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Zhou Y, Wang F, Hu M, Xia S, Li Y, Zheng S, Zhang F. Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells. Pharmaceuticals (Basel) 2025; 18:219. [PMID: 40006033 PMCID: PMC11859973 DOI: 10.3390/ph18020219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/01/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Hepatic fibrosis (HF) is a progressive liver disease characterized by the activation of hepatic stellate cells (HSCs) and changes in lipid metabolism. Abnormal ketone body (KD) levels, including acetoacetate (AcAc) and beta-hydroxybutyrate (BHB), have been observed in patients with HF, but the mechanisms linking ketone metabolism to fibrosis progression remain unclear. Objectives: This study aimed to investigate the role of AcAc in modulating HSCs activation and its potential mechanisms in HF. Methods: We examined the effects of AcAc on HSCs activation by Western blot analysis and RT-PCR both in vivo and in vitro. The impact of AcAc on lipid droplet accumulation in HSCs was assessed using total cholesterol (TC), triglyceride (TG), and Retinol (RET) kits, along with Nile Red and Oil Red O staining. RT-PCR screening was performed to analyze the expression of genes involved in lipid droplet formation and lipid metabolism. Results: Our findings show that AcAc inhibited HSCs activation by restoring LD levels. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) was identified as a key regulator through gene screening. AcAc primarily regulated PPARγ expression, and knocking down PPARγ significantly aggravated HF progression. Conclusions: The ability of AcAc to restore LD levels and regulate PPARγ suggests that it may represent a promising therapeutic strategy for HF by inhibiting HSCs activation.
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Affiliation(s)
| | | | | | | | | | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; (Y.Z.); (F.W.); (M.H.); (S.X.); (Y.L.)
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; (Y.Z.); (F.W.); (M.H.); (S.X.); (Y.L.)
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2
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Briganti S, Mosca S, Di Nardo A, Flori E, Ottaviani M. New Insights into the Role of PPARγ in Skin Physiopathology. Biomolecules 2024; 14:728. [PMID: 38927131 PMCID: PMC11201613 DOI: 10.3390/biom14060728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/17/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor expressed in many tissues, including skin, where it is essential for maintaining skin barrier permeability, regulating cell proliferation/differentiation, and modulating antioxidant and inflammatory responses upon ligand binding. Therefore, PPARγ activation has important implications for skin homeostasis. Over the past 20 years, with increasing interest in the role of PPARs in skin physiopathology, considerable effort has been devoted to the development of PPARγ ligands as a therapeutic option for skin inflammatory disorders. In addition, PPARγ also regulates sebocyte differentiation and lipid production, making it a potential target for inflammatory sebaceous disorders such as acne. A large number of studies suggest that PPARγ also acts as a skin tumor suppressor in both melanoma and non-melanoma skin cancers, but its role in tumorigenesis remains controversial. In this review, we have summarized the current state of research into the role of PPARγ in skin health and disease and how this may provide a starting point for the development of more potent and selective PPARγ ligands with a low toxicity profile, thereby reducing unwanted side effects.
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Affiliation(s)
| | | | | | - Enrica Flori
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (S.B.); (S.M.); (A.D.N.); (M.O.)
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3
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Osama HM, Khadrawy SM, El-Nahass ES, Othman SI, Mohamed HM. Eltroxin and Hesperidin mitigate testicular and renal damage in hypothyroid rats: amelioration of oxidative stress through PPARγ and Nrf2/HO-1 signaling pathway. Lab Anim Res 2024; 40:19. [PMID: 38745206 PMCID: PMC11092223 DOI: 10.1186/s42826-024-00204-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 04/22/2024] [Accepted: 04/28/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Thyroid hormones (THs) regulate growth, development and function of different tissues. Hypothyroidism is a common clinical disorder characterized by deficiency in THs and adversely affects the development and functions of several organs. This work aimed to investigate the ameliorative effect of eltroxin (ELT), a hypothyroidism medication, and hesperidin (HSP), a flavonoid, against testicular and renal toxicity in hypothyroid rats. Twenty-four rats were divided into four groups and treated orally for 12 weeks. Group I (control), group II (hypothyroidism) received 20 mg/kg carbimazole (CBZ), group III received CBZ and 0.045 mg/kg ELT, and group IV received CBZ and 200 mg/kg HSP. RESULTS CBZ administration induced biochemical and histopathological changes in testis and kidney. Co-administration of ELT or HSP significantly (P < 0.05) ameliorated THs, reduced urea and creatinine while raised follicle stimulating hormone (FSH), Luteinizing hormone (LH), and testosterone in serum. Testicular and renal malondialdehyde level as a lipid peroxidation indicator, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were significantly (P < 0.05) decreased while glutathione content, glutathione peroxidase, and glutathione-s-transferase activities were significantly (P < 0.05) increased. The histopathological changes were also diminished. Decreased mRNA and protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and peroxisome proliferator-activated receptor gamma(PPARγ) in hypothyroid rats were up-regulated after ELT or HSP treatment. CONCLUSIONS ELT and HSP showed antioxidant and anti-inflammatory effects against CBZ-induced testicular and renal toxicity, and these effects may be promoted via activating Nrf2/HO-1 and PPARγ signaling pathways.
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Affiliation(s)
- Hadeel M Osama
- Genetics and Molecular Biology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Sally M Khadrawy
- Genetics and Molecular Biology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt.
| | - El-Shaymaa El-Nahass
- Pathology Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Sarah I Othman
- Biology Department, College of Science, Princess Nourah bint Abdulrahman University, P.O. BOX 84428, Riyadh, 11671, Saudi Arabia
| | - Hanaa M Mohamed
- Genetics and Molecular Biology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
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4
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Slanovc J, Mikulčić M, Jahn N, Wizsy NGT, Sattler W, Malle E, Hrzenjak A. Prostaglandin 15d-PGJ 2 inhibits proliferation of lung adenocarcinoma cells by inducing ROS production and activation of apoptosis via sirtuin-1. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166924. [PMID: 37898426 DOI: 10.1016/j.bbadis.2023.166924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 09/26/2023] [Accepted: 10/20/2023] [Indexed: 10/30/2023]
Abstract
Lung adenocarcinoma (LUADC) belongs to the most prevalent and lethal cancer types. As 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) displays anti-oxidative, -inflammatory, and -cancer properties, we investigated whether this cyclopentenone PG, a stable degradation end-product of cyclooxygenase-generated PGD2, exerts beneficial effects in three LUADC cell lines (A549, H1299, H23). We here report that 15d-PGJ2 had substantial cytotoxic effects in all three LUADC cell lines by promoting early apoptosis and inhibiting the cell cycle, proliferation, and migration. As indicators of cell malignancy, scratch closure and colony formation were significantly inhibited by 15d-PGJ2. 15d-PGJ2 induced generation of ROS and subsequent activation of MAPKs. Expression of Nrf-2, a well-known tumor driver, was markedly diminished by 15d-PGJ2 treatment. Although PPARγ, DP1, and DP2 are expressed in LUADC cells, blocking these receptors with specific inhibitors (SR16832 and BW245C) did not reverse 15d-PGJ2-mediated cytotoxicity, suggesting receptor-independent effects. 15d-PGJ2 decreased SIRT1 expression in LUADC cells and the knockdown of SIRT1 diminished the cytotoxic effects of 15d-PGJ2. Importantly, 15d-PGJ2 significantly reduced tumor growth using the chorioallantoic membrane (CAM) assay. The structural analog of 15d- PGJ2, 9,10-dihydro-15d-PGJ2 (lacking the α,β-unsaturated ketone structural element), did not show any toxic effects in LUADC cells. Altogether, our findings suggest that 15d-PGJ2 led to significantly reduced tumor growth and cell proliferation in three LUADC cell lines. The CAM assay results suggest that 15d-PGJ2 is a suitable endogenous compound to interfere with LUADC tumor progression. We show that SIRT1 modulates the effects of 15d-PGJ2 and may be used as a therapeutic target for LUADC.
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Affiliation(s)
- Julia Slanovc
- Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, 8036 Graz, Austria.
| | - Mateja Mikulčić
- Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, 8036 Graz, Austria.
| | - Nicole Jahn
- Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, 8036 Graz, Austria.
| | | | - Wolfgang Sattler
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
| | - Ernst Malle
- Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
| | - Andelko Hrzenjak
- Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, 8036 Graz, Austria; Ludwig Boltzmann Institute for Lung Vascular Research, Medical University of Graz, 8010 Graz, Austria.
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5
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Liu M, Zhang Z, Chen Y, Feng T, Zhou Q, Tian X. Circadian clock and lipid metabolism disorders: a potential therapeutic strategy for cancer. Front Endocrinol (Lausanne) 2023; 14:1292011. [PMID: 38189049 PMCID: PMC10770836 DOI: 10.3389/fendo.2023.1292011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 11/30/2023] [Indexed: 01/09/2024] Open
Abstract
Recent research has emphasized the interaction between the circadian clock and lipid metabolism, particularly in relation to tumors. This review aims to explore how the circadian clock regulates lipid metabolism and its impact on carcinogenesis. Specifically, targeting key enzymes involved in fatty acid synthesis (SREBP, ACLY, ACC, FASN, and SCD) has been identified as a potential strategy for cancer therapy. By disrupting these enzymes, it may be possible to inhibit tumor growth by interfering with lipid metabolism. Transcription factors, like SREBP play a significant role in regulating fatty acid synthesis which is influenced by circadian clock genes such as BMAL1, REV-ERB and DEC. This suggests a strong connection between fatty acid synthesis and the circadian clock. Therefore, successful combination therapy should target fatty acid synthesis in addition to considering the timing and duration of drug use. Ultimately, personalized chronotherapy can enhance drug efficacy in cancer treatment and achieve treatment goals.
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Affiliation(s)
- Mengsi Liu
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Changsha, China
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention and Treatment, Hunan University of Chinese Medicine, Changsha, China
| | - Zhen Zhang
- Department of Oncology, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, China
| | - Yating Chen
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Changsha, China
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention and Treatment, Hunan University of Chinese Medicine, Changsha, China
| | - Ting Feng
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Changsha, China
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention and Treatment, Hunan University of Chinese Medicine, Changsha, China
| | - Qing Zhou
- Department of Andrology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Xuefei Tian
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Changsha, China
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention and Treatment, Hunan University of Chinese Medicine, Changsha, China
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6
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Wagner N, Wagner KD. Recent Insights into the Role of PPARs in Disease. Cells 2023; 12:1572. [PMID: 37371042 DOI: 10.3390/cells12121572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 06/04/2023] [Indexed: 06/29/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that play important roles in cell proliferation, differentiation, metabolism, and cancer [...].
