scholarly journals The Role of PPAR in the Cyclooxygenase Pathway in Lung Cancer

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-7 ◽  
Author(s):  
Saswati Hazra ◽  
Katherine A. Peebles ◽  
Sherven Sharma ◽  
Jenny T. Mao ◽  
Steven M. Dubinett
Keyword(s):  
Lung Cancer ◽  
Peroxisome Proliferator ◽  
Cardiac Events ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lung Cancer Patients ◽  
Increased Risk ◽  
Prostaglandin Dehydrogenase ◽  
Ppar Agonists ◽  
Cox 2

Decreased expression of peroxisome proliferator activated receptor- (PPAR) and high levels of the proinflammatory enzyme cyclooxygenase-2 (COX-2) have been observed in many tumor types. Both reduced (PPAR) 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 (PPAR) 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 (PPAR) 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 (PPAR), TZDs, and the COX-2/PGE2 pathways in lung cancer.

scholarly journals The Novel Role of PGC1α in Bone Metabolism

2021 ◽  
Vol 22 (9) ◽  
pp. 4670
Author(s):  
Cinzia Buccoliero ◽  
Manuela Dicarlo ◽  
Patrizia Pignataro ◽  
Francesco Gaccione ◽  
Silvia Colucci ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Osteoblastic Differentiation ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Sirtuin 3 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Increased Risk

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

scholarly journals Anti- and Protumorigenic Effects of PPARγin Lung Cancer Progression: A Double-Edged Sword

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Howard Li ◽  
Mary C. M. Weiser-Evans ◽  
Raphael Nemenoff
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Peroxisome Proliferator ◽  
Lung Carcinogenesis ◽  
Cancer Treatments ◽  
Peroxisome Proliferator Activated Receptor ◽  
Control Of Gene Expression ◽  
Inhibition Of Growth

Peroxisome proliferator-activated receptor-γ(PPARγ) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that plays an important role in the control of gene expression linked to a variety of physiological processes, including cancer. Ligands for PPARγinclude naturally occurring fatty acids and the thiazolidinedione class of antidiabetic drugs. Activation of PPARγin a variety of cancer cells leads to inhibition of growth, decreased invasiveness, reduced production of proinflammatory cytokines, and promotion of a more differentiated phenotype. However, systemic activation of PPARγhas been reported to be protumorigenic in somein vitrosystems andin vivomodels. Here, we review the available data that implicate PPARγin lung carcinogenesis and highlight the challenges of targeting PPARγin lung cancer treatments.

scholarly journals PPAR Agonists for the Prevention and Treatment of Lung Cancer

PPAR Research ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Sowmya P. Lakshmi ◽  
Aravind T. Reddy ◽  
Asoka Banno ◽  
Raju C. Reddy
Keyword(s):  
Lung Cancer ◽  
Cancer Biology ◽  
Hormone Receptors ◽  
Biological Activities ◽  
Treatment Strategies ◽  
Distant Metastases ◽  
Peroxisome Proliferator ◽  
Lung Cancer Patients ◽  
Prevention And Treatment ◽  
Ppar Agonists

Lung cancer is the most common and most fatal of all malignancies worldwide. Furthermore, with more than half of all lung cancer patients presenting with distant metastases at the time of initial diagnosis, the overall prognosis for the disease is poor. There is thus a desperate need for new prevention and treatment strategies. Recently, a family of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs), has attracted significant attention for its role in various malignancies including lung cancer. Three PPARs, PPARα, PPARβ/δ, and PPARγ, display distinct biological activities and varied influences on lung cancer biology. PPARαactivation generally inhibits tumorigenesis through its antiangiogenic and anti-inflammatory effects. Activated PPARγis also antitumorigenic and antimetastatic, regulating several functions of cancer cells and controlling the tumor microenvironment. Unlike PPARαand PPARγ, whether PPARβ/δactivation is anti- or protumorigenic or even inconsequential currently remains an open question that requires additional investigation. This review of current literature emphasizes the multifaceted effects of PPAR agonists in lung cancer and discusses how they may be applied as novel therapeutic strategies for the disease.

scholarly journals Peroxisome Proliferators-Activated Receptor (PPAR) Modulators and Metabolic Disorders

