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D P, Hani U, Haider N, Talath S, Shanmugarajan D, P P, P A, Prashantha Kumar BR. Novel PPAR-γ agonists as potential neuroprotective agents against Alzheimer's disease: rational design, synthesis , in silico evaluation, PPAR-γ binding assay and transactivation and expression studies. RSC Adv 2024; 14:33247-33266. [PMID: 39434987 PMCID: PMC11492828 DOI: 10.1039/d4ra06330a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 09/30/2024] [Indexed: 10/23/2024] Open
Abstract
Alzheimer's disease (AD) is a neurological disorder. It is caused by accumulation of amyloid beta (Aβ) plaques and tau tangles, which gradually leads to cognitive decline and memory loss. Peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor, plays a significant role in regulating genes responsible for metabolism and inflammation. Studies have shown that PPAR-γ activation has neuroprotective effects, can potentially reduce inflammation and oxidative stress, and stimulates mitochondrial biogenesis. Current study presents the design, synthesis and in vitro evaluation of PPAR-γ agonists for AD that are tailored to optimize binding with the PPAR-γ receptor. The compounds 4a, 4h and 4j exhibited notable binding affinities towards PPAR-γ LBD, with IC50 values of 8.607, 9.242, and 5.974 μM, respectively, in TR-FRET binding assay. These compounds were cell proliferative and non-cytotoxic in a neuroblastoma cell line (SH-SY5Y). They also demonstrated dose-dependent PPAR-γ activation in transactivation assay. Their neuroprotective effect was studied based on their anti-inflammatory and anti-oxidant potential by reducing the levels of proinflammatory markers (TNF-α, IL-6 and IL-1β) and ROS in Aβ-induced SH-SY5Y neuroblastoma cells using a flow cytometry method. The synthesized compounds also showed interactions in molecular docking study with the PPAR-γ receptor and demonstrated good stability in MD simulation. Our results highlight that through activation of PPAR-γ, the compounds 4a, 4h and 4j offer neuroprotective effects by reducing neuroinflammation and oxidative stress, and hence, they may be considered lead molecules for treating AD.
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Affiliation(s)
- Priya D
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Sri Shivarathreeshwara Nagara Mysuru 570015 India +91-821-2548359 +91-821-2548353
| | - Umme Hani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University Abha 62529 Saudi Arabia
| | - Nazima Haider
- Department of Pathology, College of Medicine, King Khalid University Abha 62529 Saudi Arabia
| | - Sirajunisa Talath
- Department of Pharmaceutical Chemistry, RAK College of Pharmacy, RAK Medical and Health Sciences University Ras Al Khaimah 11172 United Arab Emirates
| | - Dhivya Shanmugarajan
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Sri Shivarathreeshwara Nagara Mysuru 570015 India +91-821-2548359 +91-821-2548353
| | - Prabitha P
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Sri Shivarathreeshwara Nagara Mysuru 570015 India +91-821-2548359 +91-821-2548353
| | - Archana P
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Sri Shivarathreeshwara Nagara Mysuru 570015 India +91-821-2548359 +91-821-2548353
| | - B R Prashantha Kumar
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Sri Shivarathreeshwara Nagara Mysuru 570015 India +91-821-2548359 +91-821-2548353
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Nomier Y, Asaad GF, Salama A, Shabana ME, Alshahrani S, Firoz Alam M, Anwer T, Sultana S, ur Rehman Z, Khalid A. Explicit mechanistic insights of Prosopis juliflora extract in streptozotocin-induced diabetic rats at the molecular level. Saudi Pharm J 2023; 31:101755. [PMID: 37727228 PMCID: PMC10505680 DOI: 10.1016/j.jsps.2023.101755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 08/17/2023] [Indexed: 09/21/2023] Open
Abstract
Background The Ancient system of medicine showed the limelight on the use of herbal remedies and was found to possess minimal side effects and acceptable therapeutic outcomes. In this context, Prosopis juliflora gained importance in managing chronic diseases such as cancer, dermatological diseases, and chronic inflammatory disorders. Hence, P. juliflora was selected for further investigation associated with diabetes and inflammation. Aim The present study aimed to evaluate the anti-diabetic activity in chemically induced experimental rats and explore the nature of phytocomponents that may produce this activity. Methods Experimentally, diabetes was induced by a single administration of streptozotocin at 50 mg/kg intraperitoneally in Wistar rats. The animals were treated orally with P. juliflora at low and high doses (200 and 400 mg/kg) for 10 days. Blood collected from the retro-orbital plexus was analyzed for parameters like blood glucose levels, insulin, adiponectin, Keap1 and Nrf2. PPAR-γ, AMPK and GLUT 2 levels were analyzed in the pancreatic tissue. Besides, at the end of the experiment, animals were sacrificed, and the pancreatic tissue sections were subjected for histopathological, morphometrical and immune histochemical exploration. The phytochemical composition of the plant was investigated by GC-MS. Results The administration of P. juliflora higher dose showed a significant decrease (**p< 0.001) in blood glucose levels with a rise in adiponectin, PPARγ, Keap1, Nrf2, Glut 2, and AMPK significantly (**p< 0.001). The inflammatory cytokine TNFα was also estimated and was found to be lowered significantly (**p< 0.001) in test drug-treated animals. Furthermore, in the pancreatic tissue, the number of Islets, the area, and the number of β-cells were improved significantly with the sub-chronic treatment of P. juliflora extract. The structure and function of β-cells were also revamped. Conclusion The study results demonstrated a significant effect of P. juliflora on glycemic status, inflammatory condition, and the architecture of pancreatic tissue. In the identification and isolation process by GC MS, it was noticed that P. juliflora contained few phytochemical constituents from which it might be considered a promising drug for type 2 diabetes mellitus.
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Affiliation(s)
- Yousra Nomier
- Department of Pharmacology and Clinical Pharmacy, College of Medicine, and Health Sciences, Sultan Qaboos University, Muscat, Oman
- Department of Pharmacology and Toxicology, Pharmacy College, Jazan University, P.O. Box 114 45142, Jazan, Saudi Arabia
| | - Gihan F. Asaad
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt
| | - Abeer Salama
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt
| | - Marwa E. Shabana
- Department of Pathology, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt
| | - Saeed Alshahrani
- Department of Pharmacology and Toxicology, Pharmacy College, Jazan University, P.O. Box 114 45142, Jazan, Saudi Arabia
| | - Mohammad Firoz Alam
- Department of Pharmacology and Toxicology, Pharmacy College, Jazan University, P.O. Box 114 45142, Jazan, Saudi Arabia
| | - Tarique Anwer
- Department of Pharmacology and Toxicology, Pharmacy College, Jazan University, P.O. Box 114 45142, Jazan, Saudi Arabia
| | - Shahnaz Sultana
- Department of Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114 45142, Jazan, Saudi Arabia
| | - Zia ur Rehman
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, P.O. Box 114 45142, Jazan, Saudi Arabia
| | - Asaad Khalid
- Substance Abuse and Toxicology Research Centre, Jazan University, P.O. Box 114 45142, Jazan, Saudi Arabia
- Medicinal and Aromatic Plants and Traditional Medicine Research Institute, National Centre for Research, P.O. Box: 2424, Khartoum 11111, Sudan
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Ansari AI, Rizvi AA, Verma S, Abbas M, Siddiqi Z, Mishra D, Verma S, Raza ST, Mahdi F. Interactions between diabetic and hypertensive drugs: a pharmacogenetics approach. Mol Genet Genomics 2023; 298:803-812. [PMID: 37149837 DOI: 10.1007/s00438-023-02011-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 03/24/2023] [Indexed: 05/08/2023]
Abstract
Diabetes is known to increase susceptibility to hypertension due to increase in inflammation, oxidative stress, and endothelial dysfunction, leading to vascular stiffness. The polytherapy might lead to several drug-drug interactions (DDIs), which cause certain life-threatening complications such as diabetic nephropathy and hypoglycaemia. So, in this review we focused on drug-drug interactions and impact of genetic factors on drug responses for better disease management. Drug-drug interactions (DDIs) may act either synergistically or antagonistically. For instance, a combination of metformin with angiotensin II receptor antagonist or angiotensin-converting enzyme inhibitors (ACEIs) synergistically improves glucose absorption, whereas the same hypertensive drug combination with sulphonylurea might cause severe hypoglycaemia sometimes. Thiazolidinediones (TDZs) can cause fluid retention and heart failure when taken alone, but a combination of angiotensin II receptor antagonist with TZDs prevents these side effects. Interindividual genetic variation affects the DDI response. We found two prominent genes, GLUT4 and PPAR-γ, which are common targets for most of the drug. So, all of these findings established a connection between drug-drug interaction and genetics, which might be used for effective disease management.
