scholarly journals Peroxisome Proliferator-Activated Receptor-γLigands: Potential Pharmacological Agents for Targeting the Angiogenesis Signaling Cascade in Cancer

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-12 ◽  
Author(s):  
Costas Giaginis ◽  
Anna Tsantili-Kakoulidou ◽  
Stamatios Theocharis
Keyword(s):  
Tumor Angiogenesis ◽  
In Vivo Studies ◽  
Signaling Cascade ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pharmacological Agents ◽  
Downstream Signaling ◽  
Underlying Mechanisms

Peroxisome proliferator-activated receptor-γ(PPAR-γ) has currently been considered as molecular target for the treatment of human metabolic disorders. Experimental data from in vitro cultures, animal models, and clinical trials have shown that PPAR-γligand activation regulates differentiation and induces cell growth arrest and apoptosis in a variety of cancer types. Tumor angiogenesis constitutes a multifaceted process implicated in complex downstream signaling pathways that triggers tumor growth, invasion, and metastasis. In this aspect, accumulating in vitro and in vivo studies have provided extensive evidence that PPAR-γligands can function as modulators of the angiogenic signaling cascade. In the current review, the crucial role of PPAR-γligands and the underlying mechanisms participating in tumor angiogenesis are summarized. Targeting PPAR-γmay prove to be a potential therapeutic strategy in combined treatments with conventional chemotherapy; however, special attention should be taken as there is also substantial evidence to support that PPAR-γligands can enhance angiogenic phenotype in tumoral cells.

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 Role of Hyaluronan in Human Adipogenesis: Evidence from in-Vitro and in-Vivo Studies

2019 ◽  
Vol 20 (11) ◽  
pp. 2675 ◽  
Author(s):  
Nicholas Wilson ◽  
Robert Steadman ◽  
Ilaria Muller ◽  
Mohd Draman ◽  
D. Aled Rees ◽  
...  
Keyword(s):  
Stem Cell Differentiation ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Synthesis Inhibitor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Inhibitory Role ◽  
The Impact

Hyaluronan (HA), an extra-cellular matrix glycosaminoglycan, may play a role in mesenchymal stem cell differentiation to fat but results using murine models and cell lines are conflicting. Our previous data, illustrating decreased HA production during human adipogenesis, suggested an inhibitory role. We have investigated the role of HA in adipogenesis and fat accumulation using human primary subcutaneous preadipocyte/fibroblasts (PFs, n = 12) and subjects of varying body mass index (BMI). The impact of HA on peroxisome proliferator-activated receptor gamma (PPARγ) expression was analysed following siRNA knockdown or HA synthase (HAS)1 and HAS2 overexpression. PFs were cultured in complete or adipogenic medium (ADM) with/without 4-methylumbelliferone (4-MU = HA synthesis inhibitor). Adipogenesis was evaluated using oil red O (ORO), counting adipogenic foci, and measurement of a terminal differentiation marker. Modulating HA production by HAS2 knockdown or overexpression increased (16%, p < 0.04) or decreased (30%, p = 0.01) PPARγ transcripts respectively. The inhibition of HA by 4-MU significantly enhanced ADM-induced adipogenesis with 1.52 ± 0.18- (ORO), 4.09 ± 0.63- (foci) and 2.6 ± 0.21-(marker)-fold increases compared with the controls, also increased PPARγ protein expression (40%, (p < 0.04)). In human subjects, circulating HA correlated negatively with BMI and triglycerides (r = −0.396 (p = 0.002), r = −0.269 (p = 0.038), respectively), confirming an inhibitory role of HA in human adipogenesis. Thus, enhancing HA action may provide a therapeutic target in obesity.