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-14 ◽  
Author(s):  
Min-Chul Cho ◽  
Kyoung Lee ◽  
Sang-Gi Paik ◽  
Do-Young Yoon
Keyword(s):  
Drug Targets ◽  
Metabolic Disorders ◽  
Overweight And Obesity ◽  
Peroxisome Proliferator ◽  
Clinical Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Increased Risk ◽  
Ppar Agonists ◽  
Specific Ligand

Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR), which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (α,γ,andσ) are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators.

scholarly journals PPAR-, Microglial Cells, and Ocular Inflammation: New Venues for Potential Therapeutic Approaches

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-12 ◽  
Author(s):  
Fiorella Malchiodi-Albedi ◽  
Andrea Matteucci ◽  
Antonietta Bernardo ◽  
Luisa Minghetti
Keyword(s):  
Ocular Inflammation ◽  
Age Related Macular Degeneration ◽  
Microglial Cells ◽  
Brain Diseases ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Age Related ◽  
Ppar Agonists

The last decade has witnessed an increasing interest for the role played by the peroxisome proliferator-activated receptor- (PPAR-) in controlling inflammation in peripheral organs as well as in the brain. Activation of PPAR- has been shown to control the response of microglial cells, the main macrophage population found in brain parenchyma, and limit the inflammation. The anti-inflammatory capacity of PPAR- agonists has led to the hypothesis that PPAR- might be targeted to modulate degenerative brain diseases in which inflammation has been increasingly recognized as a significant component. Recent experimental evidence suggests that PPAR- agonists could be exploited to treat ocular diseases such as diabetic retinopathy, age-related macular degeneration, autoimmune uveitis, and optic neuritis where inflammation has relevant role. Additional PPAR- agonist beneficial effects could involve amelioration of retinal microcirculation and inhibition of neovascularization. However, PPAR- activation could, in some instances, aggravate the ocular pathology, for example, by increasing the synthesis of vascular endothelial growth factor, a proangiogenic factor that could trigger a vicious circle and further deteriorate retinal perfusion. The development of new in vivo and in vitro models to study ocular inflammation and how to modulate for the eye benefit will be instrumental for the search of effective therapies.

scholarly journals Activation and Molecular Targets of Peroxisome Proliferator-Activated Receptor-γLigands in Lung Cancer

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-8 ◽  
Author(s):  
Raphael A. Nemenoff ◽  
Mary Weiser-Evans ◽  
Robert A. Winn
Keyword(s):  
Lung Cancer ◽  
Treatment Strategies ◽  
Nonsmall Cell Lung Cancer ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Treatment And Prevention ◽  
Direct Binding ◽  
Xenograft Models ◽  
New Treatment

Lung cancer is the leading cause of cancer death, and five-year survival remains poor, raising the urgency for new treatment strategies. Activation of PPARγrepresents a potential target for both the treatment and prevention of lung cancer. Numerous studies have examined the effect of thiazolidinediones such as rosiglitazone and pioglitazone on lung cancer cells in vitro and in xenograft models. These studies indicate that activation of PPARγinhibits cancer cell proliferation as well as invasiveness and metastasis. While activation of PPARγcan occur by direct binding of pharmacological ligands to the molecule, emerging data indicate that PPARγactivation can occur through engagement of other signal transduction pathways, including Wnt signaling and prostaglandin production. Data, both from preclinical models and retrospective clinical studies, indicate that activation of PPARγmay represent an attractive chemopreventive strategy. This article reviews the existing biological and mechanistic experiments focusing on the role of PPARγin lung cancer, focusing specifically on nonsmall cell lung cancer.

scholarly journals Interaction of oestrogen and peroxisome proliferator-activated receptors with apolipoprotein(a) gene enhancers

2002 ◽  
Vol 366 (1) ◽  
pp. 157-163 ◽  
Author(s):  
Loretto H. PUCKEY ◽  
Brian L. KNIGHT
Keyword(s):  
Oestrogen Receptor ◽  
Hormone Receptors ◽  
Nuclear Hormone Receptor ◽  
Receptor Protein ◽  
Peroxisome Proliferator ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Apolipoprotein A ◽  
Increased Risk

