Anti-inflammatory effects of Selenium (Se)
- Regulation of pro-inflammatory gene expression: We are trying to understand how Se abrogates the endotoxin- and cytokine-mediated expression of pro-inflammatory genes (including COX-2 and many others) by interfering with the activation of the redox-sensitive transcription factor, nuclear factor-kappa B (NF- k B). These studies are mainly performed in bone marrow-derived macrophages from mice that are maintained on a Se-deficient, Se-adequate, and Se-supplemented diets. Along these lines, we are following up on the role of Se as an anti-inflammatory nutrient in breast cancer metastasis to the bone (in collaboration with Dr. Andrea Mastro). Studies are also in progress to understand the therapeutic role of certain organo-Se derivatives in melanoma (in collaboration with Drs. Amin, Desai, and Robertson, Department of Pharmacology, Penn State College of Medicine).
- Regulation of PG metabolism by Se: Using a macrophage model, we are attempting to understand how Se regulates the production of 15d-PGJ2. These studies will utilize genetic knock-down approach to elucidate the role of specific selenoproteins in the formation of 15d-PGJ2. Furthermore, we have initiated an in-depth investigation into the transcriptional regulation of other PG synthases (like the microsomal PGE2 synthase-1 and thromboxane synthase) by Se. The mechanism of regulation is complex and is regulated at the level of promoter by protein-protein interaction (see below)
- Increased oxidative stress leads to increased activation of NF- k B, which can modulate several transcription factors by a mechanism known as “transcription factor squelching or tethering”. Using proteomic and genetic approaches, we are making an attempt to identify these NF- k B interacting proteins. One such example is the interaction of p65 subunit with peroxisome proliferator-activated receptor- a and its role on the expression of apolipoprotein A-I (apoA-I) in the hepatocytes.
- Redox regulation of HIV-1 transcription: Many epidemiological studies have suggested supplementation of Se as a less expensive intervention method to improve the health of HIV-seropositive individuals. We are trying to understand the molecular basis of these “epi” results and have made a considerable progress in this regard. Studies currently underway are focused around the role of selenoproteins in the regulation of HIV-1 transcription and replication. These studies are being carried out in collaboration with Dr. Andrew Henderson, Boston University College of Medicine.
Through these studies, we hope to gain understanding of the molecular mechanisms underlying the anti-oxidant and anti-inflammatory properties of Se and its role as a therapeutic agent in human and animal health.
Isolation and characterization of endogenous ligands for the peroxisome proliferator-activated receptors (PPARs)
The PPARs have enjoyed the spotlight for many reasons. These transcription factors are ligand-inducible nuclear receptors that modulate gene expression in response to a broad spectrum of compounds. The recognition that PPARs are indeed nuclear receptors for polyunsaturated fatty acids, some eicosanoids and also lipid-lowering and antidiabetic drugs, has opened many exciting avenues of research and drug discovery. Recent studies on the PPAR function have extended the role of these transcription factors beyond energy homeostasis to master gene in adipogenesis and also determinants in inflammation control. Using our expertise in the large-scale synthesis of oxidized lipids, we are involved in a collaborative project with the Molecular Toxicology Group (Drs. Vanden Heuvel, Peters, Perdew, and Omiecinski) in the Department to evaluate some of the promising compounds as ligands for PPARs as well as other nuclear receptors.
Bioactive compounds of natural origin as anti-inflammatory and anti-carcinogenic agents:
Isolation and characterization of bioactive botanicals as NF- k B inhibitors: We are currently examining an array of botanicals as potential NF- k B inhibitors. These studies are steered by the requirement of specific reactive groups that are important determinants of biological activity. Biotin-tagging of these compounds is routinely utilized to “fish” out intracellular targets, particularly involving proteins of the NF- k B signaling axis.
The role of myo-inositol oxygenase in diabetic complications
myo-Inositol (MI), the dominant form of the physiological inositol isomers, is utilized in many tissues and cell types as an organic osmolytes and, more importantly, as a precursor for the synthesis of phosphoinositide second messengers. The first committed step in MI catabolism is catalyzed by a poorly studied enzyme called MI oxygenase (MIOX; EC 220.127.116.11) and it predominantly occurs in the proximal tubular cells of the kidney cortex.
Current projects in this area:
- Elucidating the physiological role of MIOX
- The transcriptional regulation of expression of MIOX by hyperosmotic and hyperglycemic stress
- Characterization of a multimeric-MIOX complex in cells and its physiological role,
- Understanding the catalytic mechanism of MIOX. Being a unique internal mono-oxygenase, MIOX is one of the enzymes that catalyze the oxidative glycol cleavage reactions of MI and D-chiro-inositol. The elucidation of the catalytic mechanism, using a combination of enzyme kinetic methodologies and X-ray crystallography, is being performed in collaboration with Dr. Martin Bollinger, Associate Professor of Biochemistry and Molecular Biology, at Penn State .