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Affiliation(s)
- Nicole Wagner
- CNRS, INSERM, iBV, Université Côte d'Azur, 06107 Nice, France
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7
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Zhu J, Min N, Gong W, Chen Y, Li X. Identification of Hub Genes and Biological Mechanisms Associated with Non-Alcoholic Fatty Liver Disease and Triple-Negative Breast Cancer. Life (Basel) 2023; 13:life13040998. [PMID: 37109526 PMCID: PMC10146727 DOI: 10.3390/life13040998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/20/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
The relationship between non-alcoholic fatty liver disease (NAFLD) and triple-negative breast cancer (TNBC) has been widely recognized, but the underlying mechanisms are still unknown. The objective of this study was to identify the hub genes associated with NAFLD and TNBC, and to explore the potential co-pathogenesis and prognostic linkage of these two diseases. We used GEO, TCGA, STRING, ssGSEA, and Rstudio to investigate the common differentially expressed genes (DEGs), conduct functional and signaling pathway enrichment analyses, and determine prognostic value between TNBC and NAFLD. GO and KEGG enrichment analyses of the common DEGs showed that they were enriched in leukocyte aggregation, migration and adhesion, apoptosis regulation, and the PPAR signaling pathway. Fourteen candidate hub genes most likely to mediate NAFLD and TNBC occurrence were identified and validation results in a new cohort showed that ITGB2, RAC2, ITGAM, and CYBA were upregulated in both diseases. A univariate Cox analysis suggested that high expression levels of ITGB2, RAC2, ITGAM, and CXCL10 were associated with a good prognosis in TNBC. Immune infiltration analysis of TNBC samples showed that NCF2, ICAM1, and CXCL10 were significantly associated with activated CD8 T cells and activated CD4 T cells. NCF2, CXCL10, and CYBB were correlated with regulatory T cells and myeloid-derived suppressor cells. This study demonstrated that the redox reactions regulated by the NADPH oxidase (NOX) subunit genes and the transport and activation of immune cells regulated by integrins may play a central role in the co-occurrence trend of NAFLD and TNBC. Additionally, ITGB2, RAC2, and ITGAM were upregulated in both diseases and were prognostic protective factors of TNBC; they may be potential therapeutic targets for treatment of TNBC patients with NAFLD, but further experimental studies are still needed.
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Affiliation(s)
- Jingjin Zhu
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Ningning Min
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Wenye Gong
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
- Medical School of Chinese PLA, Beijing 100853, China
| | - Yizhu Chen
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
- Medical School of Chinese PLA, Beijing 100853, China
| | - Xiru Li
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
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8
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Dana N, Ferns GA, Nedaeinia R, Haghjooy Javanmard S. Leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ. Clin Transl Oncol 2023; 25:601-610. [PMID: 36348225 DOI: 10.1007/s12094-022-02988-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 10/18/2022] [Indexed: 11/09/2022]
Abstract
Obesity may create a mitogenic microenvironment that influences tumor initiation and progression. The obesity-associated adipokine, leptin regulates energy metabolism and has been implicated in cancer development. It has been shown that some cell types other than adipocytes can express leptin and leptin receptors in tumor microenvironments. It has been shown that peroxisome proliferator-activated receptors (PPAR) agonists can affect leptin levels and vice versa leptin can affect PPARs. Activation of PPARs affects the expression of several genes involved in aspects of lipid metabolism. In addition, PPARs regulate cancer cell progression through their action on the tumor cell proliferation, metabolism, and cellular environment. Some studies have shown an association between obesity and several types of cancer, including breast cancer. There is some evidence that suggests that there is crosstalk between PPARs and leptin during the development of breast cancer. Through a systematic review of previous studies, we have reviewed the published relevant articles regarding leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.
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Affiliation(s)
- Nasim Dana
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton and Sussex Medical School, Falmer, Brighton, BN1 9PH, Sussex, UK
| | - Reza Nedaeinia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.
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9
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Chatziantoniou A, Zaravinos A. Signatures of Co-Deregulated Genes and Their Transcriptional Regulators in Lung Cancer. Int J Mol Sci 2022; 23:10933. [PMID: 36142846 PMCID: PMC9504879 DOI: 10.3390/ijms231810933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 09/13/2022] [Indexed: 11/24/2022] Open
Abstract
Despite the significant progress made towards comprehending the deregulated signatures in lung cancer, these vary from study to study. We reanalyzed 25 studies from the Gene Expression Omnibus (GEO) to detect and annotate co-deregulated signatures in lung cancer and in single-gene or single-drug perturbation experiments. We aimed to decipher the networks that these co-deregulated genes (co-DEGs) form along with their upstream regulators. Differential expression and upstream regulators were computed using Characteristic Direction and Systems Biology tools, including GEO2Enrichr and X2K. Co-deregulated gene expression profiles were further validated across different molecular and immune subtypes in lung adenocarcinoma (TCGA-LUAD) and lung adenocarcinoma (TCGA-LUSC) datasets, as well as using immunohistochemistry data from the Human Protein Atlas, before being subjected to subsequent GO and KEGG enrichment analysis. The functional alterations of the co-upregulated genes in lung cancer were mostly related to immune response regulating the cell surface signaling pathway, in contrast to the co-downregulated genes, which were related to S-nitrosylation. Networks of hub proteins across the co-DEGs consisted of overlapping TFs (SOX2, MYC, KAT2A) and kinases (MAPK14, CSNK2A1 and CDKs). Furthermore, using Connectivity Map we highlighted putative repurposing drugs, including valproic acid, betonicine and astemizole. Similarly, we analyzed the co-DEG signatures in single-gene and single-drug perturbation experiments in lung cancer cell lines. In summary, we identified critical co-DEGs in lung cancer providing an innovative framework for their potential use in developing personalized therapeutic strategies.
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Affiliation(s)
- Angeliki Chatziantoniou
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia 1516, Cyprus
- Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia 1516, Cyprus
| | - Apostolos Zaravinos
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia 1516, Cyprus
- Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia 1516, Cyprus
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10
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The Regulatory Roles of PPARs in Skeletal Muscle Fuel Metabolism and Inflammation: Impact of PPAR Agonism on Muscle in Chronic Disease, Contraction and Sepsis. Int J Mol Sci 2021; 22:ijms22189775. [PMID: 34575939 PMCID: PMC8465345 DOI: 10.3390/ijms22189775] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/06/2021] [Accepted: 09/08/2021] [Indexed: 12/13/2022] Open
Abstract
The peroxisome proliferator-activated receptor (PPAR) family of transcription factors has been demonstrated to play critical roles in regulating fuel selection, energy expenditure and inflammation in skeletal muscle and other tissues. Activation of PPARs, through endogenous fatty acids and fatty acid metabolites or synthetic compounds, has been demonstrated to have lipid-lowering and anti-diabetic actions. This review will aim to provide a comprehensive overview of the functions of PPARs in energy homeostasis, with a focus on the impacts of PPAR agonism on muscle metabolism and function. The dysregulation of energy homeostasis in skeletal muscle is a frequent underlying characteristic of inflammation-related conditions such as sepsis. However, the potential benefits of PPAR agonism on skeletal muscle protein and fuel metabolism under these conditions remains under-investigated and is an area of research opportunity. Thus, the effects of PPARγ agonism on muscle inflammation and protein and carbohydrate metabolism will be highlighted, particularly with its potential relevance in sepsis-related metabolic dysfunction. The impact of PPARδ agonism on muscle mitochondrial function, substrate metabolism and contractile function will also be described.
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11
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Menzel A, Samouda H, Dohet F, Loap S, Ellulu MS, Bohn T. Common and Novel Markers for Measuring Inflammation and Oxidative Stress Ex Vivo in Research and Clinical Practice-Which to Use Regarding Disease Outcomes? Antioxidants (Basel) 2021; 10:antiox10030414. [PMID: 33803155 PMCID: PMC8001241 DOI: 10.3390/antiox10030414] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 02/06/2023] Open
Abstract
Many chronic conditions such as cancer, chronic obstructive pulmonary disease, type-2 diabetes, obesity, peripheral/coronary artery disease and auto-immune diseases are associated with low-grade inflammation. Closely related to inflammation is oxidative stress (OS), which can be either causal or secondary to inflammation. While a low level of OS is physiological, chronically increased OS is deleterious. Therefore, valid biomarkers of these signalling pathways may enable detection and following progression of OS/inflammation as well as to evaluate treatment efficacy. Such biomarkers should be stable and obtainable through non-invasive methods and their determination should be affordable and easy. The most frequently used inflammatory markers include acute-phase proteins, essentially CRP, serum amyloid A, fibrinogen and procalcitonin, and cytokines, predominantly TNFα, interleukins 1β, 6, 8, 10 and 12 and their receptors and IFNγ. Some cytokines appear to be disease-specific. Conversely, OS-being ubiquitous-and its biomarkers appear less disease or tissue-specific. These include lipid peroxidation products, e.g., F2-isoprostanes and malondialdehyde, DNA breakdown products (e.g., 8-OH-dG), protein adducts (e.g., carbonylated proteins), or antioxidant status. More novel markers include also -omics related ones, as well as non-invasive, questionnaire-based measures, such as the dietary inflammatory-index (DII), but their link to biological responses may be variable. Nevertheless, many of these markers have been clearly related to a number of diseases. However, their use in clinical practice is often limited, due to lacking analytical or clinical validation, or technical challenges. In this review, we strive to highlight frequently employed and useful markers of inflammation-related OS, including novel promising markers.
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Affiliation(s)
- Alain Menzel
- Laboratoires Réunis, 38, Rue Hiehl, L-6131 Junglinster, Luxembourg; (A.M.); (F.D.)
| | - Hanen Samouda
- Nutrition and Health Research Group, Department of Population Health, Luxembourg Institute of Health, 1 A-B, Rue Thomas Edison, L-1445 Strassen, Luxembourg;
| | - Francois Dohet
- Laboratoires Réunis, 38, Rue Hiehl, L-6131 Junglinster, Luxembourg; (A.M.); (F.D.)
| | - Suva Loap
- Clinic Cryo Esthetic, 11 Rue Éblé, 75007 Paris, France;
| | - Mohammed S. Ellulu
- Department of Clinical Nutrition, Faculty of Applied Medical Sciences, Al-Azhar University of Gaza (AUG), Gaza City 00970, Palestine;
| | - Torsten Bohn
- Nutrition and Health Research Group, Department of Population Health, Luxembourg Institute of Health, 1 A-B, Rue Thomas Edison, L-1445 Strassen, Luxembourg;
- Correspondence:
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Garay-Sevilla ME, Gomez-Ojeda A, González I, Luévano-Contreras C, Rojas A. Contribution of RAGE axis activation to the association between metabolic syndrome and cancer. Mol Cell Biochem 2021; 476:1555-1573. [PMID: 33398664 DOI: 10.1007/s11010-020-04022-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 12/11/2020] [Indexed: 02/07/2023]
Abstract
Far beyond the compelling proofs supporting that the metabolic syndrome represents a risk factor for diabetes and cardiovascular diseases, a growing body of evidence suggests that it is also a risk factor for different types of cancer. However, the involved molecular mechanisms underlying this association are not fully understood, and they have been mainly focused on the individual contributions of each component of the metabolic syndrome such as obesity, hyperglycemia, and high blood pressure to the development of cancer. The Receptor for Advanced Glycation End-products (RAGE) axis activation has emerged as an important contributor to the pathophysiology of many clinical entities, by fueling a chronic inflammatory milieu, and thus supporting an optimal microenvironment to promote tumor growth and progression. In the present review, we intend to highlight that RAGE axis activation is a crosswise element on the potential mechanistic contributions of some relevant components of metabolic syndrome into the association with cancer.
