Development And Biological Evaluation Of Selective Small-Molecule Inhibitors Of The Human Cytochrome P450 1b1,
2023
University of Kentucky
Development And Biological Evaluation Of Selective Small-Molecule Inhibitors Of The Human Cytochrome P450 1b1, Austin Hachey
Theses and Dissertations--Chemistry
The human cytochrome P450 1B1 (CYP1B1) is an emerging target for small- molecule therapeutics. Several solid tumors overexpress CYP1B1 to the degree that it has been referred to as a universal tumor antigen. Conversely, its expression is low in healthy tissues. CYP1B1 may drive tumorigenesis through promoting the formation of reactive toxins from environmental pollutants or from endogenous hormone substrates. Additionally, the expression of CYP1B1 in tumors is associated with resistance to several common chemotherapies and with poor prognoses in cancer patients. However, inhibiting CYP1B1 with small molecules has been demonstrated in cellular and murine model systems to reverse this …
Modulatory Effects Of Deacetylated Sialic Acids (A Sugar Residue) In Nk-Mediated Cytotoxicity And Targeted Therapy By Receptor Tyrosine Kinase Inhibitors,
2023
South Dakota State University
Modulatory Effects Of Deacetylated Sialic Acids (A Sugar Residue) In Nk-Mediated Cytotoxicity And Targeted Therapy By Receptor Tyrosine Kinase Inhibitors, Mathias Tawiah Anim
Electronic Theses and Dissertations
The complex nature of the biology of cancer is still an unraveling science, yielding several biomarkers that have served as molecular targets for detection and treatment of the disease. How sugars, glycans, play a role has remained relatively uninvestigated. Sialic acid (Sia), a sugar residue on the surface of cells, has been identified as a hallmark of cancer and its progression. Sialic acid can be highly functionalized, but we became interested in acetylated Sias. This functional group is modulated by Sialate O- acetylesterase (encoded by the gene SIAE) and Sialate O-acetyltransferase (encoded by CASD1), enzymes that play a crucial role …
Arginine-178 Is An Essential Residue For Itpa Function,
2023
Eastern Washington University
Arginine-178 Is An Essential Residue For Itpa Function, Nicholas E. Burgis, Caitlin April, Kandise Vanwormer
Chemistry and Biochemistry Faculty Publications
The inosine triphosphate pyrophosphatase (ITPA) enzyme plays a critical cellular role by removing noncanonical nucleoside triphosphates from nucleotide pools. One of the first pathological ITPA mutants identified is R178C (rs746930990), which causes a fatal infantile encephalopathy, termed developmental and epileptic encephalopathy 35 (DEE 35). The accumulation of noncanonical nucleotides such as inosine triphosphate (ITP), is suspected to affect RNA and/or interfere with normal nucleotide function, leading to development of DEE 35. Molecular dynamics simulations have shown that the very rare R178C mutation does not significantly perturb the overall structure of the protein, but results in a high level of structural …
Cisplatin - Loaded Calcium Citrate Nanoparticlesfor Inhibition Of Lung Cancer Cell Growthand Quantum Mechanical Study Of Cisplatin And Citrate,
2023
Faculty of Science
Cisplatin - Loaded Calcium Citrate Nanoparticlesfor Inhibition Of Lung Cancer Cell Growthand Quantum Mechanical Study Of Cisplatin And Citrate, Lipika Oopkaew
Chulalongkorn University Theses and Dissertations (Chula ETD)
The International Organization for Research on Cancer (International Agency for Research on Cancer (IARC) issued a statement saying lung cancer is a cancer with high incidence rates of new cases and deaths. Although there are current therapeutic approaches such as surgery, radiation therapy, and chemotherapy. However, these treatments exhibit ineffectiveness; the main limitation is severe side effects to normal cells or non-target organs. To address this challenge, the development of targeted therapy by nanoparticle-based drug delivery system is applied to increase drug stability and control the specificity to cancer cells with target-specific proteins that play an important role in intracellular …