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Affiliation(s)
- Asma Imran Ansari
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, 226003, India
| | - Aliya Abbas Rizvi
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, 226003, India
| | - Shrikant Verma
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, 226003, India
| | - Mohammad Abbas
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, 226003, India
- Department of Microbiology, Era University, Lucknow, Uttar Pradesh, 226003, India
| | - Zeba Siddiqi
- Department of Medicine, Eras Lucknow Medical College and Hospital, Era University, Lucknow, Uttar Pradesh, 226003, India
| | - Divakar Mishra
- Department of Medicine, Eras Lucknow Medical College and Hospital, Era University, Lucknow, Uttar Pradesh, 226003, India
| | - Sushma Verma
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, 226003, India.
| | - Syed Tasleem Raza
- Department of Biochemistry, Eras Lucknow Medical College and Hospital, Era University, Lucknow, Uttar Pradesh, 226003, India
| | - Farzana Mahdi
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, 226003, India
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Su Q, Huang J, Chen X, Wang Y, Shao M, Yan H, Chen C, Ren H, Zhang F, Ni Y, Jose PA, Zhong J, Yang J. Long-Term High-Fat Diet Decreases Renal Insulin-Degrading Enzyme Expression and Function by Inhibiting the PPARγ Pathway. Mol Nutr Food Res 2023; 67:e2200589. [PMID: 36726048 PMCID: PMC10085830 DOI: 10.1002/mnfr.202200589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 12/29/2022] [Indexed: 02/03/2023]
Abstract
SCOPE Long-term high-fat diet (HFD) causes insulin resistance, which is a primary etiological factor in the development of obesity and type 2 diabetes mellitus. Impaired insulin clearance is not only a consequence but also a cause of insulin resistance. The kidney is a major site of insulin clearance, where the insulin-degrading enzyme (IDE) plays a vital role in the proximal tubule. Thus, the study investigates the role of renal IDE in the regulation of insulin resistance in HFD-induced obese mice. METHODS AND RESULTS Twenty four-weeks of HFD in C57BL/6 mice causes insulin resistance and impaires insulin clearance, accompanied by a decrease in renal IDE expression and activity. Palmitic acid decreases IDE mRNA and protein expressions in HK-2 cells. RNA-Seq analysis found that the PPAR pathway is involved. 24-weeks of HFD decreases renal PPARγ, but not PPARα or PPARβ/δ mRNA expression. The inhibition of IDE expression by palmitic acid is prevented by the PPARγ agonist rosiglitazone. The amount of PPARγ bound to the promoters of IDE is decreased in palmitic acid-treated cells. Rosiglitazone improves insulin clearance and insulin resistance and increases renal IDE expression in HFD fed-mice. CONCLUSION Long-term HFD decreases renal IDE expression and activity, and causes insulin resistance, which involves PPARγ.