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Affiliation(s)
- Ma Eugenia Garay-Sevilla
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Armando Gomez-Ojeda
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Ileana González
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Claudia Luévano-Contreras
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, Chile.
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13
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Liu X, Yin M, Liu X, Da J, Zhang K, Zhang X, Liu L, Wang J, Jin H, Liu Z, Zhang B, Li Y. Analysis of Hub Genes Involved in Distinction Between Aged and Fetal Bone Marrow Mesenchymal Stem Cells by Robust Rank Aggregation and Multiple Functional Annotation Methods. Front Genet 2020; 11:573877. [PMID: 33424919 PMCID: PMC7793715 DOI: 10.3389/fgene.2020.573877] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 11/24/2020] [Indexed: 12/25/2022] Open
Abstract
Stem cells from fetal tissue protect against aging and possess greater proliferative capacity than their adult counterparts. These cells can more readily expand in vitro and senesce later in culture. However, the underlying molecular mechanisms for these differences are still not fully understood. In this study, we used a robust rank aggregation (RRA) method to discover robust differentially expressed genes (DEGs) between fetal bone marrow mesenchymal stem cells (fMSCs) and aged adult bone marrow mesenchymal stem cells (aMSCs). Multiple methods, including gene set enrichment analysis (GSEA), Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed for functional annotation of the robust DEGs, and the results were visualized using the R software. The hub genes and other genes with which they interacted directly were detected by protein–protein interaction (PPI) network analysis. Correlation of gene expression was measured by Pearson correlation coefficient. A total of 388 up-regulated and 289 down-regulated DEGs were identified between aMSCs and fMSCs. We found that the down-regulated genes were mainly involved in the cell cycle, telomerase activity, and stem cell proliferation. The up-regulated DEGs were associated with cell adhesion molecules, extracellular matrix (ECM)–receptor interactions, and the immune response. We screened out four hub genes, MYC, KIF20A, HLA-DRA, and HLA-DPA1, through PPI-network analysis. The MYC gene was negatively correlated with TXNIP, an age-related gene, and KIF20A was extensively involved in the cell cycle. The results suggested that MSCs derived from the bone marrow of an elderly donor present a pro-inflammatory phenotype compared with that of fMSCs, and the HLA-DRA and HLA-DPA1 genes are related to the immune response. These findings provide new insights into the differences between aMSCs and fMSCs and may suggest novel strategies for ex vivo expansion and application of adult MSCs.
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Affiliation(s)
- Xiaoyao Liu
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Mingjing Yin
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinpeng Liu
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Junlong Da
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Kai Zhang
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinjian Zhang
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lixue Liu
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jianqun Wang
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Han Jin
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhongshuang Liu
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bin Zhang
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Ying Li
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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14
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Peroxisome Proliferator-Activated Receptors as Molecular Links between Caloric Restriction and Circadian Rhythm. Nutrients 2020; 12:nu12113476. [PMID: 33198317 PMCID: PMC7696073 DOI: 10.3390/nu12113476] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
The circadian rhythm plays a chief role in the adaptation of all bodily processes to internal and environmental changes on the daily basis. Next to light/dark phases, feeding patterns constitute the most essential element entraining daily oscillations, and therefore, timely and appropriate restrictive diets have a great capacity to restore the circadian rhythm. One of the restrictive nutritional approaches, caloric restriction (CR) achieves stunning results in extending health span and life span via coordinated changes in multiple biological functions from the molecular, cellular, to the whole-body levels. The main molecular pathways affected by CR include mTOR, insulin signaling, AMPK, and sirtuins. Members of the family of nuclear receptors, the three peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ, and PPARγ take part in the modulation of these pathways. In this non-systematic review, we describe the molecular interconnection between circadian rhythm, CR-associated pathways, and PPARs. Further, we identify a link between circadian rhythm and the outcomes of CR on the whole-body level including oxidative stress, inflammation, and aging. Since PPARs contribute to many changes triggered by CR, we discuss the potential involvement of PPARs in bridging CR and circadian rhythm.
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15
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Li J, Li Q, Su Z, Sun Q, Zhao Y, Feng T, Jiang J, Zhang F, Ma H. Lipid metabolism gene-wide profile and survival signature of lung adenocarcinoma. Lipids Health Dis 2020; 19:222. [PMID: 33050938 PMCID: PMC7557101 DOI: 10.1186/s12944-020-01390-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 09/24/2020] [Indexed: 12/24/2022] Open
Abstract
Background Lung cancer has high morbidity and mortality across the globe, and lung adenocarcinoma (LUAD) is the most common histologic subtype. Disordered lipid metabolism is related to the development of cancer. Analysis of lipid-related transcriptome helps shed light on the diagnosis and prognostic biomarkers of LUAD. Methods In this study, expression analysis of 1045 lipid metabolism-related genes was performed between LUAD tumors and normal tissues derived from the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) cohort. The interaction network of differentially expressed genes (DEGs) was constructed to identify the hub genes. The association between hub genes and overall survival (OS) was evaluated and formed a model to predict the prognosis of LUAD using a nomogram. The model was validated by another cohort, GSE13213. Results A total of 217 lipid metabolism-related DEGs were detected in LUAD. Genes were significantly enriched in glycerophospholipid metabolism, fatty acid metabolic process, and eicosanoid signaling. Through network analysis and cytoHubba, 6 hub genes were identified, including INS, LPL, HPGDS, DGAT1, UGT1A6, and CYP2C9. High expression of CYP2C9, UGT1A6, and INS, and low expressions of DGAT1, HPGDS, and LPL, were associated with worse overall survival for 1925 LUAD patients. The model showed that the high-risk score group had a worse OS, and the validated cohort showed the same result. Conclusions In this study, a signature of 6 lipid metabolism genes was constructed, which was significantly associated with the diagnosis and prognosis of LUAD patients. Thus, the gene signature can be used as a biomarker for LUAD.
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Affiliation(s)
- Jinyou Li
- Department of Thoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214000, China.,Department of Thoracic Surgery, First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Qiang Li
- Public Health School, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhenyu Su
- Department of Thoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214000, China
| | - Qi Sun
- Department of Thoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214000, China
| | - Yong Zhao
- Department of Thoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214000, China
| | - Tienan Feng
- Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jiayuan Jiang
- Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Feng Zhang
- Department of Thoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214000, China.
| | - Haitao Ma
- Department of Thoracic Surgery, First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
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16
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Quantitative proteomics reveals stage-specific protein regulation of triple negative breast cancer. Breast Cancer Res Treat 2020; 185:39-52. [PMID: 32920739 DOI: 10.1007/s10549-020-05916-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 09/01/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUNDS Triple negative breast cancer (TNBC) is a heterogeneous disease with more aggressive clinical courses than other subtypes of breast cancer. In this study, we performed high-resolution mass spectrometry-based quantitative proteomics with TNBC clinical tissue specimens to explore the early and sensitive diagnostic signatures and potential therapeutic targets for TNBC patients. METHODS We performed an iTRAQ labeling coupled LC-MS/MS approach to explore the global proteome in tumor tissues and corresponding para-tumor tissues from 24 patients with grade I-II and grade III primary TNBC. Relative peptide quantification and protein identification were performed by Proteome Discoverer™ software with Mascot search engine. Differentially expressed proteins were analyzed by bioinformatic analyses, including GO function classification annotation and KEGG enrichment analysis. Pathway analyses for protein-protein interactions and upstream regulations of differentially expressed candidates were performed by Ingenuity Pathway Analysis (IPA) software. RESULTS Totally, 5401 unique proteins were identified and quantified in different stage of TNBCs. 845 proteins were changed in patients with grade I or II TNBC, among which 304 were up-regulated and 541 were down-regulated. Meanwhile, for patients with grade III TNBC, 358 proteins were increased and 651 proteins were decreased. Comparing to para-cancerous tissues, various signaling pathways and metabolic processes, including PPAR pathways, PI3K-Akt pathway, one-carbon metabolism, amino acid synthesis, and lipid metabolism were activated in TNBC cancer tissues. Death receptor signaling was significantly activated in grade I-II TNBCs, however, remarkably inhibited in grade III TNBCs. Western blot experiments were conducted to validate expression levels of CYCS, HMGA1 and XIAP with samples from individual patients. CONCLUSIONS Overall, our proteomic data presented precise quantification of potential signatures, signaling pathways, regulatory networks, and characteristic differences in each clinicopathological subgroup. The proteome provides complementary information for TNBC accurate subtype classification and therapeutic targets research.
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17
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Wagner N, Wagner KD. PPARs and Angiogenesis-Implications in Pathology. Int J Mol Sci 2020; 21:ijms21165723. [PMID: 32785018 PMCID: PMC7461101 DOI: 10.3390/ijms21165723] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 08/03/2020] [Accepted: 08/06/2020] [Indexed: 12/22/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to the family of ligand-activated nuclear receptors. The PPAR family consists of three subtypes encoded by three separate genes: PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3). PPARs are critical regulators of metabolism and exhibit tissue and cell type-specific expression patterns and functions. Specific PPAR ligands have been proposed as potential therapies for a variety of diseases such as metabolic syndrome, cancer, neurogenerative disorders, diabetes, cardiovascular diseases, endometriosis, and retinopathies. In this review, we focus on the knowledge of PPAR function in angiogenesis, a complex process that plays important roles in numerous pathological conditions for which therapeutic use of PPAR modulation has been suggested.
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18
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Peroxisome Proliferator-Activated Receptors and Caloric Restriction-Common Pathways Affecting Metabolism, Health, and Longevity. Cells 2020; 9:cells9071708. [PMID: 32708786 PMCID: PMC7407644 DOI: 10.3390/cells9071708] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/14/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Caloric restriction (CR) is a traditional but scientifically verified approach to promoting health and increasing lifespan. CR exerts its effects through multiple molecular pathways that trigger major metabolic adaptations. It influences key nutrient and energy-sensing pathways including mammalian target of rapamycin, Sirtuin 1, AMP-activated protein kinase, and insulin signaling, ultimately resulting in reductions in basic metabolic rate, inflammation, and oxidative stress, as well as increased autophagy and mitochondrial efficiency. CR shares multiple overlapping pathways with peroxisome proliferator-activated receptors (PPARs), particularly in energy metabolism and inflammation. Consequently, several lines of evidence suggest that PPARs might be indispensable for beneficial outcomes related to CR. In this review, we present the available evidence for the interconnection between CR and PPARs, highlighting their shared pathways and analyzing their interaction. We also discuss the possible contributions of PPARs to the effects of CR on whole organism outcomes.
