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Analysis of Retinoid X Receptor (RXR) Homodimerization Driven by RXR Ligands Using Yeast Two-Hybrid

Description

Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors

Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors (RXR), which allows bexarotene to act as a ligand-activated-transcription factor and in return control cell differentiation and proliferation. Bexarotene targets RXR homodimerization to drive transcription of tumor suppressing genes; however, adverse reactions occur simultaneously when bound to other nuclear receptors. In this study, we used novel bexarotene analogs throughout 5 iterations synthesized in the laboratory of Dr. Wagner to test for their potency and ability to bind RXR. The aim of our study is to quantitatively measure RXR homodimerization driven by bexarotene analogs using a yeast two-hybrid system. Our results suggests there to be several compounds with higher protein activity than bexarotene, particularly in generations 3.0 and 5.0. This higher affinity for RXR homodimers may help scientists identify a compound that will minimize adverse effects and toxicity of bexarotene and serve as a better cancer treatment alternative.

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Date Created
2015-05

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Characterization of Second and Third Generation, Novel RXR Selction Agonists for the Treatment of Cutaneous T-Cell Lymphoma

Description

Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost

Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective in the treatment of multiple types of cancer, including lung cancer. However, the disadvantages of using Bex include increased instances of hypothyroidism and excessive concentrations of blood triglycerides. If an analog of Bex can be developed which retains high affinity RXR binding similar to the 9-cis retinoic acid while exhibiting less interference for heterodimerization pathways, it would be of great clinical significance in improving the quality of life for patients with CTCL. This thesis will detail the biological profiling of additional novel (Generation Two) analogs, which are currently in submission for publication, as well as that of Generation Three analogs. The results from these studies reveal that specific alterations in the core structure of the Bex "parent" compound structure can have dramatic effects in modifying the biological activity of RXR agonists.

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2012-05

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The Effects of Ferulic Acid Concentration on Yeast DNA Repair After Exposure to UV Radiation

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Exposure of harmful ultraviolet rays (UV) is a great concern in many locations around the world, as skin diseases and cancer continue to surge. With the number of skin cancer skyrocketing past all the types of known cancers, a vast

Exposure of harmful ultraviolet rays (UV) is a great concern in many locations around the world, as skin diseases and cancer continue to surge. With the number of skin cancer skyrocketing past all the types of known cancers, a vast majority of cases are reported daily. When the skin is exposed to UVA or UVB radiation, primarily from the sun, the UV radiation damages the DNA within the cells, which results in skin cancer. However, most damaged DNA of cells can undergo nucleotide excision repair. This involves a nuclease molecule that cuts the damaged bases. Preliminary research has developed other ways of repairing DNA damage in cells by implementing organic compounds. An organic chemical such as, ferulic acid has the ability to aid the mechanisms involved in nucleotide excision repair that takes place in your cells after DNA damage.

To test this, Saccharomyces cerevisiae was utilized. This is a primary model used in most medicinal studies due to the resemblance to human cells. This study evaluates the effect of ferulic acid, concentrations on ultraviolet radiated Rad 1 (mutant) and HB0 (wild type) yeast cells. The yeast strains were grown in two different concentrations for ferulic acid and treated with long-wave UV light under 30 seconds, 45 seconds, and 60 seconds. It is observed that, Rad 1 had heavier growth in the presence of high concentration of ferulic acid after UV treatment than HB0. But, HB0 yeast had heavier growth in the presence of lower concentrations of ferulic acid after UV treatment. Ferulic acid concentrations of 1 mM can influence cell repair after UV application by mRNA expression during nucleotide excision repair and higher absorption of UV.

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2020-12