Cup Is Essential For Oskar Mrna Translational Repression During Early Drosophila Oogenesis,
2023
CUNY Hunter College
Cup Is Essential For Oskar Mrna Translational Repression During Early Drosophila Oogenesis, Livia V. Bayer, Samantha Milano, Stephen K. Formel, Harpreet Kaur, Rishi Ravichandran, Juan A. Cambeiro, Lizaveta Slinko, Irina E. Catrina, Diana P. Bratu
Publications and Research
Study of the timing and location for mRNA translation across model systems has begun to shed light on molecular events fundamental to such processes as intercellular communication, morphogenesis, and body pattern formation. In D. melanogaster, the posterior mRNA determinant, oskar, is transcribed maternally but translated only when properly localized at the oocyte’s posterior cortex. Two effector proteins, Bruno1 and Cup, mediate steps of oskar mRNA regulation. The current model in the field identifies Bruno1 as necessary for Cup’s recruitment to oskar mRNA and indispensable for oskar’s translational repression. We now report that this Bruno1-Cup interaction leads …
Molecular Mechanism Behind The Safe Immunostimulatory Effect Of Withania Somnifera,
2023
CUNY Graduate Center
Molecular Mechanism Behind The Safe Immunostimulatory Effect Of Withania Somnifera, Kriti Kalpana, Shen Yap, Moriya Tsuji, Akira Kawamura
Publications and Research
Withania somnifera (L.) Dunal (family Solanaceae) is a medicinal plant known for, among many pharmacological properties, an immune boosting effect. Our recent study revealed that its key immunostimulatory factor is lipopolysaccharide of plant-associated bacteria. This is peculiar, because, although LPS can elicit protective immunity, it is an extremely potent pro-inflammatory toxin (endotoxin). However, W. somnifera is not associated with such toxicity. In fact, despite the presence of LPS, it does not trigger massive inflammatory responses in macrophages. To gain insights into the safe immunostimulatory effect of W. somnifera, we conducted a mechanistic study on its major phytochemical constituent, …
Structure–Activity Relationship Studies On 6-Chloro-1-Phenylbenzazepines Leads To The Identification Of A New Dopamine D1 Receptor Antagonist,
2023
CUNY Hunter College
Structure–Activity Relationship Studies On 6-Chloro-1-Phenylbenzazepines Leads To The Identification Of A New Dopamine D1 Receptor Antagonist, Rajan Giri, Hari K. Namballa, Vishwashiv Emogaje, Wayne W. Harding
Publications and Research
The 1-phenylbenzazepine template has yielded a number of D1R-like ligands, which, though useful as pharmacological tools, have significant drawbacks in terms of selectivity versus D5R as well as pharmacokinetic behavior. A number of 1-phenylbenzazepines contain a 6-chloro functional group, but extensive SAR studies around the 6-chloro-1-phenylbenzazepine framework have not been reported in the literature. To further understand the tolerance of the 6-chloro-1-phenylbenzazepine template for various substituent groups towards affinity and selectivity at D1R, we synthesized two series of analogs with structural variations at the C-7, C-8, N-3, C-3′ and C-4′ positions. The series 2 analogs differed from …
C-Glycopyranosyl Aldehydes: Emerging Chiral Synthons In Organic Synthesis,
2023
University of Delhi
C-Glycopyranosyl Aldehydes: Emerging Chiral Synthons In Organic Synthesis, Sandeep Kumar, Vinod Khatri, Priyanka Mangla, Rajni Johar Chhatwal, Virinder S. Parmar, Ashok K. Prasad
Publications and Research
Herein, we have summarized the vast array of synthetic processes that have been developed for the synthesis of C-glycopyranosyl aldehydes and diverse C-glycoconjugates derived from them by covering the literature reported from 1979 to 2023. Notwithstanding its challenging chemistry, C-glycosides are considered stable pharmacophores and are used as important bioactive molecules. The discussed synthetic methodologies to access C-glycopyranosyl aldehydes take advantage of seven key intermediates, viz. allene, thiazole, dithiane, cyanide, alkene, and nitromethane. Furthermore, the integration of complex C-glycoconjugates derived from varied C-glycopyranosyl aldehydes involves nucleophilic addition/substitution, reduction, condensation, oxidation, cyclo condensation, coupling, and …