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19
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Yang M, Wang Y, Wang Q, Zhou Z, Yu Y, Wei S, Wang S, Qin Q. Characterization of Kruppel-like factor 6 in Epinephelus coioides: The role in viral infection and the transcriptional regulation on Peroxisome proliferator-activated receptor δ. FISH & SHELLFISH IMMUNOLOGY 2020; 99:9-18. [PMID: 32007559 DOI: 10.1016/j.fsi.2020.01.061] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/29/2020] [Accepted: 01/29/2020] [Indexed: 06/10/2023]
Abstract
The Kruppel-like factor 6 (KLF6) is a member of Kruppel-like factor family, which belong to the Zinc finger family of transcription factors that mediates various cellular processes, such as proliferation, differentiation, development, and programmed cell death. Peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors belonging to the nuclear receptor superfamily and they regulate numerous genes through ligand-dependent transcriptional activation and repression. In this study, we focus on the role of KLF6 gene in virus infection and the regulation of KLF6 on PPAR-δ in orange-spotted grouper (Epinephelus coioides). The ORF sequence of EcKLF6 was 846 bp, encoding a polypeptide of 282 amino acids with three conserved Zinc finger (type Cys2-His2) domain in the C-terminal region. Basing on the detection of the mRNA levels of viral genes, western blotting of MCP protein, and morphological CPEs, we found that the overexpression of EcKLF6 suppressed the replication of Singapore grouper iridovirus (SGIV), exerting its antiviral activity against fish virus. Moreover, promoter analysis was performed to investigate whether EcKLF6 was a regulator of EcPPAR-δ. The luciferase reporter assay and real time PCR results indicated a negative regulatory role of EcKLF6 on EcPPAR-δ transcription in grouper. Further experimental analysis shows that the potential EcKLF6 binding sites may locate in the EcPPAR-δ-4-M3 (+133 to +154) and EcPPAR-δ-4-M4 (+354 to +368) region of the EcPPAR-δ promoter. Electrophoretic mobile shift assays (EMSAs) verified that EcKLF6 interacted with the binding site of the EcPPAR-δ-4-M4 promoter region. In addition, we also found that KLF6 promotes inflammatory responses in GS cells. Considering that KLF6 and PPAR-δ play opposite roles in regulating inflammatory responses, we speculated the promoting effect of KLF6 on inflammatory response may be related to its negative regulation on EcPPAR-δ. In conclusion, the present study provides the first evidence of the negative regulation of EcPPAR-δ transcription by EcKLF6 and contributes to a better understanding of the transcriptional mechanisms of EcKLF6 in fish.
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Affiliation(s)
- Min Yang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Yuxin Wang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Qing Wang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Zhekai Zhou
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Yepin Yu
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Shina Wei
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Shaowen Wang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Qiwei Qin
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266000, China.
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20
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Ekhtari S, Razeghi J, Hasanpur K, Kianianmomeni A. Different regulations of cell-type transcription by UV-B in multicellular green alga Volvox carteri. PLANT SIGNALING & BEHAVIOR 2019; 14:1657339. [PMID: 31446835 PMCID: PMC6804692 DOI: 10.1080/15592324.2019.1657339] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 08/12/2019] [Accepted: 08/14/2019] [Indexed: 06/03/2023]
Abstract
There is a scarcity of research reports on the effect of ultraviolet (UV)-B radiation on genome-wide transcriptional regulation in the multicellular green microalga including Volvox carteri (V. carteri). This microalga possesses only two cell types including mortal and motile somatic cells, as well as immortal and immotile reproductive cells. Therefore, the present study evaluated the effect of low-dose UV-B radiation on the cell-type-specific gene expression pattern of reproductive and somatic cells in an asexual life cycle of V. carteri using RNA sequence method. To this end, the separated reproductive and somatic cells were treated for 1 hour at an intensity of 0.056 mW/cm-2 UV-B radiation. Then, a transcriptome analysis was conducted between the UV-B and white light treated groups in either of the cell types. Based on differential gene expression analyses, no differentially expressed genes were found in reproductive cells under the treatment as compared to the control group. This type of cell maintained its steady state. However, treating the somatic cells with UV-B radiation led to at least 126 differentially expressed genes compared to the untreated control group. In addition, the results of a direct comparison demonstrated a restricted and wide response to UV-B radiation in somatic cells as compared to reproductive cells. Based on the results, UV-B radiation could be involved in cell-type-specific regulation of biological pathways.
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Affiliation(s)
- S. Ekhtari
- Department of Plant Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - J. Razeghi
- Department of Plant Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - K. Hasanpur
- Department of Animal Science, Faculty of Agriculture, University of Tabriz, Tabriz, Iran
| | - A. Kianianmomeni
- Department of Cellular and Developmental Biology of Plants, Faculty of Natural Sciences, University of Bielefeld, Bielefeld, Germany
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21
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Oh HYP, Visvalingam V, Wahli W. The PPAR-microbiota-metabolic organ trilogy to fine-tune physiology. FASEB J 2019; 33:9706-9730. [PMID: 31237779 DOI: 10.1096/fj.201802681rr] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The human gut is colonized by commensal microorganisms, predominately bacteria that have coevolved in symbiosis with their host. The gut microbiota has been extensively studied in recent years, and many important findings on how it can regulate host metabolism have been unraveled. In healthy individuals, feeding timing and type of food can influence not only the composition but also the circadian oscillation of the gut microbiota. Host feeding habits thus influence the type of microbe-derived metabolites produced and their concentrations throughout the day. These microbe-derived metabolites influence many aspects of host physiology, including energy metabolism and circadian rhythm. Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-activated transcription factors that regulate various metabolic processes such as fatty acid metabolism. Similar to the gut microbiota, PPAR expression in various organs oscillates diurnally, and studies have shown that the gut microbiota can influence PPAR activities in various metabolic organs. For example, short-chain fatty acids, the most abundant type of metabolites produced by anaerobic fermentation of dietary fibers by the gut microbiota, are PPAR agonists. In this review, we highlight how the gut microbiota can regulate PPARs in key metabolic organs, namely, in the intestines, liver, and muscle. Knowing that the gut microbiota impacts metabolism and is altered in individuals with metabolic diseases might allow treatment of these patients using noninvasive procedures such as gut microbiota manipulation.-Oh, H. Y. P., Visvalingam, V., Wahli, W. The PPAR-microbiota-metabolic organ trilogy to fine-tune physiology.
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Affiliation(s)
- Hui Yun Penny Oh
- Interdisciplinary Graduate School, Institute for Health Technologies, Nanyang Technological University, Singapore.,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Vivegan Visvalingam
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Walter Wahli
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.,Unité Mixte de Recherche (UMR) 1331, Institut National de la Recherche Agronomique (INRA)-ToxAlim, Toulouse, France.,Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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22
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Martín-Sierra C, Laranjeira P, Domingues MR, Paiva A. Lipoxidation and cancer immunity. Redox Biol 2019; 23:101103. [PMID: 30658904 PMCID: PMC6859558 DOI: 10.1016/j.redox.2019.101103] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 12/14/2018] [Accepted: 01/08/2019] [Indexed: 12/11/2022] Open
Abstract
Lipoxidation is a well-known reaction between electrophilic carbonyl species, formed during oxidation of lipids, and specific proteins that, in most cases, causes an alteration in proteins function. This can occur under physiological conditions but, in many cases, it has been associated to pathological process, including cancer. Lipoxidation may have an effect in cancer development through their effects in tumour cells, as well as through the alteration of immune components and the consequent modulation of the immune response. The formation of protein adducts affects different proteins in cancer, triggering different mechanism, such as proliferation, cell differentiation and apoptosis, among others, altering cancer progression. The divergent results obtained documented that the formation of lipoxidation adducts can have either anti-carcinogenic or pro-carcinogenic effects, depending on the cell type affected and the specific adduct formed. Moreover, lipoxidation adducts may alter the immune response, consequently causing either positive or negative alterations in cancer progression. Therefore, in this review, we summarize the effects of lipoxidation adducts in cancer cells and immune components and their consequences in the evolution of different types of cancer.
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Affiliation(s)
- C Martín-Sierra
- Unidade de Gestão Operacional em Citometria, Centro Hospitalar e Universitário de Coimbra (CHUC), Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - P Laranjeira
- Unidade de Gestão Operacional em Citometria, Centro Hospitalar e Universitário de Coimbra (CHUC), Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - M R Domingues
- Mass Spectrometry Centre, Department of Chemistry & QOPNA, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal; Department of Chemistry & CESAM, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - A Paiva
- Unidade de Gestão Operacional em Citometria, Centro Hospitalar e Universitário de Coimbra (CHUC), Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Ciências Biomédicas Laboratoriais, Portugal.
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23
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Rahman SB, Mir A, Ahmad N, Haider SH, Malik SA, Nasir M. Identification and association of recurrent ALOXE3 mutation with non-bullous congenital ichthyosiform erythroderma in two ethnically distinct Pakistani families. Congenit Anom (Kyoto) 2019; 59:93-98. [PMID: 29935003 PMCID: PMC6309665 DOI: 10.1111/cga.12303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/14/2018] [Accepted: 06/19/2018] [Indexed: 11/29/2022]
Abstract
Non-bullous congenital ichthyosiform erythroderma (NCIE) is characterized by skin scaling with erythema. In this study, two Pakistani families with NCIE are genetically characterized through Whole Exome and Sanger sequencing to identify molecular basis of the disease. We identified a nonsense homozygous c.2026C>T mutation of ALOXE3, causing premature termination of the eLOX3 protein (p.Q676X). In silico studies predicted impaired enzymatic activity of the premature truncated eLOX3, leading to abnormal synthesis of specific hepoxilin derivatives, essential for epidermal barrier formation. It is the first ever study reporting homozygotes of p.Q676X mutation in ethnically distinct two Pakistani families; otherwise, heterozygotes of the said mutation have been reported in South Asian population only. Hence, mutation seems to be region-specific and may be useful for molecular diagnosis of NCIE. Moreover, our findings should help in genetic counseling and career screening.
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Affiliation(s)
| | - Asif Mir
- Department of Biotechnology, International Islamic University, Islamabad, Pakistan
| | - Nafees Ahmad
- Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan
| | | | - Salman Akbar Malik
- Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan
| | - Muhammad Nasir
- Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan
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24
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Mahmoudvand S, Shokri S, Taherkhani R, Farshadpour F. Hepatitis C virus core protein modulates several signaling pathways involved in hepatocellular carcinoma. World J Gastroenterol 2019; 25:42-58. [PMID: 30643357 PMCID: PMC6328967 DOI: 10.3748/wjg.v25.i1.42] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/07/2018] [Accepted: 12/13/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer, and hepatitis C virus (HCV) infection plays a major role in HCC development. The molecular mechanisms by which HCV infection leads to HCC are varied. HCV core protein is an important risk factor in HCV-associated liver pathogenesis and can modulate several signaling pathways involved in cell cycle regulation, cell growth promotion, cell proliferation, apoptosis, oxidative stress and lipid metabolism. The dysregulation of signaling pathways such as transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), Wnt/β-catenin (WNT), cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor α (PPARα) by HCV core protein is implicated in the development of HCC. Therefore, it has been suggested that this protein be considered a favorable target for further studies in the development of HCC. In addition, considering the axial role of these signaling pathways in HCC, they are considered druggable targets for cancer therapy. Therefore, using strategies to limit the dysregulation effects of core protein on these signaling pathways seems necessary to prevent HCV-related HCC.
