scholarly journals Liver Cancer: Therapeutic Challenges and the Importance of Experimental Models

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Marina Galicia-Moreno ◽  
Jorge A Silva-Gomez ◽  
Silvia Lucano-Landeros ◽  
Arturo Santos ◽  
Hugo C Monroy-Ramirez ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Hepatitis Virus ◽  
Primary Liver Cancer ◽  
Therapeutic Option ◽  
Experimental Models ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver

Liver cancer is one of the main causes of death related to cancer worldwide; its etiology is related with infections by C or B hepatitis virus, alcohol consumption, smoking, obesity, nonalcoholic fatty liver disease, diabetes, and iron overload, among other causes. Several kinds of primary liver cancer occur, but we will focus on hepatocellular carcinoma (HCC). Numerous cellular signaling pathways are implicated in hepatocarcinogenesis, including YAP-HIPPO, Wnt-β-catenin, and nuclear factor-κB (NF-κB); these in turn are considered novel therapeutic targets. In this review, the role of lipid metabolism regulated by peroxisome proliferator-activated receptor gamma (PPARγ) in the development of HCC will also be discussed. Moreover, recent evidence has been obtained regarding the participation of epigenetic changes such as acetylation and methylation of histones and DNA methylation in the development of HCC. In this review, we provide detailed and current information about these topics. Experimental models represent useful tools for studying the different stages of liver cancer and help to develop new pharmacologic treatments. Each model in vivo and in vitro has several characteristics and advantages to offer for the study of this disease. Finally, the main therapies approved for the treatment of HCC patients, first- and second-line therapies, are described in this review. We also describe a novel option, pirfenidone, which due to its pharmacological properties could be considered in the future as a therapeutic option for HCC treatment.

PPARs and angiogenesis

2011 ◽  
Vol 39 (6) ◽  
pp. 1601-1605 ◽  
Author(s):  
David Bishop-Bailey
Keyword(s):  
Endothelial Cells ◽  
Critical Role ◽  
Molecular Target ◽  
Experimental Models ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Angiogenic Switch ◽  
Receptor Family

The PPAR (peroxisome-proliferator-activated receptor) family consists of three ligand-activated nuclear receptors: PPARα, PPARβ/δ and PPARγ. These PPARs have important roles in the regulation of glucose and fatty acid metabolism, cell differentiation and immune function, but were also found to be expressed in endothelial cells in the late 1990s. The early endothelial focus of PPARs was PPARγ, the molecular target for the insulin-sensitizing thiazolidinedione/glitazone class of drugs. Activation of PPARγ was shown to inhibit angiogenesis in vitro and in models of retinopathy and cancer, whereas more recent data point to a critical role in the development of the vasculature in the placenta. Similarly, PPARα, the molecular target for the fibrate class of drugs, also has anti-angiogenic properties in experimental models. In contrast, unlike PPARα or PPARγ, activation of PPARβ/δ induces angiogenesis, in vitro and in vivo, and has been suggested to be a critical component of the angiogenic switch in pancreatic cancer. Moreover, PPARβ/δ is an exercise mimetic and appears to contribute to the angiogenic remodelling of cardiac and skeletal muscle induced by exercise. This evidence and the emerging mechanisms by which PPARs act in endothelial cells are discussed in more detail.

scholarly journals Recreating Tumour Complexity in a Dish: Organoid Models to Study Liver Cancer Cells and their Extracellular Environment

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1706 ◽  
Author(s):  
van Tienderen ◽  
Groot Koerkamp ◽  
IJzermans ◽  
van der Laan ◽  
Verstegen
Keyword(s):  
Liver Cancer ◽  
Cancer Progression ◽  
Primary Liver Cancer ◽  
Tumour Microenvironment ◽  
In Vitro Models ◽  
Experimental Models ◽  
Liver Tumours ◽  
Extracellular Environment

Primary liver cancer, consisting predominantly of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), remains one of the most lethal malignancies worldwide. This high malignancy is related to the complex and dynamic interactions between tumour cells, stromal cells and the extracellular environment. Novel in vitro models that can recapitulate the tumour are essential in increasing our understanding of liver cancer. Herein, primary liver cancer-derived organoids have opened up new avenues due to their patient-specificity, self-organizing ability and potential recapitulation of many of the tumour properties. Organoids are solely of epithelial origin, but incorporation into co-culture models can enable the investigation of the cellular component of the tumour microenvironment. However, the extracellular component also plays a vital role in cancer progression and representation is lacking within current in vitro models. In this review, organoid technology is discussed in the context of liver cancer models through comparisons to other cell culture systems. In addition, the role of the tumour extracellular environment in primary liver cancer will be highlighted with an emphasis on its importance in in vitro modelling. Converging novel organoid-based models with models incorporating the native tumour microenvironment could lead to experimental models that can better recapitulate liver tumours in vivo.