scholarly journals PPAR, PTEN, and the Fight against Cancer

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Rosemary E. Teresi ◽  
Kristin A. Waite
Keyword(s):  
Tumor Suppressor ◽  
Hormone Receptors ◽  
Susceptibility Gene ◽  
Genetic Alterations ◽  
Cellular Growth ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator-activated receptor gamma (PPAR) is a ligand-activated transcription factor, which belongs to the family of nuclear hormone receptors. Recent in vitro studies have shown that PPAR can regulate the transcription ofphosphatase and tensin homolog on chromosometen(PTEN), a known tumor suppressor.PTENis a susceptibility gene for a number of disorders, including breast and thyroid cancer. Activation of PPAR through agonists increases functional PTEN protein levels that subsequently induces apoptosis and inhibits cellular growth, which suggests that PPAR may be a tumor suppressor. Indeed, several in vivo studies have demonstrated that genetic alterations of PPAR can promote tumor progression. These results are supported by observations of the beneficial effects of PPAR agonists in the in vivo cancer setting. These studies signify the importance of PPAR andPTEN's interaction in cancer prevention.

Estrogen receptor mediates the effects of pseudoprotodiocsin on adipogenesis in 3T3-L1 cells

2010 ◽  
Vol 299 (1) ◽  
pp. C128-C138 ◽  
Author(s):  
Jing Xiao ◽  
Nai-li Wang ◽  
Bing Sun ◽  
Guo-ping Cai
Keyword(s):  
Leucine Zipper ◽  
Binding Protein ◽  
Adipogenic Differentiation ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Underlying Mechanisms

Estrogen receptors (ERs) play a pivotal role in adipogenesis; therefore, compounds targeting ERs may also affect fat formation. Recent studies have shown that the Dioscorea plant (commonly called yam) exhibits an antiobesity effect on rodents. However, the active compounds and underlying mechanisms responsible for this effect are not yet fully understood. We evaluated the effects of pseudoprotodiocsin (PPD), a steroid saponin from Dioscorea nipponica Makino (a type of Dioscorea), on adipogenesis and the mechanisms underlying this effect. Treatment with PPD at the onset of adipogenic differentiation resulted in significantly decreased adipogenesis in both in vitro and in vivo experimental systems. An increased amount of ERα mRNA, protein, and the accumulation of ERα in the nucleus were also observed. However, the expression pattern of ERβ was not altered. Furthermore, the antiadipogenic effect of PPD was found to be ER dependent. It was also accompanied by the decreased expression of several genes involved in adipogenesis, including lipoprotein lipase (LPL), leptin, CCAAT/enhancer-binding-protein-α (C/EBPα), and peroxisome proliferator-activated receptor-γ (PPARγ), as well as the increased expression of some negative factors of adipogenesis, including preadipocyte factor 1 (Pre-1), GATA-binding protein 2 (GATA-2), GC-induced leucine-zipper protein (GILZ), and C/EBP homologous protein (CHOP-10). In addition to its estrogenic action, PPD also abolished the p38 mitogen-activated protein kinase (p38 MAPK) activation. Our results suggest that PPD inhibits adipogenesis in an ER-dependent manner and induces the expression of ERα. These findings may provide a lead toward a novel agent that can be used to treat obesity.

scholarly journals Study of the Radiosensitizing and Radioprotective Efficacy of Bromelain (a Pineapple Extract): In Vitro and In Vivo

2020 ◽  
Vol 19 ◽  
pp. 153473542095046 ◽  
Author(s):  
Mai H. Mekkawy ◽  
Hanan A. Fahmy ◽  
Ahmed S. Nada ◽  
Ola S. Ali
Keyword(s):  
Radiation Effects ◽  
Histopathological Examination ◽  
Ehrlich Ascites Carcinoma ◽  
In Vivo Studies ◽  
Pon1 Activity ◽  
Peroxisome Proliferator ◽  
Γ Irradiation ◽  
Peroxisome Proliferator Activated Receptor