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Affiliation(s)
- Shahab Mahmoudvand
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Somayeh Shokri
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Reza Taherkhani
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| | - Fatemeh Farshadpour
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
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The Role of PPARβ/δ in Melanoma Metastasis. Int J Mol Sci 2018; 19:ijms19102860. [PMID: 30241392 PMCID: PMC6213649 DOI: 10.3390/ijms19102860] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 09/14/2018] [Accepted: 09/18/2018] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Peroxisome proliferator⁻activated receptor (PPAR) β/δ, a ligand-activated transcription factor, is involved in diverse biological processes including cell proliferation, cell differentiation, inflammation and energy homeostasis. Besides its well-established roles in metabolic disorders, PPARβ/δ has been linked to carcinogenesis and was reported to inhibit melanoma cell proliferation, anchorage-dependent clonogenicity and ectopic xenograft tumorigenicity. However, PPARβ/δ's role in tumour progression and metastasis remains controversial. METHODS In the present studies, the consequence of PPARβ/δ inhibition either by global genetic deletion or by a specific PPARβ/δ antagonist, 10h, on malignant transformation of melanoma cells and melanoma metastasis was examined using both in vitro and in vivo models. RESULTS Our study showed that 10h promotes epithelial-mesenchymal transition (EMT), migration, adhesion, invasion and trans-endothelial migration of mouse melanoma B16/F10 cells. We further demonstrated an increased tumour cell extravasation in the lungs of wild-type mice subjected to 10h treatment and in Pparβ/δ-/- mice in an experimental mouse model of blood-borne pulmonary metastasis by tail vein injection. This observation was further supported by an increased tumour burden in the lungs of Pparβ/δ-/- mice as demonstrated in the same animal model. CONCLUSION These results indicated a protective role of PPARβ/δ in melanoma progression and metastasis.
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Li X, Hong X, Gao X, Gu X, Xiong W, Zhao J, Yu H, Cui M, Xie M, Bai Y, Sun S. Methyl jasmonate enhances the radiation sensitivity of esophageal carcinoma cells by inhibiting the 11-ketoprostaglandin reductase activity of AKR1C3. Cancer Manag Res 2018; 10:3149-3158. [PMID: 30214307 PMCID: PMC6124458 DOI: 10.2147/cmar.s166942] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Purpose In our previous study, we found that AKR1C3 was a radioresistance gene in KY170R cells. Downregulating the expression of AKR1C3 could enhance the radiosensitivity of esophageal carcinoma cells. In this study, we investigated whether methyl jasmonate (MeJ), an inhibitor of Aldo-keto reductase family1 member C3 (AKR1C3), could overcome radiation resistance in AKR1C3 highly expressed cells. Patients and methods We used clone formation assays to detect radiosensitivity effects. Flow cytometry assays were used to detect reactive oxygen species (ROS) accumulation and apoptosis. Enzyme linked immunosorbent assays (ELISAs) were used to detect the concentrations of prostaglandin F2 (PGF2) and prostaglandin D2 (PGD2) in the cells after incubation with MeJ. Western blotting was used to detect AKR1C3 and peroxisome proliferator-activated receptor gamma (PPARγ) expression. Results We found that AKR1C3 was highly expressed in radioresistant esophageal carcinoma cells. MeJ inhibited the expression of AKR1C3 and enhanced the radiation sensitivity of esophageal carcinoma cells expressing high levels of AKR1C3 (P<0.05). MeJ could inhibit the 11-ketoprostaglandin reductase activity of AKR1C3 in a dose-dependent manner in KY170R cells. Incubation of KY170R cells with 200 µmol/L of MeJ for 24 h reduced the expression of PGF2 by roughly 30% (P<0.05). The PPAR pathway inhibitor GW9662 prevented the radiation sensitivity enhancement imparted by MeJ. After adding GW9662, there were no significant differences between the radiation sensitivities of MeJ-treated and -untreated KY170R cells (P>0.05). The radiation sensitivity effect of MeJ also depended upon the generation of ROS in KY170R cells; 48 h after irradiation, ROS levels in the MeJ group was twofold higher than in the untreated KY170R cells (P<0.05). The ROS scavenger, N-acetyl cysteine, could reverse the radiosensitivity effects of MeJ (P>0.05). Conclusion Our results indicate that MeJ can increase the radiation sensitivity of AKR1C3-overexpressing KY170R cells by inhibiting the 11-ketoprostaglandin reductase activity of AKR1C3 and increasing cellular ROS levels.
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Affiliation(s)
- Xiaoying Li
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China,
| | - Xin Hong
- Department of Urology, Peking University International Hospital, Peking University, Beijing, China
| | - Xianshu Gao
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China,
| | - Xiaobin Gu
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China,
| | - Wei Xiong
- Department of Oncology, Tangshan People's Hospital, Hebei, China
| | - Jing Zhao
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Hongliang Yu
- Department of Radiation Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Ming Cui
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China,
| | - Mu Xie
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China,
| | - Yun Bai
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China,
| | - Shaoqian Sun
- College of Biochemical Engineering, Beijing Union University, Beijing, China
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Temporini C, Brusotti G, Pochetti G, Massolini G, Calleri E. Affinity-based separation methods for the study of biological interactions: The case of peroxisome proliferator-activated receptors in drug discovery. Methods 2018; 146:12-25. [DOI: 10.1016/j.ymeth.2018.02.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 01/30/2018] [Accepted: 02/05/2018] [Indexed: 10/18/2022] Open
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Duszka K, Wahli W. Enteric Microbiota⁻Gut⁻Brain Axis from the Perspective of Nuclear Receptors. Int J Mol Sci 2018; 19:ijms19082210. [PMID: 30060580 PMCID: PMC6121494 DOI: 10.3390/ijms19082210] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 07/18/2018] [Accepted: 07/23/2018] [Indexed: 12/12/2022] Open
Abstract
Nuclear receptors (NRs) play a key role in regulating virtually all body functions, thus maintaining a healthy operating body with all its complex systems. Recently, gut microbiota emerged as major factor contributing to the health of the whole organism. Enteric bacteria have multiple ways to influence their host and several of them involve communication with the brain. Mounting evidence of cooperation between gut flora and NRs is already available. However, the full potential of the microbiota interconnection with NRs remains to be uncovered. Herewith, we present the current state of knowledge on the multifaceted roles of NRs in the enteric microbiota–gut–brain axis.
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Affiliation(s)
- Kalina Duszka
- Department of Nutritional Sciences, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
| | - Walter Wahli
- Lee Kong Chian School of Medicine, Nanyang Technological, 11 Mandalay Road, Singapore 308232, Singapore.
- Center for Integrative Genomics, University of Lausanne, Génopode, CH-1015 Lausanne, Switzerland.
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Hints on ATGL implications in cancer: beyond bioenergetic clues. Cell Death Dis 2018; 9:316. [PMID: 29472527 PMCID: PMC5833653 DOI: 10.1038/s41419-018-0345-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/22/2018] [Accepted: 01/23/2018] [Indexed: 12/21/2022]
Abstract
Among metabolic rearrangements occurring in cancer cells, lipid metabolism alteration has become a hallmark, aimed at sustaining accelerated proliferation. In particular, fatty acids (FAs) are dramatically required by cancer cells as signalling molecules and membrane building blocks, beyond bioenergetics. Along with de novo biosynthesis, free FAs derive from dietary sources or from intracellular lipid droplets, which represent the storage of triacylglycerols (TAGs). Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme of lipolysis, catalysing the first step of intracellular TAGs hydrolysis in several tissues. However, the roles of ATGL in cancer are still neglected though a putative tumour suppressor function of ATGL has been envisaged, as its expression is frequently reduced in different human cancers (e.g., lung, muscle, and pancreas). In this review, we will introduce lipid metabolism focusing on ATGL functions and regulation in normal cell physiology providing also speculative perspectives on potential non-energetic functions of ATGL in cancer. In particular, we will discuss how ATGL is implicated, mainly through the peroxisome proliferator-activated receptor-α (PPAR-α) signalling, in inflammation, redox homoeostasis and autophagy, which are well-known processes deregulated during cancer formation and/or progression.
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Wu K, Yang Y, Liu D, Qi Y, Zhang C, Zhao J, Zhao S. Activation of PPARγ suppresses proliferation and induces apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway. Oncotarget 2018; 7:44572-44582. [PMID: 27323819 PMCID: PMC5190119 DOI: 10.18632/oncotarget.10067] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/29/2016] [Indexed: 01/07/2023] Open
Abstract
Although substantial studies on peroxisome proliferator-activated receptor γ (PPARγ) have focused on the mechanisms by which PPARγ regulates glucose and lipid metabolism, recent reports have suggested that PPARγ shows tumorigenic or antitumorigenic effects. The roles and mechanisms of PPARγ activation in esophageal cancer remain unclarified. EC109 and TE10 esophageal cancer cells were treated with 0, 10, 20 and 40 mM of PPARγ agonist rosiglitazone (RGZ) for 24, 48, and 72 h, and the cell viability and apoptosis were detected using methyl thiazolyl tetrazolium (MTT) assay and Flow cytometric (FCM) analysis, respectively. Moreover, the effects of inhibition of PPARγ by antagonist or specific RNA interference on cell viability, apoptosis, the Toll-like receptor 4 (TLR4) and mitogen-activated protein kinase (MAPK) pathways were evaluated. Additionally, the effect of TLR4 signaling on the MAPK pathway, cell viability and apoptosis was assessed. The results showed that RGZ suppressed proliferation and induced apoptosis of esophageal cancer cells, which could be partly restored by inactivation of PPARγ. RGZ suppressed the MAPK and TLR4 pathways, and the inhibitory effect could be counteracted by PPARγ antagonist or specific RNA interference. We also suggested that MAPK activation was regulated by the TLR4 pathway and that blocking the TLR4 and MAPK pathways significantly suppressed proliferation and induced apoptosis of esophageal cancer cells. In conclusion, our data suggested that activation of PPARγ suppressed proliferation and induced apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway.
