Thesis (M.S.)--Ohio State University, 2008. / Title from first page of PDF file. Non-Latin script record Includes bibliographical references (p. 76-87).

Abstract Cisplatin is one of the most effective chemotherapeutic agents used in treatment of a variety of human solid tumors. The most common adverse side effect limiting the use of Cisplatin is nephrotoxicity. Recent studies indicate that inflammatory and oxidative signaling play critical role in pathogenesis of Cisplatin related nephrotoxicity. Cisplatin-induced nephrotoxicity is associated with lipid peroxidation and the superoxide anion and hydroxyl radical scavenger could prevent acute renal failure through both attenuation of tubular damage and enhanced regenerative response of the damaged tubular cells. It has been shown that green tea polyphenols with antioxidant properties inhibit inflammatory and oxidative responses in mice. However, the evidence indicating the protective effect of epigallocatechin gallate (EGCG), the major polyphenol found in green tea, on Cisplatin-induced nephrotoxicity is lacking. The present study is to evaluate the effect of EGCG injection on Cisplatin-induced nephrotoxicity in rats. The male rats were divided into four groups (n = 6 each); control group, Cisplatin group, EGCG group and Cisplatin + EGCG group. The control group received only intraperitoneal normal saline injection. Cisplatin (6 mg/kg) was given single dose intraperitoneally at day 0, EGCG (10 mg/time) was given subcutaneously at day 4, day 2 and day 0 before Cisplatin challenge and day 2 and day 4 after Cisplatin injection. Nephrotoxicity was evaluated by biochemical analysis of blood and histopathological observations of rat kidney. Nuclear factor-kappa B (NF-£eB) activation, inducible nitric oxide synthase (iNOS) expression and malonyldialdehyde (MDA) content were also determined in rat kidney. Cisplatin injection induced an increase in serum blood urea nitrogen, creatinine and tubular necrosis, and upregulation of NF-£eB and iNOS expression and MDA content in kidney. All the increases were significantly inhibited by EGCG treatment. The results suggest that EGCG may attenuate Cisplatin induced nephrotoxicity through the anti-inflammatory/oxidative effects.

Basal-like breast cancer represents a subgroup of mammary cancers associated with a particularly poor prognosis, as they are refractory to current targeted therapies employed for the treatment of breast cancer. In this work I aimed to explore the therapeutic potential of selective estrogen receptor modulators (SERMs), a targeted breast cancer treatment, in combination with epigallocatechin gallate (EGCG), for the treatment of basal-like breast cancer, using MDA-MB-231 cell as an in vitro model of the disease. A significant reduction in MDA-MB-231 cell number and a significant increase in cytotoxicity was observed following treatment with 25 [mu]M of EGCG in combination with 1 [mu]M of 4-hydroxytamoxifen (4-OHT) (EGCG+4-OHT) or 4 [mu]M of raloxifene (EGCG+Ral) over a 36 h time course. However, these effects were not resolved in time, with an increase in G₁-phase cell cycle arrest. Changes in the metabolism of EGCG were dismissed as a possible mechanism through which the combination treatments may be eliciting the cytotoxicity. Changes in the expression and phosphorylation of various signaling proteins, important for the proliferation and survival of basal-like breast cancer, were investigated through Western blotting. Interestingly, the two combination treatments produced very similar results; reductions in the phosphorylation of EGFR and AKT occurred after 6, 12, and 18 h with EGCG+4-OHT and 6, 12, 18 and 24 h with EGCG+Ral, while a reduction in S6K phosphorylation was observed following 6, 12, 18 and 24 h of both combination treatments. Interestingly, both SERMs contributed significantly to the net reduction in S6K phosphorylation, induced by the combination treatments. Both combination treatments were also associated with a significant increase in the phosphorylation and total expression of stress activated protein kinases, p38 and JNK1/2 following 12, 18 and 24 h of treatment. As changes were observed at an intracellular signaling level, the effect of the combination treatments were investigated at the transcriptomic level after 18 h of treatment, using human oligonucleotide microarrays. This transcriptomic analysis revealed that both combination treatments reduced the transcript expression of five enzymes involved with cholesterol synthesis, which was confirmed through qRT-PCR. Cholesterol is an important component of the plasma membrane and is critical for the transduction of extracellular signals. Furthermore, both combination treatments induced the transcriptomic expression of the zinc coordinating metallothionein (MT) proteins. This was associated with an increased nuclear localization of MTF-1, the transcription factor responsible for MT expression, after 6, 12 and 18 h of both combination treatments. Finally, nuclear Western blotting of the NF-[kappa]B subunit, p65, revealed that both combination treatments reduced the nuclear localization of NF-[kappa]B following 6, 12 and 18 h. In collating this data, it appears that the combination treatments of EGCG+4-OHT and EGCG+Ral are inducing cytotoxicity through various mechanisms, including reduced cellular signaling through EGFR, AKT and S6K, increased stress signaling through JNK1/2 and p38 and altered gene expression of MTs and enzymes involved with cholesterol synthesis. Therefore, the combination treatment of EGCG+SERMs exhibits therapeutic potential in MDA-MB-231 cells, a model of basal-like breast cancer.

Thesis (Ph. D.)--Oregon State University, 2010. / Printout. Includes bibliographical references (leaves 102-115). Also available on the World Wide Web.

Thesis (M. Sc.)--University of Canterbury, 2008. / Typescript (photocopy). "June 2008." Includes bibliographical references (leaves 65-72). Also available via the World Wide Web.