Lead Induced Differences In Bone Properties In Osteocalcin +/+ And −/− Female Mice,
2023
CUNY Brooklyn College
Lead Induced Differences In Bone Properties In Osteocalcin +/+ And −/− Female Mice, G. Yildirim, W. C. Budell, O. Berezovska, S. Yagerman, S. S. Maliath, P. Mastrokostas, S. Tommasini, T. L. Dowd
Publications and Research
Lead (Pb) toxicity is a major health problem and bone is the major reservoir. Lead is detrimental to bone, affects bone remodelingand is associated with elderly fractures. Osteocalcin (OC) affects bone remodeling, improves fracture resistance and decreases with age and in some diseases. The effect of lead in osteocalcin depleted bone is unknown and of interest. We compared bone mineral properties of control and Pb exposed (from 2 to 6 months) femora from female adult C57BL6 OC+/+ and OC−/− mice using Fourier Transform Infrared Imaging (FTIRI), Micro-computed tomography (uCT), bone biomechanical measurements and serum turnover markers (P1NP, CTX). Lead significantly …
Characterizing The Dynamic Localization Of Cmi In Early Drosophila Development,
2023
Loyola University Chicago
Characterizing The Dynamic Localization Of Cmi In Early Drosophila Development, Asra Habibullah
Master's Theses
The COMPASS-like family of lysine methyltransferases, MLR/MLX complexes, are epigenetic regulators that are essential for normal development through the methylation of the fourth lysine residue on histone 3 (H3K4), a universal epigenetic mark associated with active transcription. This family of complexes is highly conserved from yeast to mammals and the genes encoding the human MLR complexes have been associated with various developmental diseases and cancers (Dingwall and Fagan, 2019). In D. melanogaster, the enzymatic methyltransferase core of this complex is composed of two proteins: Cara Mitad (Cmi, also known as Lpt) and Trithorax-related (Trr). Although these proteins have been shown …
The Molecular Mechanisms Of Ifn-Γ Promoted Necroptosis In Macrophages,
2023
University of Texas at Tyler Health Science Center
The Molecular Mechanisms Of Ifn-Γ Promoted Necroptosis In Macrophages, Meghan R. Vogt
Biotechnology Theses
Necroptosis, a form of programmed lytic cell death, has emerged as a driving factor in the pathogenesis of acute lung injury. One specific inflammatory mediator that is of interest is interferon-γ (IFN-γ). Our laboratory has reported that IFN-γ is the most potent enhancer of necroptosis in primary lung epithelial cells and macrophages by upregulating MLKL expression. How IFN-γ enhances necroptosis and MLKL upregulation is currently unknown. In this research, we utilized multiple approaches to study the potential molecular mechanisms of IFN-γ promoted necroptosis in macrophages. We found that MLKL and ZBP1 are significantly upregulated by IFN-γ through an unknown pathway …
Investigating The Relationship Between Metabolic Reprogramming And Peripheral Cd4+ T-Cell Inflammation In Human Type 2 Diabetes Pathogenesis,
2023
University of Kentucky
Investigating The Relationship Between Metabolic Reprogramming And Peripheral Cd4+ T-Cell Inflammation In Human Type 2 Diabetes Pathogenesis, Gabriella Kalantar
Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics
Chronic, low-grade systemic inflammation rises in obesity and promotes type 2 diabetes (T2D). Circulating immune cells are key indicators of obesity and T2D pathogenesis. T cells outnumber monocytes, in blood, suggesting that T cells might fuel peripheral inflammation in obesity/T2D. Our lab’s work supports this idea by identification of a Th17 cytokine profile in T2D from T-cell stimulated peripheral blood mononuclear cells. Work described herein further supported this work by demonstrating that T cells dominate peripheral inflammation over monocytes across the spectrum of obesity and glycemic control. Our lab has also recently shown that inflammation changes during prediabetes (preT2D), identified …
