The Role of PPARgamma in the Cyclooxygenase Pathway in Lung Cancer.

Decreased expression of peroxisome proliferator activated receptor-gamma (PPARgamma) and high levels of the proinflammatory enzyme cyclooxygenase-2 (COX-2) have been observed in many tumor types. Both reduced (PPARgamma) expression and elevated COX-2 within the tumor are associated with poor prognosis in lung cancer patients, and recent work has indicated that these signaling pathways may be interrelated. Synthetic (PPARgamma) agonists such as the thiazolidinedione (TZD) class of anti-diabetic drugs can decrease COX-2 levels, inhibit growth of non-small-cell lung cancer (NSCLC) cells in vitro, and block tumor progression in xenograft models. TZDs alter the expression of COX-2 and consequent production of the protumorigenic inflammatory molecule prostaglandin E2 (PGE2) through both (PPARgamma) dependent and independent mechanisms. Certain TZDs also reduce expression of PGE2 receptors or upregulate the PGE2 catabolic enzyme 15-prostaglandin dehydrogenase. As several COX-2 enzymatic products have antitumor properties and specific COX-2 inhibition has been associated with increased risk of adverse cardiac events, directly reducing the effects or concentration of PGE2 may provide a more safe and effective strategy for lung cancer treatment. Understanding the mechanisms underlying these effects may be helpful for designing anticancer therapies. This article summarizes recent research on the relationship between (PPARgamma), TZDs, and the COX-2/PGE2 pathways in lung cancer

PPAR Gamma and Hepatic Stellate Cells

Activation of Hepatic stellate cells (HSC) in fibrogenesis involves distinct morphological and biochemical changes. This activation requires the coordinated changes in activity of several transcription factors. Peroxisome proliferator-activated receptor gamma (PPAR gamma) is one such factor whose activity is decreased in activated HSC. PPAR gamma ligands suppress several markers of HSC activation such as expression of collagen and alpha smooth muscle actin (alpha-SMA), cell proliferation and migration. Expression of PPAR gamma, per se, also inhibits HSC activation. These findings support the role of PPAR gamma in reversion of activated HSC toward their quiescent state

HPLC OF PHENOLIC COMPOUNDS, ANTIOXIDANT AND ANTIMICROBIAL ACTIVITY OF BULBS FROM THREE ORNITHOGALUM SPECIES AVAILABLE IN INDIA

Objective: The aim of the study was to analyze phenolic compounds of three species of Ornithogalum viz Ornithogalum virens, Ornithogalum thyrsoides, Ornithogalum dubium and to assess their bioactivity in terms of antimicrobial and antioxidant potential.Methods: Extracts were prepared in 20% aqueous methanol. Each extract was subjected to phenolic and flavonoid estimation. Antioxidant activity was tested using DPPH method, and their antimicrobial activity was tested on six pathogenic strains namely Enterobacter cloacae, Serratia marcescens, Escherichia coli, Shigella dysenteriae, Staphylococcus aureus and Pseudomonas aeruginosa. The extracts were subjected to HPLC analysis with different standards namely gallic acid, caffeic acid, p-coumaric acid, syringic acid, sinapic acid, ferulic acid, methyl gallate, catechin, rutin, apigenin, quercetin, myricetin, and kaempherol.Results: O. dubium was found to have highest antioxidant activity (IC50 311 µg/g extract). Inhibition zone was minimum in S. marcescens and E. coli on the application of extracts of O. virens, and the consequent MIC was 670 µg and 650µg/g dry weight respectively. None of the three extracts was found to have any effect either on S. aureus or P. aeruginosa. HPLC analyses have shown that myricetin was the primary flavonoid constituent of the extract of O. dubium and gallic acid of O. virens.Conclusion: O. dubium shows maximum antioxidant and antimicrobial activity. Extracts of O. virens also shows maximum polyphenol content. From the HPLC results, it is evident that the flavonoids present in O. dubium are myricetin, rutin, p-coumaric acid along with some phenolic compounds, which confers bioactivity to the extract.Keywords: Ornithogalum, Phenolic acid, Flavonoids, HPLC, Antioxidant activity, Antimicrobial activit

The Role of PPARγ in the Cyclooxygenase Pathway in Lung Cancer

Decreased expression of peroxisome proliferator activated receptor-γ (PPARγ) and high levels of the proinflammatory enzyme cyclooxygenase-2 (COX-2) have been observed in many tumor types. Both reduced (PPARγ) expression and elevated COX-2 within the tumor are associated with poor prognosis in lung cancer patients, and recent work has indicated that these signaling pathways may be interrelated. Synthetic (PPARγ) agonists such as the thiazolidinedione (TZD) class of anti-diabetic drugs can decrease COX-2 levels, inhibit growth of non-small-cell lung cancer (NSCLC) cells in vitro, and block tumor progression in xenograft models. TZDs alter the expression of COX-2 and consequent production of the protumorigenic inflammatory molecule prostaglandin E2 (PGE2) through both (PPARγ) dependent and independent mechanisms. Certain TZDs also reduce expression of PGE2 receptors or upregulate the PGE2 catabolic enzyme 15-prostaglandin dehydrogenase. As several COX-2 enzymatic products have antitumor properties and specific COX-2 inhibition has been associated with increased risk of adverse cardiac events, directly reducing the effects or concentration of PGE2 may provide a more safe and effective strategy for lung cancer treatment. Understanding the mechanisms underlying these effects may be helpful for designing anticancer therapies. This article summarizes recent research on the relationship between (PPARγ), TZDs, and the COX-2/PGE2 pathways in lung cancer