A high plasma concentration of lipoprotein(a) [Lp(a)] confers an increased risk for the development of coronary heart disease. Hormones, such as oestrogen, are some of the few compounds known to reduce plasma Lp(a) levels. A putative enhancer region, located at the DHII DNase I hypersensitive site approx. 28kb upstream of the apolipoprotein(a) [apo(a)] gene, contains a number of sequences similar to the binding half-sites for nuclear hormone receptors, such as the oestrogen receptor and the peroxisome proliferator-activated receptor (PPAR). The 180bp core DHII enhancer increased the activity of the apo(a) promoter by over 7-fold in reporter-gene assays in HepG2 cells in vitro. Almost 60% of this increase was lost in the presence of co-transfected oestrogen receptor and oestrogen. In contrast, co-transfection with PPARα increased the effect of the DHII enhancer on apo(a) transcriptional activity by approx. 70% and could overcome the inhibitory effect of the oestrogen receptor on apo(a) transcription. Gel mobility-shift assays showed that oestrogen receptor protein bound to one half of a sequence corresponding to a predicted oestrogen receptor response element. PPARα also bound to this site and competed with oestrogen receptors for binding. In addition, PPARα bound to a separate site that comprised part of a direct repeat of nuclear hormone receptor half-sites. The results suggest that nuclear hormones affect plasma Lp(a) concentrations by binding to the sequences within the DHII enhancer, thereby altering the amount by which the enhancer increases the transcription of the apo(a) gene.

scholarly journals The Effect of Biotinylated PAMAM G3 Dendrimers Conjugated with COX-2 Inhibitor (celecoxib) and PPARγ Agonist (Fmoc-L-Leucine) on Human Normal Fibroblasts, Immortalized Keratinocytes and Glioma Cells in Vitro

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3801 ◽  
Author(s):  
Łukasz Uram ◽  
Maria Misiorek ◽  
Monika Pichla ◽  
Aleksandra Filipowicz-Rachwał ◽  
Joanna Markowicz ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Treatment Strategies ◽  
Pge2 Production ◽  
Peroxisome Proliferator ◽  
Central Nervous System Tumor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Pparγ Agonist ◽  
Cox 2

Glioblastoma multiforme (GBM) is the most malignant type of central nervous system tumor that is resistant to all currently used forms of therapy. Thus, more effective GBM treatment strategies are being investigated, including combined therapies with drugs that may cross the blood brain barrier (BBB). Another important issue considers the decrease of deleterious side effects of therapy. It has been shown that nanocarrier conjugates with biotin can penetrate BBB. In this study, biotinylated PAMAM G3 dendrimers substituted with the recognized anticancer agents cyclooxygenase-2 (COX-2) inhibitor celecoxib and peroxisome proliferator-activated receptor γ (PPARγ) agonist Fmoc-L-Leucine (G3-BCL) were tested in vitro on human cell lines with different p53 status: glioblastoma (U-118 MG), normal fibroblasts (BJ) and immortalized keratinocytes (HaCaT). G3-BCL penetrated efficiently into the lysosomal and mitochondrial compartments of U-118 MG cells and induced death of U-118 MG cells via apoptosis and inhibited proliferation and migration at low IC50 = 1.25 µM concentration, considerably lower than either drug applied alone. Comparison of the effects of G3-BCL on expression of COX-2 and PPARγ protein and PGE2 production of three different investigated cell line phenotypes revealed that the anti-glioma effect of the conjugate was realized by other mechanisms other than influencing PPAR-γ expression and regardless of p53 cell status, it was dependent on COX-2 protein level and high PGE2 production. Similar G3-BCL cytotoxicity was seen in normal fibroblasts (IC50 = 1.29 µM) and higher resistance in HaCaT cells (IC50 = 4.49 µM). Thus, G3-BCL might be a good candidate for the targeted, local glioma therapy with limited site effects.

scholarly journals α-Mangostin Alleviated Inflammation in Rats With Adjuvant-Induced Arthritis by Disrupting Adipocytes-Mediated Metabolism-Immune Feedback

2021 ◽  
Vol 12 ◽  
Author(s):  
Ying-Hao Hu ◽  
Jun Han ◽  
Lin Wang ◽  
Chao Shi ◽  
Yan Li ◽  
...  
Keyword(s):  
Oral Treatment ◽  
Fat Metabolism ◽  
Sirtuin 1 ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Adjuvant Induced Arthritis ◽  
Cox 2