This study hypothesizes that, bromelain (BL) acts as radiosensitizer of tumor cells and that it protects normal cells from radiation effects. In vitro and in vivo studies have been carried out to prove that assumption. In vitro MTT cell proliferation assay has shown that the irradiated Ehrlich ascites carcinoma (EAC) cell line could be sensitized by BL pretreatment. In vivo: animals were randomly divided into 5 groups, Group 1: control (PBS i.p for 10 days), Group 2: Ehrlich solid tumor (EST) bearing mice, Group 3: EST + γ-radiation (fractionated dose, 1 Gy × 5), Group 4: EST + BL (6 mg/kg, i.p), daily for 10 days, Group 5: EST + BL for 10 days followed by γ-irradiation (1 Gy × 5). The size and weight of tumors in gamma-irradiated EST bearing mice treated with BL decreased significantly with a significant amelioration in the histopathological examination. Besides, BL mitigated the effect of γ-irradiation on the liver relative gene expression of poly ADP ribose polymerase-1 (PARP1), nuclear factor kappa activated B cells (NF-κB), and peroxisome proliferator-activated receptor α (PPAR-α), and it restored liver function via amelioration of paraoxonase1 (PON1) activity, reactive oxygen species (ROS) content, lipid peroxidation (LPO) and serum aspartate transaminase (AST), alanine transaminase (ALT), and albumin (ALB). It is concluded that BL can be considered as a radio-sensitizer and radio-protector, suggesting a possible role in reducing radiation exposure dose during radiotherapy.

scholarly journals Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1301
Author(s):  
Melissa L. D. Rayner ◽  
Jess Healy ◽  
James B. Phillips
Keyword(s):  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Neural Cells ◽  
Loss Of Function ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

The slow rate of neuronal regeneration that follows peripheral nerve repair results in poor recovery, particularly where reinnervation of muscles is delayed, leading to atrophy and permanent loss of function. There is a clear clinical need to develop drug treatments that can accelerate nerve regeneration safely, restoring connections before the target tissues deteriorate irreversibly. The identification that the Rho/Rho-associated kinase (ROCK) pathway acts to limit neuronal growth rate is a promising advancement towards the development of drugs. Targeting Rho or ROCK directly can act to suppress the activity of this pathway; however, the pathway can also be modulated through the activation of upstream receptors; one of particular interest being peroxisome proliferator-activated receptor gamma (PPAR-γ). The connection between the PPAR-γ receptor and the Rho/ROCK pathway is the suppression of the conversion of inactive guanosine diphosphate (GDP)-Rho to active guanosine triphosphate GTP-Rho, resulting in the suppression of Rho/ROCK activity. PPAR-γ is known for its role in cellular metabolism that leads to cell growth and differentiation. However, more recently there has been a growing interest in targeting PPAR-γ in peripheral nerve injury (PNI). The localisation and expression of PPAR-γ in neural cells following a PNI has been reported and further in vitro and in vivo studies have shown that delivering PPAR-γ agonists following injury promotes nerve regeneration, leading to improvements in functional recovery. This review explores the potential of repurposing PPAR-γ agonists to treat PNI and their prospective translation to the clinic.

scholarly journals Knockdown of PPARδ Induces VEGFA-Mediated Angiogenesis via Interaction With ERO1A in Human Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Wenjun Luo ◽  
Diao He ◽  
Jianhao Zhang ◽  
Zida Ma ◽  
Keling Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Underlying Mechanisms ◽  
Exact Effect ◽  
Endothelial Growth Factor ◽  
Hct116 Cells

Angiogenesis is an important mechanism underlying the development and metastasis of colorectal cancer (CRC) and has emerged as a therapeutic target for metastatic CRC (mCRC). Our recent studies found that Peroxisome proliferator-activated receptor β/δ/D (PPARδ) regulates vascular endothelial growth factor A(VEGFA) secretion and the sensitivity to bevacizumab in CRC. However, its exact effect and underlying mechanisms remain unidentified. In this study, we showed that PPARδ expression was inversely associated with the microvascular density in human CRC tissues. Knockdown of PPARδ enhanced VEGFA expression in HCT116 cells and HUVEC angiogenesis in vitro; these phenomena were replicated in the experimental in vivo studies. By tandem mass tag (TMT)-labeling proteomics and chromatin immunoprecipitation sequencing (ChIP-seq) analyses, endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) was screened and predicted as a target gene of PPARδ. This was verified by exploring the effect of coregulation of PPARδ and ERO1A on the VEGFA expression in HCT116 cells. The results revealed that PPARδ induced VEGFA by interacting with ERO1A. In conclusion, our results suggest that knockdown of PPARδ can promote CRC angiogenesis by upregulating VEGFA through ERO1A. This pathway may be a potential target for mCRC treatment.