Thesis (M.S.)--University of Alabama at Birmingham, 2007. / Title from PDF title page (viewed Jan. 29, 2010). Includes bibliographical references (p. 55-60).

Endothelial inflammation is a pivotal early event in the development of atherosclerosis. Long term exposure to cardiovascular risk factors will ultimately exhaust those protective anti-inflammatory factors such as the heme oxygenase (HO) system. The HO system plays a critical role in cellular and tissue self-defense against oxidative stress and inflammation. Caveolae are membrane domains and are particularly abundant in endothelial cells, where they are believed to play a major role in the regulation of endothelial vesicular trafficking as well as the uptake of lipids and related lipophilic compounds, possibly including bioactive food components such as flavonoids. Research in this dissertation addresses the role of HO-1 and caveolae on dietary flavonoid epigallocatechin gallate (EGCG) mediated protection against pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and linoleic acid-induced activation of endothelial cells. The data support the hypothesis that EGCG protects against TNF-α-induced monocyte recruitment and adhesion partially through the induction of HO-1 and bilirubin. The observed anti-inflammatory effects of EGCG are mimicked by the HO-1 inducer cobalt protoporphyrin (CoPP) and abolished by HO-1 gene silencing. Nrf2 is the major transcription factor of phase II antioxidant enzymes including HO-1. Results clearly show that EGCG-induced HO-1 expression and subsequent bilirubin productions are dependent on functional Nrf2. EGCG also can down-regulate the base-line level of caveolin-1. Furthermore, silencing of the caveolin-1 gene can markedly down-regulate linoleic acid-induced COX-2 and MCP-1, indicating that caveolae may be a critical platform regulating inflammatory signaling pathways. Similar to EGCG treatment, silencing of caveolin-1 can also result in the activation of Nrf2, up-regulation of HO-1 and bilirubin. This may be one of the mechanisms to explain the protection effect of caveolin-1 gene silencing against endothelial inflammation. Moreover, EGCG rapidly accumulates in caveolae, which is associated with caveolin-1 displacement from the plasma membrane towards the cytosol. Caveolin-1 gene silencing can significantly reduce the uptake of EGCG in endothelial cells within 30 min. These data suggest that caveolae may play a role in the uptake and transport of EGCG in endothelial cells. These studies provide a novel target through which EGCG functions to protect against inflammatory diseases such as atherosclerosis.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Additional advisors: Ada Elgavish, Vithal Ghanta, Hui-Chen Hsu, Thane Wibbels. Description based on contents viewed June 11, 2008; title from title screen. Includes bibliographical references.

No description available.

Duchenne muscular dystrophy is a debilitating genetic disorder characterized by severe muscle wasting and early death in affected boys. The primary cause of this disease is mutations in the dystrophin gene resulting in the loss of the dystrophin protein from the plasma membrane of muscle fibers. In the absence of dystrophin, muscles undergo massive muscle degeneration and inflammation. Inflammation is believed to contribute substantially to dystrophic muscle pathology. The transcription factor NF-κB regulates inflammatory gene expression and provides a logical target for therapeutic treatments. Green tea extract and its primary polyphenol, epigallocatechin gallate, have been shown to have anti-inflammatory properties and to improve dystrophic muscle pathology. The purpose of these studies was to determine if dietary treatment with green tea extract or epigallocatechin gallate administered prior to disease onset could reduce dystrophic muscle pathology during the early disease time course and identify potential mechanisms through which NF-κB may be involved. Green tea extract has been shown to decrease muscle pathology and increase muscle function in mdx mice, a dystrophic mouse model. These changes have been attributed to the antioxidant potential of epigallocatechin gallate; however, other mechanisms such as suppression of the inflammatory response have not been evaluated. In the studies reported herein, both green tea extract and epigallocatechin gallate significantly decreased muscle pathology in mdx mice when provided in their diets prior to disease onset. In green tea extract (0.25% and 0.5%) treated mdx mice, serum creatine kinase, a systemic marker of muscle damage, was decreased by 85% at age 42 days. Normal fiber morphology in the tibialis anterior muscle was increased by 32% at this age (P≤0.05). The primary histopathological change was a 21% decrease in regenerating fibers (P≤0.05). NF-κB staining in central nuclei of regenerating fibers was decreased by 34% (P≤0.05). In epigallocatechin gallate (0.1%) treated mdx mice, serum creatine kinase was unchanged; however, normal fiber morphology in the tibialis anterior was increased by 20% at ages 28 and 42 days (P≤0.05). At age 42 days, the primary histopathological change was a 21% decrease in regenerating fibers (P≤0.05). NF-κB staining in central nuclei of regenerating muscle fibers was decreased by 21% at this age (P≤0.05). Epigallocatechin gallate appears to be the primary polyphenol of green tea extract responsible for many of the beneficial changes in dystrophic muscle. These data suggest that both green tea extract and epigallocatechin gallate decrease NF-κB activity in regenerating fibers resulting in reduced muscle pathology. Complimentary and alternative medicine approaches, including the use of green tea, provide important therapeutic options for ameliorating Duchenne muscular dystrophy. Green tea extract and epigallocatechin gallate are effective at decreasing muscle pathology potentially by reducing NF-κB activity in regenerating fibers in mdx mice. Use of these botanicals appears to elicit a beneficial response in dystrophic muscle that may ultimately lead to effective therapies for patients with this incurable disease. / Ph. D.