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Affiliation(s)
- Kai Wu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yang Yang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Donglei Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yu Qi
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Chunyang Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Jia Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Song Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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Mahmoud AM, Alexander MY, Tutar Y, Wilkinson FL, Venditti A. Oxidative Stress in Metabolic Disorders and Drug-Induced Injury: The Potential Role of Nrf2 and PPARs Activators. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:2508909. [PMID: 29348787 PMCID: PMC5733955 DOI: 10.1155/2017/2508909] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 10/26/2017] [Indexed: 11/17/2022]
Affiliation(s)
- Ayman M. Mahmoud
- Physiology Division, Department of Zoology, Faculty of Science, Beni Suef University, Beni Suef, Egypt
| | - M. Yvonne Alexander
- Vascular Pathology Group, Centre for Biomedicine, School of Healthcare Science, Manchester Metropolitan University, Manchester, UK
| | - Yusuf Tutar
- University of Health Sciences, Mekteb-i Tıbbiye-i Şahane, Istanbul, Turkey
| | - Fiona L. Wilkinson
- Vascular Pathology Group, Centre for Biomedicine, School of Healthcare Science, Manchester Metropolitan University, Manchester, UK
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Alaimo S, Marceca GP, Ferro A, Pulvirenti A. Detecting Disease Specific Pathway Substructures through an Integrated Systems Biology Approach. Noncoding RNA 2017; 3:ncrna3020020. [PMID: 29657291 PMCID: PMC5831934 DOI: 10.3390/ncrna3020020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Revised: 03/28/2017] [Accepted: 04/10/2017] [Indexed: 12/14/2022] Open
Abstract
In the era of network medicine, pathway analysis methods play a central role in the prediction of phenotype from high throughput experiments. In this paper, we present a network-based systems biology approach capable of extracting disease-perturbed subpathways within pathway networks in connection with expression data taken from The Cancer Genome Atlas (TCGA). Our system extends pathways with missing regulatory elements, such as microRNAs, and their interactions with genes. The framework enables the extraction, visualization, and analysis of statistically significant disease-specific subpathways through an easy to use web interface. Our analysis shows that the methodology is able to fill the gap in current techniques, allowing a more comprehensive analysis of the phenomena underlying disease states.
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Affiliation(s)
- Salvatore Alaimo
- Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, c/o Dipartimento di Matematica e Informatica, Viale A. Doria 6, 95125 Catania, Italy.
| | - Gioacchino Paolo Marceca
- Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, c/o Dipartimento di Matematica e Informatica, Viale A. Doria 6, 95125 Catania, Italy.
| | - Alfredo Ferro
- Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, c/o Dipartimento di Matematica e Informatica, Viale A. Doria 6, 95125 Catania, Italy.
| | - Alfredo Pulvirenti
- Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, c/o Dipartimento di Matematica e Informatica, Viale A. Doria 6, 95125 Catania, Italy.
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PPAR Agonists for the Prevention and Treatment of Lung Cancer. PPAR Res 2017; 2017:8252796. [PMID: 28316613 PMCID: PMC5337885 DOI: 10.1155/2017/8252796] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 12/08/2016] [Indexed: 12/12/2022] Open
Abstract
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. PPARα activation generally inhibits tumorigenesis through its antiangiogenic and anti-inflammatory effects. Activated PPARγ is also antitumorigenic and antimetastatic, regulating several functions of cancer cells and controlling the tumor microenvironment. Unlike PPARα and PPARγ, whether PPARβ/δ activation 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.
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Abdella EM, Mahmoud AM, El-Derby AM. Brown seaweeds protect against azoxymethane-induced hepatic repercussions through up-regulation of peroxisome proliferator-activated receptor gamma and attenuation of oxidative stress. PHARMACEUTICAL BIOLOGY 2016; 54:2496-2504. [PMID: 27050090 DOI: 10.3109/13880209.2016.1160938] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
CONTEXT Seaweeds of the genera Turbinaria and Padina have long been used as food and in traditional medicine for treating several diseases. OBJECTIVE The current study determines the protective efficacy of the brown seaweeds Turbinaria ornata (Turner) J. Agardh (Sargassaceae) and Padina pavonia (Linnaeus) J.V. Lamouroux (Dictyotaceae) against liver injury induced by azoxymethane (AOM). MATERIALS AND METHODS Male Swiss mice received 10 mg/kg AOM once a week for two consecutive weeks and then 100 mg/kg daily dose of either T. ornata or P. pavonia ethanolic extract. Thirteen weeks after the first AOM administration and 24 h after the last treatment, overnight fasted mice were sacrificed and samples collected. RESULTS Compared with the AOM group, both T. ornata and P. pavonia significantly decreased the activity of aminotransferases and the concentration of bilirubin while increased albumin levels in the serum. The antioxidative effect of both extracts was observed from the increased activity of superoxide dismutase and glutathione peroxidase activities in the liver, both of which were decreased by AOM. Moreover, the levels of malondialdehyde and nitric oxide were reduced, and histological findings also confirmed the antihepatotoxic activity. In addition, treatment with T. ornata and P. pavonia significantly increased PPARγ and decreased NF-κB expression in the liver of AOM-administered mice. DISCUSSION AND CONCLUSION Our findings indicate that the protective function of T. ornata and P. pavonia on AOM-induced liver injury may be possibly exerted by multiple pathways including abolishment of inflammation and oxidative damage, and activation of PPARγ.
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Affiliation(s)
- Ehab M Abdella
- a Cell Biology and Genetics Division, Zoology Department, Faculty of Science , Beni-Suef University , Beni-Suef , Egypt
| | - Ayman M Mahmoud
- b Physiology Division, Zoology Department, Faculty of Science , Beni-Suef University , Beni-Suef , Egypt
| | - Azza M El-Derby
- a Cell Biology and Genetics Division, Zoology Department, Faculty of Science , Beni-Suef University , Beni-Suef , Egypt
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PPAR γ as a Novel Therapeutic Target in Lung Cancer. PPAR Res 2016; 2016:8972570. [PMID: 27698657 PMCID: PMC5028876 DOI: 10.1155/2016/8972570] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 08/07/2016] [Indexed: 02/08/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related death, with more than half the patients having advanced-stage disease at the time of initial diagnosis and thus facing a poor prognosis. This dire situation poses a need for new approaches in prevention and treatment. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. Its involvement in adipocyte differentiation and glucose and lipid homeostasis is well-recognized, but accumulating evidence now suggests that PPARγ may also function as a tumor suppressor, inhibiting development of primary tumors and metastases in lung cancer and other malignancies. Besides having prodifferentiation, antiproliferative, and proapoptotic effects, PPARγ agonists have been shown to prevent cancer cells from acquiring the migratory and invasive capabilities essential for successful metastasis. Angiogenesis and secretion of certain matrix metalloproteinases and extracellular matrix proteins within the tumor microenvironment are also regulated by PPARγ. This review of the current literature highlights the potential of PPARγ agonists as novel therapeutic modalities in lung cancer, either as monotherapy or in combination with standard cytotoxic chemotherapy.
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Milone MR, Pucci B, Colangelo T, Lombardi R, Iannelli F, Colantuoni V, Sabatino L, Budillon A. Proteomic characterization of peroxisome proliferator-activated receptor-γ (PPARγ) overexpressing or silenced colorectal cancer cells unveils a novel protein network associated with an aggressive phenotype. Mol Oncol 2016; 10:1344-62. [PMID: 27499265 DOI: 10.1016/j.molonc.2016.07.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 07/19/2016] [Indexed: 01/06/2023] Open
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor of the nuclear hormone receptor superfamily implicated in a wide range of processes, including tumorigenesis. Its role in colorectal cancer (CRC) is still debated; most reports support that PPARγ reduced expression is associated with poor prognosis. We employed 2-Dimensional Differential InGel Electrophoresis (2-D DIGE) followed by Liquid Chromatography (LC)-tandem Mass Spectrometry (MS/MS) to identify differentially expressed proteins and the molecular pathways underlying PPARγ expression in CRC progression. We identified several differentially expressed proteins in HT29 and HCT116 CRC cells and derived clones either silenced or overexpressing PPARγ, respectively. In Ingenuity Pathway Analysis (IPA) they showed reciprocal relation with PPARγ and a strong relationship with networks linked to cell death, growth and survival. Interestingly, five of the identified proteins, ezrin (EZR), isoform C of prelamin-A/C (LMNA), alpha-enolase (ENOA), prohibitin (PHB) and RuvB-like 2 (RUVBL2) were shared by the two cell models with opposite expression levels, suggesting a possible regulation by PPARγ. mRNA and western blot analysis were undertaken to obtain a technical validation and confirm the expression trend observed by 2-D DIGE data. We associated EZR upregulation with increased cell surface localization in PPARγ-overexpressing cells by flow cytometry and immunofluorescence staining. We also correlated EZR and PPARγ expression in our series of CRC specimens and the expression profiling of all five proteins levels in the publicly available colon cancer genomic data from Oncomine and Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) datasets. In summary, we identified a panel of proteins correlated with PPARγ expression that could be associated with CRC unveiling new pathways to be investigated for the selection of novel potential prognostic/predictive biomarkers and/or therapeutic targets.
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Affiliation(s)
- Maria Rita Milone
- Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
| | - Biagio Pucci
- Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
| | - Tommaso Colangelo
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Rita Lombardi
- Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
| | - Federica Iannelli
- Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
| | - Vittorio Colantuoni
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Lina Sabatino
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy.
| | - Alfredo Budillon
- Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy; Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy.
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Hecker M, Behnk A, Morty RE, Sommer N, Vadász I, Herold S, Seeger W, Mayer K. PPAR-α activation reduced LPS-induced inflammation in alveolar epithelial cells. Exp Lung Res 2016; 41:393-403. [PMID: 26151160 DOI: 10.3109/01902148.2015.1046200] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
PURPOSE OF THE STUDY Acute respiratory distress syndrome (ARDS) represents a major cause of mortality in intensive care patients. Activation of peroxisome proliferator-activated receptor-α (PPAR-α) by fibrates, such as WY-14643 (WY), has been described to beneficially influence inflammation and experimental lung injury. The impact of PPAR-α activation on alveolar epithelial cells (AEC) has not been studied yet. MATERIALS AND METHODS To investigate the effect of PPAR-α activator WY in wild-type (WT) and in PPAR-α knockout (PPAR-α(-/-)) animals, mice were treated in different regimes: mice received chow enriched with or without WY for 14 days prior AEC isolation (in-vivo treatment). Furthermore, isolated AEC from both groups were subsequently cultured with or without WY (in-vitro treatment). AEC were stimulated with lipopolysaccharide (LPS). Cell culture supernatant and cell lysate were used for analysis of pro-inflammatory mediators. RESULTS AEC challenged with LPS showed a significantly increased generation of pro-inflammatory mediators. After in-vivo WY-exposure, AEC displayed significantly reduced concentration of TNF-α, MIP-2, and TxB2 after LPS stimulation. This beneficial effect was abrogated in PPAR-α(-/-) animals. Interestingly, sole in-vitro application of WY-14643 failed to reduce levels of pro-inflammatory mediators whereas we found an additive effect of a combined in-vivo and in-vitro PPAR-α activation. PGE2 concentration remained high after LPS challenge and was unaffected by WY treatment. CONCLUSION PPAR-α activation by in-vivo exposure to fibrates reduced the inflammatory response in isolated AEC. These findings may facilitate further studies investigating the translation of pharmacological PPAR-α activation into clinical therapy of ARDS.
