A5067230085- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Drug Transport and Resistance Mechanisms
- Pharmacogenetics and Drug Metabolism
- Estrogen and related hormone effects
- Effects and risks of endocrine disrupting chemicals
- Hormonal Regulation and Hypertension
- Pediatric Hepatobiliary Diseases and Treatments
- Heavy Metal Exposure and Toxicity
- Pharmacological Effects and Toxicity Studies
- Pregnancy and Medication Impact
- Chemical Reactions and Isotopes
- Cancer, Hypoxia, and Metabolism
- Immune cells in cancer
- Retinoids in leukemia and cellular processes
- Cholinesterase and Neurodegenerative Diseases
- Peroxisome Proliferator-Activated Receptors
- Nuclear Receptors and Signaling
- Genetics, Aging, and Longevity in Model Organisms
- Ferroptosis and cancer prognosis
- Cholesterol and Lipid Metabolism
- Nitric Oxide and Endothelin Effects
- Liver Disease Diagnosis and Treatment
- Lung Cancer Treatments and Mutations
- Light effects on plants
University of Kentucky
2015-2025
University of Rhode Island
2003-2015
Bile salt export pump (BSEP) is responsible for biliary secretion of bile acids, a rate-limiting step in the enterohepatic circulation acids and transactivated by nuclear receptor farnesoid X (FXR). Intrahepatic cholestasis pregnancy (ICP) most prevalent disorder among diseases unique to primarily occurs third trimester pregnancy, with hallmark elevated serum acids. Currently, transcriptional regulation BSEP during its underlying mechanisms involvement ICP are not fully understood. In this...
As a canalicular bile acid effluxer, the salt export pump (BSEP) plays vital role in maintaining homeostasis. BSEP deficiency leads to severe cholestasis and hepatocellular carcinoma (HCC) young children. Regardless of etiology, chronic inflammation is common pathological process for HCC development. Clinical studies have shown that homeostasis disrupted patients with elevated serum level as proposed marker HCC. However, underlying mechanisms remain largely unknown. In this study, we found...
Abstract Two important factors that contribute to resistance immune checkpoint inhibitors (ICI) are an immune-suppressive microenvironment and limited antigen presentation by tumor cells. In this study, we examine whether inhibition of the methyltransferase enhancer zeste 2 (EZH2) can increase ICI response in lung squamous cell carcinomas (LSCC). Our vitro experiments using two-dimensional human cancer lines as well three-dimensional murine patient-derived organoids treated with two EZH2...
Human DEC (differentiallyexpressed in chondrocytes), mouse STRA (stimulated with retinoic acid), and rat SHARP (split hairyrelated protein) proteins constitute a new structurally distinct class of the basic helix-loop-helix proteins. In each species, two members are identified sequence identity >907 region ∼407 total proteins, respectively. Recently, we have reported that DEC1 is abundantly expressed colon carcinomas but not adjacent normal tissues. The present study was undertaken to extend...
Carboxylesterases constitute a class of enzymes that play important roles in the hydrolytic metabolism drugs and other xenobiotics. Patients with liver conditions such as cirrhosis show increased secretion proinflammatory cytokines [e.g., interleukin-6 (IL-6)] decreased capacity hydrolysis. In this study, we provide molecular explanation linking cytokine directly to biotransformation. both primary hepatocytes HepG2 cells, treatment IL-6 expression <i>h</i>uman...
The metabolic conversion of cholesterol into bile acids in liver is initiated by the rate-limiting 7α-hydroxylase (CYP7A1), whereas salt export pump (BSEP) responsible for canalicular secretion acids. Liver receptor homolog 1 (LRH-1) a key transcriptional factor required hepatic expression CYP7A1. We hypothesized that LRH-1 was also involved regulation BSEP. In support our hypothesis, we found overexpression induced, knockdown decreased, BSEP expression. Consistent with its role regulation,...
Abstract Lung diseases, including fibrosis and cancer, are major health problems that together lead to millions of deaths each year. Non-small-cell lung cancer (NSCLC) has high morbidity mortality rates, patient prognosis survival very poor. Similarly, pulmonary is a life-threatening respiratory disease characterized by scarring damage caused increased abundance collagen-secreting myofibroblasts. An autopsy study showed as many one third non-small cell patients have some amount fibrosis1,...
Abstract Non-Small Cell Lung Cancer (NSCLC) is a continual issue across the United States as leading cause of cancer-related mortalities. Within NSCLC, Epidermal Growth Factor Receptor (EGFR) mutations have emerged main genetic driver. Treatment for EGFR mutated lung cancers has evolved over past two decades, starting with tyrosine kinase inhibitors gefitinib and erlotinib, more recently moving to osimertinib. These treatments are typically successful initially, but resistance inevitable...
Abstract Non-small cell lung cancer (NSCLC) is currently the leading cause of related death in United States. Despite improvements treatment, success extremely varied due to tumor heterogeneity. Our laboratory hypothesis that targeting heterogeneity could improve treatment responses for NSCLCs. first method accomplish this inhibit histone methyltransferase EZH2, which tri-methylates 3 lysine 27 silence genes. Using a syngeneic model, we observed EZH2 inhibitor valemetostat combined with...