Peroxisome Proliferator-activated Receptor γ Induces a Phenotypic Switch from Activated to Quiescent Hepatic Stellate Cells

Depletion of peroxisome proliferator-activated receptor gamma (PPARgamma) accompanies myofibroblastic transdifferentiation of hepatic stellate cells (HSC), the primary cellular event underlying liver fibrogenesis. The treatment of activated HSC in vitro or in vivo with synthetic PPARgamma ligands suppresses the fibrogenic activity of HSC. However, it is uncertain whether PPARgamma is indeed a molecular target of this effect, because the ligands are also known to have receptor-independent actions. To test this question, the present study examined the effects of forced expression of PPARgamma via an adenoviral vector on morphologic and biochemical features of culture-activated HSC. The vector-mediated expression of PPARgamma itself is sufficient to reverse the morphology of activated HSC to the quiescent phenotype with retracted cytoplasm, prominent dendritic processes, reduced stress fibers, and accumulation of retinyl palmitate. These effects are abrogated by concomitant expression of a dominant negative mutant of PPARgamma that prevents transactivation of but not binding to the PPAR response element. PPARgamma expression also inhibits the activation markers such as the expression of alpha-smooth muscle actin, type I collagen, and transforming growth factor beta1; DNA synthesis; and JunD binding to the activator protein-1 (AP-1) site and AP-1 promoter activity. Inhibited JunD activity by PPARgamma is not due to reduced JunD expression or JNK activity or to a competition for p300. But it is due to a JunD-PPARgamma interaction as demonstrated by co-immunoprecipitation and glutathione S-transferase pull-down analysis. Further, the use of deletion constructs reveals that the DNA binding region of PPARgamma is the JunD interaction domain. In summary, our results demonstrate that the restoration of PPARgamma reverses the activated HSC to the quiescent phenotype and suppresses AP-1 activity via a physical interaction between PPARgamma and JunD

Pre-clinical characterization of GMP grade CCL21-gene modified dendritic cells for application in a phase I trial in Non-Small Cell Lung Cancer

<p>Abstract</p> <p>Background</p> <p>Our previous studies have demonstrated that transduction of human dendritic cells (DC) with adenovirus encoding secondary lymphoid chemokine, CCL21, led to secretion of biologically active CCL21 without altering DC phenotype or viability. In addition, intratumoral injections of CCL21-transduced DC into established murine lung tumors resulted in complete regression and protective anti-tumor immunity. These results have provided the rationale to generate a clinical grade adenoviral vector encoding CCL-21 for <it>ex vivo </it>transduction of human DC in order to assess intratumoral administration in late stage human lung cancer.</p> <p>Methods</p> <p>In the current study, human monocyte-derived DC were differentiated by exposure to GM-CSF and IL-4 from cryopreserved mononuclear cells obtained from healthy volunteers. Transduction with clinical grade adenoviral vector encoding CCL21 (1167 viral particles per cell) resulted in secretion of CCL21 protein.</p> <p>Results</p> <p>CCL21 protein production from transduced DC was detected in supernatants (24–72 hours, 3.5–6.7 ng/4–5 × 10⁶cells). DC transduced with the clinical grade adenoviral vector were > 88% viable (n = 16), conserved their phenotype and maintained integral biological activities including dextran uptake, production of immunostimulatory cytokines/chemokines and antigen presentation. Furthermore, supernatant from CCL21-DC induced the chemotaxis of T2 cells <it>in vitro</it>.</p> <p>Conclusion</p> <p>Viable and biologically active clinical grade CCL21 gene-modified DC can be generated from cryopreserved PBMC.</p

The Role of PPARgamma in the Cyclooxygenase Pathway in Lung Cancer.

Decreased expression of peroxisome proliferator activated receptor-gamma (PPARgamma) and high levels of the proinflammatory enzyme cyclooxygenase-2 (COX-2) have been observed in many tumor types. Both reduced (PPARgamma) expression and elevated COX-2 within the tumor are associated with poor prognosis in lung cancer patients, and recent work has indicated that these signaling pathways may be interrelated. Synthetic (PPARgamma) agonists such as the thiazolidinedione (TZD) class of anti-diabetic drugs can decrease COX-2 levels, inhibit growth of non-small-cell lung cancer (NSCLC) cells in vitro, and block tumor progression in xenograft models. TZDs alter the expression of COX-2 and consequent production of the protumorigenic inflammatory molecule prostaglandin E2 (PGE2) through both (PPARgamma) dependent and independent mechanisms. Certain TZDs also reduce expression of PGE2 receptors or upregulate the PGE2 catabolic enzyme 15-prostaglandin dehydrogenase. As several COX-2 enzymatic products have antitumor properties and specific COX-2 inhibition has been associated with increased risk of adverse cardiac events, directly reducing the effects or concentration of PGE2 may provide a more safe and effective strategy for lung cancer treatment. Understanding the mechanisms underlying these effects may be helpful for designing anticancer therapies. This article summarizes recent research on the relationship between (PPARgamma), TZDs, and the COX-2/PGE2 pathways in lung cancer