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Affiliation(s)
- Matthias Hecker
- a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany
| | - Aniella Behnk
- a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany
| | - Rory Edward Morty
- b 2 Department of Lung Development and Remodelling , Max Planck Institute for Heart and Lung Research , Bad Nauheim, Germany
| | - Natascha Sommer
- a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany
| | - István Vadász
- a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany
| | - Susanne Herold
- a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany
| | - Werner Seeger
- a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany
| | - Konstantin Mayer
- a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany
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Iglesias J, Morales L, Barreto GE. Metabolic and Inflammatory Adaptation of Reactive Astrocytes: Role of PPARs. Mol Neurobiol 2016; 54:2518-2538. [PMID: 26984740 DOI: 10.1007/s12035-016-9833-2] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 03/04/2016] [Indexed: 01/10/2023]
Abstract
Astrocyte-mediated inflammation is associated with degenerative pathologies such as Alzheimer's and Parkinson's diseases and multiple sclerosis. The acute inflammation and morphological and metabolic changes that astrocytes develop after the insult are known as reactive astroglia or astrogliosis that is an important response to protect and repair the lesion. Astrocytes optimize their metabolism to produce lactate, glutamate, and ketone bodies in order to provide energy to the neurons that are deprived of nutrients upon insult. Firstly, we review the basis of inflammation and morphological changes of the different cell population implicated in reactive gliosis. Next, we discuss the more active metabolic pathways in healthy astrocytes and explain the metabolic response of astrocytes to the insult in different pathologies and which metabolic alterations generate complications in these diseases. We emphasize the role of peroxisome proliferator-activated receptors isotypes in the inflammatory and metabolic adaptation of astrogliosis developed in ischemia or neurodegenerative diseases. Based on results reported in astrocytes and other cells, we resume and hypothesize the effect of peroxisome proliferator-activated receptor (PPAR) activation with ligands on different metabolic pathways in order to supply energy to the neurons. The activation of selective PPAR isotype activity may serve as an input to better understand the role played by these receptors on the metabolic and inflammatory compensation of astrogliosis and might represent an opportunity to develop new therapeutic strategies against traumatic brain injuries and neurodegenerative diseases.
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Affiliation(s)
- José Iglesias
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, DC, Colombia.
| | - Ludis Morales
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, DC, Colombia
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, DC, Colombia
- Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
- Universidad Científica del Sur, Lima, Peru
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Gómez de Cedrón M, Ramírez de Molina A. Microtargeting cancer metabolism: opening new therapeutic windows based on lipid metabolism. J Lipid Res 2015; 57:193-206. [PMID: 26630911 DOI: 10.1194/jlr.r061812] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Indexed: 01/04/2023] Open
Abstract
Metabolic reprogramming has emerged as a hallmark of cancer. MicroRNAs are noncoding RNAs that posttranscriptionally repress the expression of target mRNAs implicated in multiple physiological processes, including apoptosis, differentiation, and cancer. MicroRNAs can affect entire biological pathways, making them good candidates for therapeutic intervention compared with classical single target approaches. Moreover, microRNAs may become more relevant in the fine-tuning adaptation to stress situations, such as oncogenic events, hypoxia, nutrient deprivation, and oxidative stress. Furthermore, artificial microRNAs can be designed to modulate the expression of multiple targets of a specific pathway. In this review, we describe the metabolic reprogramming associated to cancer, with a special interest in the altered lipid metabolism. Next, we describe specific features of microRNAs that make them relevant to target cancer cell metabolism. Finally, in an attempt to open new therapeutic windows, we emphasize two exciting scenarios for microRNA-mediated intervention that need to be further explored: 1) the cooperation between FA biosynthesis (lipogenesis) and FA oxidation as complementary partners for the survival of cancer cells; and 2) the regulation of the intracellular lipid content modulating both lipid storage into lipid droplets, and lipid mobilization through lipolysis and/or lipophagy.
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Affiliation(s)
- Marta Gómez de Cedrón
- Molecular Oncology and Nutritional Genomics of Cancer Group, IMDEA (Madrid Institute of Advanced Studies)-Food, CEI UAM + CSIC, Madrid, Spain
| | - Ana Ramírez de Molina
- Molecular Oncology and Nutritional Genomics of Cancer Group, IMDEA (Madrid Institute of Advanced Studies)-Food, CEI UAM + CSIC, Madrid, Spain
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Mahmoud AM, Al Dera HS. 18β-Glycyrrhetinic acid exerts protective effects against cyclophosphamide-induced hepatotoxicity: potential role of PPARγ and Nrf2 upregulation. GENES AND NUTRITION 2015; 10:41. [PMID: 26386843 DOI: 10.1007/s12263-015-0491-1] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 09/08/2015] [Indexed: 01/06/2023]
Abstract
18β-Glycyrrhetinic acid (18β-GA) has been proposed as a promising hepatoprotective agent. The current study aimed to investigate the protective action and the possible mechanisms of 18β-GA against cyclophosphamide (CP)-induced liver injury in rats, focusing on the role of peroxisome proliferator-activated receptor gamma (PPARγ) and NF-E2-related factor-2 (Nrf2). Rats were administered 18β-GA at doses 25 and 50 mg/kg 2 weeks prior to CP injection. Five days after CP administration, animals were sacrificed and samples were collected. CP induced hepatic damage evidenced by the histopathological changes and significant increase in serum pro-inflammatory cytokines, liver marker enzymes, and liver lipid peroxidation and nitric oxide (NO) levels. 18β-GA counteracted CP-induced oxidative stress and inflammation as assessed by restoration of the antioxidant defenses and diminishing of pro-inflammatory cytokines, lipid peroxidation, and NO production. These hepatoprotective effects appear to depend on activation of Nrf2 and PPARγ, and subsequent suppression of nuclear factor-kappa B. In conclusion, the present study provides evidence that 18β-GA exerts hepatoprotective effects against CP through induction of antioxidant defenses and suppression of inflammatory response. This report also confers new information that 18β-GA protects liver against the toxic effect of chemotherapeutic alkylating agents via activation of Nrf2 and PPARγ.
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Affiliation(s)
- Ayman M Mahmoud
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni Suef, 62514, Egypt.
| | - Hussein S Al Dera
- Basic Medical Sciences Department, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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Adhikary T, Wortmann A, Schumann T, Finkernagel F, Lieber S, Roth K, Toth PM, Diederich WE, Nist A, Stiewe T, Kleinesudeik L, Reinartz S, Müller-Brüsselbach S, Müller R. The transcriptional PPARβ/δ network in human macrophages defines a unique agonist-induced activation state. Nucleic Acids Res 2015; 43:5033-51. [PMID: 25934804 PMCID: PMC4446423 DOI: 10.1093/nar/gkv331] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 04/01/2015] [Indexed: 02/06/2023] Open
Abstract
Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor with established metabolic functions, whereas its anti-inflammatory function is poorly understood. To address this issue, we determined the global PPARβ/δ-regulated signaling network in human monocyte-derived macrophages. Besides cell type-independent, canonical target genes with metabolic and immune regulatory functions we identified a large number of inflammation-associated NFκB and STAT1 target genes that are repressed by agonists. Accordingly, PPARβ/δ agonists inhibited the expression of multiple pro-inflammatory mediators and induced an anti-inflammatory, IL-4-like morphological phenotype. Surprisingly, bioinformatic analyses also identified immune stimulatory effects. Consistent with this prediction, PPARβ/δ agonists enhanced macrophage survival under hypoxic stress and stimulated CD8+ T cell activation, concomitantly with the repression of immune suppressive target genes and their encoded products CD274 (PD-1 ligand), CD32B (inhibitory Fcγ receptor IIB) and indoleamine 2,3-dioxygenase 1 (IDO-1), as well as a diminished release of the immune suppressive IDO-1 metabolite kynurenine. Comparison with published data revealed a significant overlap of the PPARβ/δ transcriptome with coexpression modules characteristic of both anti-inflammatory and pro-inflammatory cytokines. Our findings indicate that PPARβ/δ agonists induce a unique macrophage activation state with strong anti-inflammatory but also specific immune stimulatory components, pointing to a context-dependent function of PPARβ/δ in immune regulation.
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Affiliation(s)
- Till Adhikary
- Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Annika Wortmann
- Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Tim Schumann
- Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Florian Finkernagel
- Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Sonja Lieber
- Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Katrin Roth
- Cellular Imaging Core Facility, Philipps University, Center for Tumor Biology and Immunology (ZTI), 35043 Marburg, Germany
| | - Philipp M Toth
- Medicinal Chemistry Core Facility and Institute of Pharmaceutical Chemistry, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Wibke E Diederich
- Medicinal Chemistry Core Facility and Institute of Pharmaceutical Chemistry, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Andrea Nist
- Genomics Core Facility, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Thorsten Stiewe
- Genomics Core Facility, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Lara Kleinesudeik
- Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Silke Reinartz
- Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Sabine Müller-Brüsselbach
- Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Rolf Müller
- Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
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Giordano Attianese GMP, Desvergne B. Integrative and systemic approaches for evaluating PPARβ/δ (PPARD) function. NUCLEAR RECEPTOR SIGNALING 2015; 13:e001. [PMID: 25945080 PMCID: PMC4419664 DOI: 10.1621/nrs.13001] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 03/09/2015] [Indexed: 12/13/2022]
Abstract
The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of genes involved in cellular differentiation, development, metabolism and also tumorigenesis. Three PPAR isotypes (α, β/δ and γ) have been identified, among which PPARβ/δ is the most difficult to functionally examine due to its tissue-specific diversity in cell fate determination, energy metabolism and housekeeping activities. PPARβ/δ acts both in a ligand-dependent and -independent manner. The specific type of regulation, activation or repression, is determined by many factors, among which the type of ligand, the presence/absence of PPARβ/δ-interacting corepressor or coactivator complexes and PPARβ/δ protein post-translational modifications play major roles. Recently, new global approaches to the study of nuclear receptors have made it possible to evaluate their molecular activity in a more systemic fashion, rather than deeply digging into a single pathway/function. This systemic approach is ideally suited for studying PPARβ/δ, due to its ubiquitous expression in various organs and its overlapping and tissue-specific transcriptomic signatures. The aim of the present review is to present in detail the diversity of PPARβ/δ function, focusing on the different information gained at the systemic level, and describing the global and unbiased approaches that combine a systems view with molecular understanding.
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He-min Z, Guo-Rong B, Qiu H, Xiang L, Suli L. Changes in plasma PPARs levels in migraine patients. Med Sci Monit 2015; 21:735-9. [PMID: 25758678 PMCID: PMC4365761 DOI: 10.12659/msm.893272] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background The aim of this study was to observe the change in plasma PPARs (peroxisome proliferator-activated receptors) level during various periods and in different subtypes in migraine patients. Material/Methods We divided 227 patients with migraine into 2 main groups: the attack period group (n=98) and the attack-free period group (n=129). Patients were further divided into 4 subgroups according to whether they had aura symptoms. The control group consisted of 100 healthy subjects. We collected the clinical data of patients and measured the plasma levels of PPARs using enzyme-linked immunoassay (ELISA). We used SPSS software for statistical analysis. Results We found no significant difference in age, BMI, blood pressure, or blood lipid level among migraine patients during the headache attack period and during the headache-free period compared with the control group. The PPARα and PPARβ/δ levels during the headache attack period were significantly higher than during the headache free period and in healthy controls. The PPARγ levels during the headache attack period were significantly lower than those during the headache-free period and in the healthy control group. The PPARs levels during the headache attack period were significantly different from those during the headache-free period, regardless of presence or absence of aura. The PPARs levels during the headache-free period were not significantly different from those of the healthy control group. The level of PPARs has no significant differences between migraine with aura group and without aura group, regardless of whether headache attack. Conclusions PPARs involved in the pathogenesis of migraine. Presence of absence of aura had no obvious effect on PPARs level.
