (CT), vascular pericytes, and amniotic fibroblasts. In vitro, E2 stimulated development of large syncytiotrophoblast (ST) aggregates. In the present study we utilized ER-beta affinity purified polyclonal (N19:sc6820) and ER-alpha monoclonal (clone h-151) antibodies. Western blot analysis revealed a single ~52 kDa ER-beta band in chorionic villi (CV) protein extracts. In CV, strong cytoplasmic ER-beta immunoreactivity …

Variability Of Placental Expression Of Cyclin E Low Molecular Weight Variants, A Bukovsky, Maria Cekanova Ms, Rndr, Phd, Mr Caudle, J Wimalasena, Js Foster, Ja Keenan, Rf Elder

Faculty Publications and Other Works -- Biochemistry, Cellular and Molecular Biology

No abstract provided.

Evaluation Of Toxicity, Bioavailability And Speciation Of Lead, Zinc And Cadmium In Mine/Mill Wastewaters, Mujde Erten-Unal, Bobby G. Wixson, Nord Gale, Jerry L. Pitt

Civil & Environmental Engineering Faculty Publications

The toxicity of common compounds of lead, cadmium and zinc was evaluated in waters similar to that found in the world's largest lead producing area in Missouri. Static, acute toxicity tests were performed using fathead minnows (Pimephales promelas) and water fleas (Daphnia magna) respectively. Test organisms were subjected to varying amounts of sulfide, carbonate, chloride and sulfate salts of lead, zinc and cadmium mixed in hard, alkaline waters typical to this region. Median lethal concentrations were calculated using nominal versus measured metal concentrations. Measured metal concentrations included four different metal fractionation (extraction/filtration) techniques at different pH …