scholarly journals Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
KyeongJin Kim ◽  
Jin Ku Kang ◽  
Young Hoon Jung ◽  
Sang Bae Lee ◽  
Raffaela Rametta ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Whole Body ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Ph Domain ◽  
Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

scholarly journals CircFAM13B promotes the proliferation of hepatocellular carcinoma by sponging miR-212, upregulating E2F5 expression and activating the P53 pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ying Xie ◽  
Xiaofeng Hang ◽  
Wensheng Xu ◽  
Jing Gu ◽  
Yuanjing Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Gene Expression Omnibus ◽  
Differentially Expressed ◽  
In Vivo Studies ◽  
Circular Rnas ◽  
Novel Target ◽  
Underlying Mechanisms

Abstract Background Most of the biological functions of circular RNAs (circRNAs) and the potential underlying mechanisms in hepatocellular carcinoma (HCC) have not yet been discovered. Methods In this study, using circRNA expression data from HCC tumor tissues and adjacent tissues from the Gene Expression Omnibus database, we identified out differentially expressed circRNAs and verified them by qRT-PCT. Functional experiments were performed to evaluate the effects of circFAM13B in HCC in vitro and in vivo. Results We found that circFAM13B was the most significantly differentially expressed circRNA in HCC tissue. Subsequently, in vitro and in vivo studies also demonstrated that circFAM13B promoted the proliferation of HCC. Further studies revealed that circFAM13B, a sponge of miR-212, is involved in the regulation of E2F5 gene expression by competitively binding to miR-212, inhibits the activation of the P53 signalling pathway, and promotes the proliferation of HCC cells. Conclusions Our findings revealed the mechanism underlying the regulatory role played by circFAM13B, miR-212 and E2F5 in HCC. This study provides a new theoretical basis and novel target for the clinical prevention and treatment of HCC.

scholarly journals The lipid-lowering drug fenofibrate combined with si-HOTAIR can effectively inhibit the proliferation of gliomas

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Zhu ◽  
Hongyang Zhao ◽  
Fenfen Xu ◽  
Bin Huang ◽  
Xiaojing Dai ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Glioma Cells ◽  
Lipid Lowering ◽  
Fibric Acid Derivative ◽  
Peroxisome Proliferator ◽  
Glioma Invasion ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lncrna Hotair

Abstract Background Fenofibrate is a fibric acid derivative known to have a lipid-lowering effect. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcription activation has been shown to play an important role in the malignant progression of gliomas, the underlying mechanisms are poorly understood. Methods In this study, we analyzed TCGA database and found that there was a significant negative correlation between the long noncoding RNA (lncRNA) HOTAIR and PPARα. Then, we explored the molecular mechanism by which lncRNA HOTAIR regulates PPARα in cell lines in vitro and in a nude mouse glioma model in vivo and explored the effect of the combined application of HOTAIR knockdown and fenofibrate treatment on glioma invasion. Results For the first time, it was shown that after knockdown of the expression of HOTAIR in gliomas, the expression of PPARα was significantly upregulated, and the invasion and proliferation ability of gliomas were obviously inhibited. Then, glioma cells were treated with both the PPARα agonist fenofibrate and si-HOTAIR, and the results showed that the proliferation and invasion of glioma cells were significantly inhibited. Conclusions Our results suggest that HOTAIR can negatively regulate the expression of PPARα and that the combination of fenofibrate and si-HOTAIR treatment can significantly inhibit the progression of gliomas. This introduces new ideas for the treatment of gliomas.

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