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Affiliation(s)
- Zhang He-min
- Department of Neurology, Sheng Jing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Bi Guo-Rong
- Department of Neurology, Sheng Jing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - He Qiu
- Department of Neurology, The People's Hospital of Liaoning Province, Shenyang, Liaoning, China (mainland)
| | - Lin Xiang
- Department of Neurology, Dalian Medical University, Dalian, Liaoning, China (mainland)
| | - Liu Suli
- Department of Neurology, Zhu Madian Center Hospital, Zhu Madian, Henan, China (mainland)
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Read SA, Tay ES, Shahidi M, McLauchlan J, George J, Douglas MW. The Mechanism of Interferon Refractoriness During Hepatitis C Virus Infection and Its Reversal with a Peroxisome Proliferator-Activated Receptor α Agonist. J Interferon Cytokine Res 2015; 35:488-97. [PMID: 25734487 DOI: 10.1089/jir.2014.0209] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Patients who respond poorly to therapies for hepatitis C virus (HCV) infection display a characteristic phenotype with high basal hepatic interferon-stimulated gene (ISG) expression, but limited induction following interferon (IFN) treatment. The molecular pathways that mediate this refractory state are not known. We examined whether the AMPK activator metformin, the PPARγ agonist pioglitazone, or the PPARα agonist WY-14643 could potentiate IFN responses, reverse IFN refractoriness, and enhance viral eradication in hepatocytes. WY-14643 demonstrated the strongest antiviral synergy with IFN-α and so was tested in the context of chronic IFN activation. Cells rendered refractory to IFN by IFN-α pretreatment were resensitized by WY-14643, as demonstrated by improved STAT1 phosphorylation, promoter activation, and ISG expression. WY-14643 treatment reduced the expression of key negative regulators of IFN signaling: the AXL receptor tyrosine kinase, suppressor of cytokine signaling (SOCS) 1 and 3, which are upregulated in the IFN-refractory state. AXL is a novel regulator of IFN-α signaling that is induced by HCV infection in vitro and which may drive SOCS3 expression. Our data suggests that PPARα agonists could be a useful adjunct treatment for chronic HCV infection by reducing the expression of AXL/SOCS and increasing the sensitivity to IFN.
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Affiliation(s)
- Scott A Read
- 1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia
| | - Enoch S Tay
- 1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia
| | - Mahsa Shahidi
- 1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia
| | - John McLauchlan
- 2 MRC-University of Glasgow Centre for Virus Research , Glasgow, United Kingdom
| | - Jacob George
- 1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia
| | - Mark W Douglas
- 1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia .,2 MRC-University of Glasgow Centre for Virus Research , Glasgow, United Kingdom .,3 Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital , Westmead, Australia
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shafizadeh M, Rajaba A, Imran khan M, Ostadhadi S, Rastegar H, Dehpour A. Anti-pruritic activity of pioglitazone on serotonin-induced scratching in mice: Possible involvement of PPAR-gamma receptor and nitric oxide. Eur J Pharmacol 2014; 744:103-107. [DOI: 10.1016/j.ejphar.2014.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Revised: 09/28/2014] [Accepted: 10/02/2014] [Indexed: 01/03/2023]
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Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, Peters JA, Harmar AJ. The Concise Guide to PHARMACOLOGY 2013/14: nuclear hormone receptors. Br J Pharmacol 2014; 170:1652-75. [PMID: 24528240 PMCID: PMC3892290 DOI: 10.1111/bph.12448] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. Nuclear hormone receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.
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Affiliation(s)
- Stephen P H Alexander
- School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK
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Identification of host-immune response protein candidates in the sera of human oral squamous cell carcinoma patients. PLoS One 2014; 9:e109012. [PMID: 25272005 PMCID: PMC4182798 DOI: 10.1371/journal.pone.0109012] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 09/06/2014] [Indexed: 12/13/2022] Open
Abstract
One of the most common cancers worldwide is oral squamous cell carcinoma (OSCC), which is associated with a significant death rate and has been linked to several risk factors. Notably, failure to detect these neoplasms at an early stage represents a fundamental barrier to improving the survival and quality of life of OSCC patients. In the present study, serum samples from OSCC patients (n = 25) and healthy controls (n = 25) were subjected to two-dimensional gel electrophoresis (2-DE) and silver staining in order to identify biomarkers that might allow early diagnosis. In this regard, 2-DE spots corresponding to various up- and down-regulated proteins were sequenced via high-resolution MALDI-TOF mass spectrometry and analyzed using the MASCOT database. We identified the following differentially expressed host-specific proteins within sera from OSCC patients: leucine-rich α2-glycoprotein (LRG), alpha-1-B-glycoprotein (ABG), clusterin (CLU), PRO2044, haptoglobin (HAP), complement C3c (C3), proapolipoprotein A1 (proapo-A1), and retinol-binding protein 4 precursor (RBP4). Moreover, five non-host factors were detected, including bacterial antigens from Acinetobacter lwoffii, Burkholderia multivorans, Myxococcus xanthus, Laribacter hongkongensis, and Streptococcus salivarius. Subsequently, we analyzed the immunogenicity of these proteins using pooled sera from OSCC patients. In this regard, five of these candidate biomarkers were found to be immunoreactive: CLU, HAP, C3, proapo-A1 and RBP4. Taken together, our immunoproteomics approach has identified various serum biomarkers that could facilitate the development of early diagnostic tools for OSCC.
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Mahmoud AM. Hesperidin protects against cyclophosphamide-induced hepatotoxicity by upregulation of PPARγ and abrogation of oxidative stress and inflammation. Can J Physiol Pharmacol 2014; 92:717-24. [DOI: 10.1139/cjpp-2014-0204] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The most important reason for the non-approval and withdrawal of drugs by the Food and Drug Administration is hepatotoxicity. Therefore, this study was undertaken to evaluate the protective effects of hesperidin against cyclophosphamide (CYP)-induced hepatotoxicity in Wistar rats. The rats received a single intraperitoneal dose of CYP of 200 mg/kg body mass, followed by treatment with hesperidin, orally, at doses of 25 and 50 mg/kg for 11 consecutive days. CYP induced hepatic damage, as evidenced by the significantly elevated levels of serum pro-inflammatory cytokines, serum transaminases, liver lipid peroxidation, and nitric oxide. As a consequence, there was reduced glutathione content, and the activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, were markedly reduced. In addition, CYP administration induced a considerable downregulation of peroxisome proliferator activated receptor gamma (PPARγ) and upregulation of nuclear factor-kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) mRNA expression. Hesperidin, in a dose-dependent manner, rejuvenated the altered markers to an almost normal state. In conclusion, hesperidin showed a potent protective effect against CYP-induced oxidative stress and inflammation leading to hepatotoxicity. The study suggests that hesperidin exerts its protective effect against CYP-induced hepatotoxicity through upregulation of hepatic PPARγ expression and abrogation of inflammation and oxidative stress.
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Affiliation(s)
- Ayman M. Mahmoud
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, 62514 Beni-Suef, Egypt
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49
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Palmitoylethanolamide in CNS health and disease. Pharmacol Res 2014; 86:32-41. [PMID: 24844438 DOI: 10.1016/j.phrs.2014.05.006] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 05/07/2014] [Accepted: 05/08/2014] [Indexed: 01/08/2023]
Abstract
The existence of acylethanolamides (AEs) in the mammalian brain has been known for decades. Among AEs, palmitoylethanolamide (PEA) is abundant in the central nervous system (CNS) and conspicuously produced by neurons and glial cells. Antihyperalgesic and neuroprotective properties of PEA have been mainly related to the reduction of neuronal firing and to control of inflammation. Growing evidence suggest that PEA may be neuroprotective during CNS neurodegenerative diseases. Advances in the understanding of the physiology and pharmacology of PEA have potentiated its interest as useful biological tool for disease management. Several rapid non-genomic and delayed genomic mechanisms of action have been identified for PEA as peroxisome proliferator-activated receptor (PPAR)-α dependent. First, an early molecular control, through Ca(+2)-activated intermediate- and/or big-conductance K(+) channels opening, drives to rapid neuronal hyperpolarization. This is reinforced by the increase of the inward Cl(-) currents due to the modulation of the gamma aminobutyric acid A receptor and by the desensitization of the transient receptor potential channel type V1. Moreover, the gene transcription-mediated mechanism sustains the long-term anti-inflammatory effects, by reducing pro-inflammatory enzyme expression and increasing neurosteroid synthesis. Overall, the integration of these different modes of action allows PEA to exert an immediate and prolonged efficacious control in neuron signaling either on inflammatory process or neuronal excitability, maintaining cellular homeostasis. In this review, we will discuss the effect of PEA on metabolism, behavior, inflammation and pain perception, related to the control of central functions and the emerging evidence demonstrating its therapeutic efficacy in several neurodegenerative diseases.
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Wei J, Li Z, Yuan F. Evodiamine might inhibit TGF-beta1-induced epithelial-mesenchymal transition in NRK52E cells via Smad and PPAR-gamma pathway. Cell Biol Int 2014; 38:875-80. [PMID: 24604887 DOI: 10.1002/cbin.10270] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Accepted: 02/07/2014] [Indexed: 11/08/2022]
Abstract
Epithelial-mesenchymal transition (EMT) is involved in renal tubulointerstitial fibrosis. Transforming growth factor (TGF)-beta1 is the main inducer of EMT. Phosphorylation of Smad proteins and PPAR-gamma activation are required for the process of TGF-beta1-induced EMT. Evodiamine possesses anti-inflammatory, anti-obesity, anti-cancer, and anti-nociceptive effects. We have examined the effects of evodiamine in EMT induced by TGF-beta1 and the role of Smad and PPAR-gamma signal pathway in rat renal proximal tubular epithelial (NRK52E) cells in vitro. E-cadherin, alpha-smooth muscle actin (SMA), Smad 2 and PPAR-gamma mRNA and protein expressions were detected by real-time PCR and Western blot, respectively. NRK52E treated with TGF-beta1 for 48 h induced EMT, as evidenced by loss of E-cadherin and de novo expression of alpha-SMA. EMT was almost completely blocked by evodiamine and rosiglitazone. TGF-beta1 significantly increased Smad 2 expression and decreased PPAR-gamma expression in NRK52E cells compared with the control group, while evodiamine and rosiglitazone almost reversed these effects. These observations suggest that evodiamine and rosiglitazone inhibit TGF-beta1-induced EMT in NRK52E cells. Smad 2 and PPAR-gamma signal pathway might participate in the effects of evodiamine and rosiglitazone in EMT induced by TGF-beta1.
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Affiliation(s)
- Jiali Wei
- Department of Nephrology, Hainan General Hospital, Haikou, Hainan, 570311, China
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