Physiological Functions of Peroxisome Proliferator-Activated Receptor β

2014 ◽  
Vol 94 (3) ◽  
pp. 795-858 ◽  
Author(s):  
Jaap G. Neels ◽  
Paul A. Grimaldi
Keyword(s):  
Therapeutic Option ◽  
Cell Types ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
In Vivo Models ◽  
Physiological Functions ◽  
Regulatory Pathways ◽  
Inflammatory Conditions

The peroxisome proliferator-activated receptors, PPARα, PPARβ, and PPARγ, are a family of transcription factors activated by a diversity of molecules including fatty acids and fatty acid metabolites. PPARs regulate the transcription of a large variety of genes implicated in metabolism, inflammation, proliferation, and differentiation in different cell types. These transcriptional regulations involve both direct transactivation and interaction with other transcriptional regulatory pathways. The functions of PPARα and PPARγ have been extensively documented mainly because these isoforms are activated by molecules clinically used as hypolipidemic and antidiabetic compounds. The physiological functions of PPARβ remained for a while less investigated, but the finding that specific synthetic agonists exert beneficial actions in obese subjects uplifted the studies aimed to elucidate the roles of this PPAR isoform. Intensive work based on pharmacological and genetic approaches and on the use of both in vitro and in vivo models has considerably improved our knowledge on the physiological roles of PPARβ in various cell types. This review will summarize the accumulated evidence for the implication of PPARβ in the regulation of development, metabolism, and inflammation in several tissues, including skeletal muscle, heart, skin, and intestine. Some of these findings indicate that pharmacological activation of PPARβ could be envisioned as a therapeutic option for the correction of metabolic disorders and a variety of inflammatory conditions. However, other experimental data suggesting that activation of PPARβ could result in serious adverse effects, such as carcinogenesis and psoriasis, raise concerns about the clinical use of potent PPARβ agonists.

scholarly journals Inhibition of soluble epoxide hydrolase ameliorates hyperhomocysteinemia-induced hepatic steatosis by enhancing β-oxidation of fatty acid in mice

2019 ◽  
Vol 316 (4) ◽  
pp. G527-G538 ◽  
Author(s):  
Liu Yao ◽  
Boyang Cao ◽  
Qian Cheng ◽  
Wenbin Cai ◽  
Chenji Ye ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver

Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg·kg−1·day−1 for the animal model and 1 μM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-α (PPAR-α), as evidenced by elevated β-oxidation of fatty acids and the expression of PPAR-α target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-α activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-α. Of note, 11,12-EET ligand dependently activated PPAR-α. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-α was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.

scholarly journals Targeting PPARγSignaling Cascade for the Prevention and Treatment of Prostate Cancer

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Sakshi Sikka ◽  
Luxi Chen ◽  
Gautam Sethi ◽  
Alan Prem Kumar
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Option ◽  
Antitumor Agent ◽  
Endothelial Cell Proliferation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Prostate Carcinogenesis ◽  
And Migration

The peroxisome proliferator-activated receptor-gamma (PPARγ) is a member of the hormone-activated nuclear receptor superfamily. PPARγcan be activated by a diverse group of agents, such as endogenous polyunsaturated fatty acids, 15-deoxy-Δ12,14-prostaglandin J2(15d-PGJ2), and thiazolidinedione (TZD) drugs. PPARγinduces antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for downregulation of carcinogenesis. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment. TZDs have been proven for antitumor activity in a wide variety of experimental cancer models, bothin vitroandin vivo, by affecting the cell cycle, inducing cell differentiation and apoptosis, as well as by inhibiting tumor angiogenesis. Angiogenesis inhibition mechanisms of TZDs include direct inhibition of endothelial cell proliferation and migration, as well as reduction in tumor cell vascular endothelial growth factor production. In prostate cancer, PPARγligands such as troglitazone and 15d-PGJ2have also shown to inhibit tumor growth. This paper will focus on current discoveries in PPARγactivation, targeting prostate carcinogenesis as well as the role of PPARγas a possible anticancer therapeutic option. Here, we review PPARγas an antitumor agent and summarize the antineoplastic effects of PPARγagonists in prostate cancer.

scholarly journals Chitosan Oligosaccharides Improve Glucolipid Metabolism Disorder in Liver by Suppression of Obesity-Related Inflammation and Restoration of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 455 ◽  
Author(s):  
Yibo Bai ◽  
Junping Zheng ◽  
Xubing Yuan ◽  
Siming Jiao ◽  
Cui Feng ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Hepg2 Cells ◽  
Biological Activities ◽  
Experimental Models ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Chitosan Oligosaccharides ◽  
Metabolism Disorder

Chitosan oligosaccharides (COS) display various biological activities. In this study, we aimed to explore the preventive effects of COS on glucolipid metabolism disorder using palmitic acid (PA)-induced HepG2 cells and high-fat diet (HFD)-fed C57BL/6J mice as experimental models in vitro and in vivo, respectively. The results showed that COS pretreatment for 12 h significantly ameliorated lipid accumulation in HepG2 cells exposed to PA for 24 h, accompanied by a reversing of the upregulated mRNA expression of proinflammatory cytokines (IL-6, MCP-1, TNF-α) and glucolipid metabolism-related regulators (SCD-1, ACC1, PCK1-α). In addition, COS treatment alleviated glucolipid metabolism disorder in mice fed with HFD for five months, including reduction in body weight and fasting glucose, restoration of intraperitoneal glucose tolerance, and suppression of overexpression of proinflammatory cytokines and glucolipid metabolism-related regulators. Furthermore, our study found that COS pretreatment significantly reversed the downregulation of PPARγ at transcriptional and translational levels in both PA-induced HepG2 cells and liver tissues of HFD-fed mice. In summary, the study suggests that COS can improve glucolipid metabolism disorder by suppressing inflammation and upregulating PPARγ expression. This indicates a novel application of COS in preventing and treating glucolipid metabolism-related diseases.

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 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.

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 Activation of Peroxisome Proliferator-Activated Receptor γ Does Not Inhibit IL-6 or TNF-α Responses of Macrophages to Lipopolysaccharide In Vitro or In Vivo

2000 ◽  
Vol 164 (2) ◽  
pp. 1046-1054 ◽  
Author(s):  
Rolf Thieringer ◽  
Judy E. Fenyk-Melody ◽  
Cheryl B. Le Grand ◽  
Beverly A. Shelton ◽  
Patricia A. Detmers ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tnf Α
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