Among diseases unique to pregnancy, intrahepatic cholestasis of pregnancy is the most prevalent disorder with elevated serum bile acid levels. We have previously shown that estrogen 17β-estradiol (E2) transrepresses salt export pump (BSEP) through an interaction between receptor (ER)-α and farnesoid X (FXR) transrepression BSEP by E2/ERα etiological contributing factor pregnancy. Currently mechanistic insights into such are not fully understood. In this study, dynamics coregulator...
The pregnane X receptor (PXR) is a key regulator of genes encoding several major types cytochrome P450 enzymes and transporters (e.g., multidrug resistance-1, MDR1); therefore, PXR contributes significantly to drug-drug interactions. binds response elements confers transactivation. Several target such as CYP3A4 3A7 contain two (distant proximal) that are separated by more than 7000 nucleotides in the genome. Disruption distant element causes 73% decrease reporter activity, whereas...
CYP3A4 (cytochrome P450 3A4) is involved in the metabolism of more than 50% drugs and other xenobiotics. The expression induced by many structurally dissimilar compounds. PXR (pregnane X receptor) recognized as a key regulator for induction, PXR-directed transactivation gene achieved through co-ordinated mechanism distal module with proximal promoter. Recently, far was found to support constitutive CYP3A4. module, like clustered response element (F-ER6) elements HNF-4α (hepatocyte nuclear...
Thiazolidinediones (TZD), including troglitazone, rosiglitazone, and pioglitazone, are agonists of peroxisome proliferator-activated receptor (PPAR)-γ belong to a class insulin-sensitizing drugs for type 2 diabetes mellitus. However, member-specific, PPARγ-independent activities toxicity have been reported, especially troglitazone. Currently, the underlying mechanisms not fully understood. In this study, we demonstrated that troglitazone but rosiglitazone or pioglitazone modulated expression...
Expression of bile salt export pump (BSEP) is regulated by the acid/farnesoid X receptor (FXR) signaling pathway. Two FXR isoforms, FXRα1 and FXRα2, are predominantly expressed in human liver. We previously showed that BSEP was isoform-dependently diminished with altered expression FXRα2 patients hepatocellular carcinoma. In this study, we demonstrate regulate through two distinct responsive elements (FXRE): IR1a IR1b. As predominant regulator, potently transactivated IR1a, while weakly a...
Recent studies have associated endocrine-disrupting chemical (EDC) exposure with the increased risk of cardiovascular disease in humans, but underlying mechanisms responsible for these associations remain elusive. Many EDCs been implicated activation nuclear receptor pregnane X (PXR), which acts as a xenobiotic sensor to regulate metabolism liver and intestine. Here we report an important role intestinal PXR linking hyperlipidemia. We identified tributyl citrate (TBC), one large group Food...
Abstract Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of major precision medicine treatment options for lung adenocarcinoma. Due to common development drug resistance first‐ and second‐generation TKIs, third‐generation inhibitors, including osimertinib rociletinib, have been developed. A model EGFR‐driven cancer a method develop tumors distinct epigenetic states through 3D organotypic cultures are described here. It discovered that...
Inhibitors of the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase EZH2 are approved for certain cancers, but realizing their wider utility relies upon understanding PRC2 biology in each cancer system. Using a genetic model to delete Ezh2 KRAS-driven lung adenocarcinomas, we observed that haplo-insufficient tumors were less lethal and lower grade than fully-insufficient tumors, which poorly differentiated metastatic. three-dimensional cultures vivo experiments, determined...
DEC1 (differentially expressed in chondrocytes 1) and DEC2 are E-box-binding transcription factors exhibit a circadian expression pattern. Recently, both proteins were found to repress the Clock/Bmal1-activated E-box promoters (e.g. mPer1). Yeast two-hybrid assay detected interactions between Bmal1 DECs. It was hypothesized that DEC-mediated repression on mPer1 promoter is achieved by binding elements interacting with Bmal1. In present study, we report rather than interaction responsible for...
BACKGROUND AND PURPOSE Byakangelicin is found in extracts of the root Angelica dahurica , used Korea and China as a traditional medicine to treat colds, headache toothache. As byakangelicin can inhibit effects sex hormones, it may increase catabolism endogenous hormones. Therefore, this study investigated on cytochrome P450 isoform (CY) P3A4 human hepatocytes. EXPERIMENTAL APPROACH Cultures hepatocytes hepatoma cell line (Huh7 cells) were used. mRNA protein levels measured by quantitative...
Vasodilatory shock in sepsis is caused by the failure of vasculature to respond vasopressors, which results hypotension, multiorgan failure, and ultimately patient death. Recently, it was reported that CPI-17, a key player regulation smooth muscle contraction, downregulated lipopolysaccharide (LPS) mesenteric arteries concordant with vascular hypocontractilty. While Sp1 has been shown activate CPI-17 transcription, unknown whether involved LPS-induced downregulation. Here we report tumor...
The pregnane X receptor (PXR) is a key regulator on the expression of genes involved in elimination chemicals. As one most divergent members nuclear family, PXR activated highly species-dependent manner by certain Pregnenolone 16α-carbonitrile (PCN), glucocorticoid antagonist, efficaciously activates rodent but not human PXR. This study was undertaken to investigate structural basis for PCN-mediated activation rat A series rat-human chimeric PXRs were prepared gradually replace...