A previously identified anti-rheumatic compound α-mangostin (MAN) possesses notable metabolism regulatory properties. In this study, we investigated the immune implication of MAN-altered fat metabolism on adjuvant-induced arthritis (AIA) in rats. Seven days after AIA induction, the rats received oral treatment of MAN at 50 mg/kg/day for 30 days. Metabolic indicators and basic clinical parameters were evaluated using samples collected on day 20 and 38 since immunization. Expression of nicotinamide phosphoribosyltransferase (NAMPT), sirtuin 1 (SIRT1), peroxisome proliferator activated receptor gamma (PPAR-γ), stearoyl-coa desaturase 1 (SCD-1), toll like receptor 4 (TLR4), prostaglandin-endoperoxide synthase 2 (COX-2), (p)-JNK, (p)-p65 and IL-1β were investigated by either RT-qPCR or immunobloting methods. In in vitro experiments, we treated (pre)-adipocytes with monocytes/macrophages and MAN, and investigated the changes of macrophages brought by pre-adipocytes co-culture. Generally, MAN restored the impaired fat anabolism in AIA rats, indicated by increased fat reservoir, leptin and adiponectin secretion, and PPAR-γ and SCD-1 expression. Meanwhile, it decreased circulating IL-1β and IL-6 levels, restored serological lipid profile changes, and relieved oxidative stresses, demonstrating potent therapeutic effects on AIA. AIA rats-derived monocytes inhibited mRNA PPAR-γ and SCD-1 expression in pre-adipocytes. Contrarily, MAN facilitated adipocyte differentiation in vitro, and increased free fatty acids production. It also significantly increased PPAR-γ and SCD-1 expression, which can be abrogated by PPAR-γ inhibitor T0070907. Similarly, lipopolysaccharide-primed macrophages inhibited PPAR-γ expression in the co-cultured pre-adipocytes, which was reversed by MAN. In the same co-culture system, lipopolysaccharide-induced inflammation was amplified by the co-existence of pre-adipocytes. More secretion of IL-1β and IL-6 and higher levels expression of COX-2, p-JNK, p-p65 and TLR4 were observed in lipopolysaccharide-treated macrophages when co-cultured by pre-adipocytes. The intensified inflammatory situation was eased by MAN. The treatment with pre-adipocytes culture medium achieved similar effects. Medium from lipopolysaccharide-treated adipocytes promoted IL-1β, IL-6 and MCP-1 production in separately cultured macrophages, and COX-2, p-JNK, p-p65 and TLR4 expression were increased at the meantime. MAN treatment on pre-adipocytes impaired these changes. It suggests that fat anabolism in AIA rats was deficient due to increased energy expenditure caused by inflammatory conditions. MAN restored fat metabolism homeostasis by up-regulating PPAR-γ, and reshaped secretion profile of adipocytes.

scholarly journals Telmisartan Loaded Nanofibers Enhance Re-Endothelialization and Inhibit Neointimal Hyperplasia

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1756
Author(s):  
Chen-Hung Lee ◽  
Kuo-Sheng Liu ◽  
Julien George Roth ◽  
Kuo-Chun Hung ◽  
Yen-Wei Liu ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Neointimal Hyperplasia ◽  
Metal Stents ◽  
Angiotensin Ii Receptor Blocker ◽  
Peroxisome Proliferator ◽  
Angiotensin Ii Receptor ◽  
Biodegradable Stent ◽  
Peroxisome Proliferator Activated Receptor ◽  
Increased Risk

Stent implantation impairs local endothelial function and may be associated with subsequent adverse cardiovascular events. Telmisartan, an angiotensin II receptor blocker that has unique peroxisome proliferator-activated-receptor-gamma-mediated effects on cardiovascular disease, has been shown to enhance endothelial function and limit neointimal hyperplasia. This study utilized hybrid biodegradable/stent nanofibers to facilitate sustained and local delivery of telmisartan to injured arterial vessels. Telmisartan and poly(d,l)-lactide-co-glycolide (PLGA) (75:25) were dissolved in hexafluoroisopropyl alcohol and electrospun into biodegradable nanofibrous tubes which were coated onto metal stents. By releasing 20% of the loaded telmisartan in 30 days, these hybrid biodegradable/stent telmisartan-loaded nanofibers increased the migration of endothelial progenitor cells in vitro, promoted endothelialization, and reduced intimal hyperplasia. As such, this work provides insights into the use of PLGA nanofibers for treating patients with an increased risk of stent restenosis.

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