Developing A Biocatalytic Toolbox To Aid In Understanding Nucleoside Antibiotics,
2023
University of Kentucky
Developing A Biocatalytic Toolbox To Aid In Understanding Nucleoside Antibiotics, Jasmine Brianna Woods
Theses and Dissertations--Pharmacy
Antibiotic resistance happens when bacteria develop the ability to survive medications that normally terminate them. Instead, these super germs are able to survive in the body and produce a community of antibiotic resistance germs which can cause human fatalities. It is important to discover and develop new compounds and molecules that will improve this clinical obstacle. This research focused on analyzing the biosynthesis that incorporates distinctive chemical characteristic of various nucleoside antibiotics, ß-hydroxy amino acids and α-methyl-amino acids. ß-hydroxy amino acids and α-methyl-amino acids are considered an important class of industrially useful compounds, particularly for pharmaceutical development, and are found …
Molecular Mechanisms Of Wild-Type And Mutant Prion Formation,
2023
Dartmouth College
Molecular Mechanisms Of Wild-Type And Mutant Prion Formation, Daniel J. Walsh
Dartmouth College Ph.D Dissertations
Prion diseases are a class of infectious neurodegenerative disorders which affect humans and many other mammalian species. The causative agent is a unique pathogen known as a prion or PrPSc, a misfolded form of a host-encoded glycoprotein which replicates by templated conformational change. Distinct strains of prions with unique phenotypic and pathologic presentations appear to be encoded by subtle conformational changes within the misfolded protein. While the general manner of prion transmission is known, our detailed understanding of these mechanisms remains incomplete, limiting efforts for the discovery or design of therapeutic treatments for these fatal diseases. In vitro synthesis of …
Mammalian Dihydropyrimidine Dehydrogenase: Employing Transient State Kinetic Methods To Determine Catalytic And Inhibitory Mechanisms,
2023
Loyola University of Chicago Graduate School
Mammalian Dihydropyrimidine Dehydrogenase: Employing Transient State Kinetic Methods To Determine Catalytic And Inhibitory Mechanisms, Dariush Forouzesh
Dissertations
Dihydropyrimidine dehydrogenase (DPD) catalyzes the two-electron reduction of pyrimidine bases uracil and thymine as the first step in pyrimidine catabolism. The enzyme achieves this simple chemistry using a complex cofactor set including two flavins and four Fe4S4 centers. The flavins, FAD and FMN, interact with respective NADPH and pyrimidine substrates and the iron-sulfur centers form an electron transfer wire that links the two active sites that are separated by 56 Å. DPD accepts the common antineoplastic agent 5-fluorouracil (5FU) as a substrate and so undermines the establishment of efficacious toxicity. Though studied for multiple decades, a precise description of the …
Biogeography Of Special Metabolites Produced By Ant-Associated Bacteria,
2023
Claremont Colleges
Biogeography Of Special Metabolites Produced By Ant-Associated Bacteria, Katherine Hansen
Scripps Senior Theses
There is an urgent and growing need for novel antibiotics with the growing prevalence of antibiotic-resistant pathogens. Ecologically-guided discovery is a strategy that focuses on how and where specially evolved metabolites such as antibiotics are used in nature. This strategy reveals unique active molecules with potential for human use. An unexplored niche with great potential for antibiotic discovery exists with Southwestern fungus-farming Trachymyrmex ants and their Actinobacteria symbionts. In exchange for nutrients from the ant, the ants’ bacterial symbiont produces antifungal molecules that protect the ants’ fungal cultivar from invasion by pathogenic microorganisms. They also produce antibacterial molecules to protect …
Determination Of The Effects Of Added Methionine On The Toxicity Of Platinum Drugs In Saccharomyces Cerevisiae,
2023
Longwood University
Determination Of The Effects Of Added Methionine On The Toxicity Of Platinum Drugs In Saccharomyces Cerevisiae, Kassidy Owens, Jonathan White
Longwood Senior Thesis Proposal
Platinum (Pt) drugs are used in about half of all anticancer treatments. A common way to study Pt drugs is by using S. cerevisiae (brewer’s yeast) as a model cellular organism. One of the most commonly-used strains of yeast is BY4741, which is auxotrophic for (cannot synthesize) several small-molecule nutrients, including the amino acid methionine. Therefore, methionine must be supplemented in the cell culture medium. Interestingly, it is known that methionine can react with Pt compounds, including Pt drugs. Methionine-supplemented media continues to be used to study Pt drugs in yeast, especially BY4741, yet the potential for methionine to interfere …
Investigating Visinin-Like Protein 1 And Ubiquitinated Visinin-Like Protein 1 As Mild Traumatic Brain Injury Biomarkers,
2023
University of Kentucky
Investigating Visinin-Like Protein 1 And Ubiquitinated Visinin-Like Protein 1 As Mild Traumatic Brain Injury Biomarkers, Yueming Wu
Theses and Dissertations--Chemistry
Traumatic brain injury (TBI) continues to be a significant cause of morbidity and mortality worldwide. Despite significant progress in understanding the complex pathophysiology of TBI, the underlying mechanisms remain poorly understood. The primary brain damage is acute and irreversible. However, secondary brain injuries often develop gradually over months to years, creating an opportunity for critical therapeutic interventions. In the past decade, research on TBI biomarkers has seen significant progress. This progress has been driven by the diverse nature of TBI pathologies and the challenges they present for evaluation, management, and prognosis. TBI biomarker proteins resulting from axonal, neuronal, or glial …
Producing Grnas For Use In Crispr-Cas9 Dna Editing Applications Via In Vivo T7 Rna Polymerase Transcription In Escherichia Coli.,
2023
Rollins College
Producing Grnas For Use In Crispr-Cas9 Dna Editing Applications Via In Vivo T7 Rna Polymerase Transcription In Escherichia Coli., Christian A. Santiago
Honors Program Theses
The development of the CRISPR-Cas9 system is widely considered to be a breakthrough advancement in gene editing. Compared to traditional technologies, CRISPR is generally regarded as the most accessible, effective, and precise tool for inducing stable and inheritable gene edits in vivo. The CRISPR-Cas9 gene editing complex relies on the complementary binding of guide RNAs to specifically target a DNA sequence for endonuclease cleavage and mutagenesis. The production of gRNAs for use in CRISPR applications can become exceedingly complex and costly, as in vivo methodologies generally require the use of RNA polymerases that interfere with gRNA sequence identity and in …
Characterizing Cellular Injury And Inflammation With Aldob-/-Mouse Model Of Mafld,
2023
Central Washington University
Characterizing Cellular Injury And Inflammation With Aldob-/-Mouse Model Of Mafld, Andy Rashid
All Master's Theses
Metabolic-associated fatty liver disease (MAFLD) affects 1 in 3 people in the US and is a healthcare burden on the order of billions of dollars. MAFLD is characterized by pathological lipid accumulation in the liver, excess production of triglycerides and cholesterol, and export of LDL particles that raise serum lipid levels. These metabolic perturbations can lead to the development of liver fibrosis, chronic inflammation, and insulin resistance. Diagnosing MAFLD prior to fibrosis is crucial for successful intervention and prevention of advanced liver disease and other metabolic complications. Fructose-1Phospahte (F1P) accumulation from fructose overconsumption can drive hepatic lipogenesis and MAFLD progression. …