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Affiliation(s)
- Qian Su
- Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Juan Huang
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xi Chen
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yijie Wang
- Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Muqing Shao
- Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hongjia Yan
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Caiyu Chen
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Hongmei Ren
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Fuwei Zhang
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Cardiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yinxing Ni
- Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Pedro A. Jose
- Division of Renal Diseases & Hypertension, Department of Medicine and Department of Physiology and Pharmacology, The George Washington University School of Medicine & Health Sciences, Washington, DC, USA
| | - Jian Zhong
- Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jian Yang
- Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Jeong DW, Lee S, Chun YS. How cancer cells remodel lipid metabolism: strategies targeting transcription factors. Lipids Health Dis 2021; 20:163. [PMID: 34775964 PMCID: PMC8590761 DOI: 10.1186/s12944-021-01593-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/02/2021] [Indexed: 12/30/2022] Open
Abstract
Reprogramming of lipid metabolism has received increasing recognition as a hallmark of cancer cells because lipid dysregulation and the alteration of related enzyme profiles are closely correlated with oncogenic signals and malignant phenotypes, such as metastasis and therapeutic resistance. In this review, we describe recent findings that support the importance of lipids, as well as the transcription factors involved in cancer lipid metabolism. With recent advances in transcription factor analysis, including computer-modeling techniques, transcription factors are emerging as central players in cancer biology. Considering the limited number and the crucial role of transcription factors associated with lipid rewiring in cancers, transcription factor targeting is a promising potential strategy for cancer therapy.
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Affiliation(s)
- Do-Won Jeong
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.,Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Seulbee Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.,Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Yang-Sook Chun
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea. .,Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea. .,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea.
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He Z, You G, Liu Q, Li N. Alzheimer's Disease and Diabetes Mellitus in Comparison: The Therapeutic Efficacy of the Vanadium Compound. Int J Mol Sci 2021; 22:ijms222111931. [PMID: 34769364 PMCID: PMC8584792 DOI: 10.3390/ijms222111931] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/22/2021] [Accepted: 10/28/2021] [Indexed: 02/07/2023] Open
Abstract
Alzheimer’s disease (AD) is an intractable neurodegenerative disease that leads to dementia, primarily in elderly people. The neurotoxicity of amyloid-beta (Aβ) and tau protein has been demonstrated over the last two decades. In line with these findings, several etiological hypotheses of AD have been proposed, including the amyloid cascade hypothesis, the oxidative stress hypothesis, the inflammatory hypothesis, the cholinergic hypothesis, et al. In the meantime, great efforts had been made in developing effective drugs for AD. However, the clinical efficacy of the drugs that were approved by the US Food and Drug Association (FDA) to date were determined only mild/moderate. We recently adopted a vanadium compound bis(ethylmaltolato)-oxidovanadium (IV) (BEOV), which was originally used for curing diabetes mellitus (DM), to treat AD in a mouse model. It was shown that BEOV effectively reduced the Aβ level, ameliorated the inflammation in brains of the AD mice, and improved the spatial learning and memory activities of the AD mice. These finding encouraged us to further examine the mechanisms underlying the therapeutic effects of BEOV in AD. In this review, we summarized the achievement of vanadium compounds in medical studies and investigated the prospect of BEOV in AD and DM treatment.
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Affiliation(s)
- Zhijun He
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China; (Z.H.); (G.Y.); (Q.L.)
| | - Guanying You
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China; (Z.H.); (G.Y.); (Q.L.)
| | - Qiong Liu
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China; (Z.H.); (G.Y.); (Q.L.)
- Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China
| | - Nan Li
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China; (Z.H.); (G.Y.); (Q.L.)
- Shenzhen Bay Laboratory, Shenzhen 518055, China
- Correspondence: ; Tel.: +86-(0)755-2653-5432; Fax: +86-(0)755-8671-3951
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Kim S, Reed E, Monti S, Schlezinger JJ. A Data-Driven Transcriptional Taxonomy of Adipogenic Chemicals to Identify White and Brite Adipogens. ENVIRONMENTAL HEALTH PERSPECTIVES 2021; 129:77006. [PMID: 34323617 PMCID: PMC8320370 DOI: 10.1289/ehp6886] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
BACKGROUND Chemicals in disparate structural classes activate specific subsets of the transcriptional programs of peroxisome proliferator-activated receptor-γ (PPARγ) to generate adipocytes with distinct phenotypes. OBJECTIVES Our objectives were to a) establish a novel classification method to predict PPARγ ligands and modifying chemicals; and b) create a taxonomy to group chemicals on the basis of their effects on PPARγ's transcriptome and downstream metabolic functions. We tested the hypothesis that environmental adipogens highly ranked by the taxonomy, but segregated from therapeutic PPARγ ligands, would induce white but not brite adipogenesis. METHODS 3T3-L1 cells were differentiated in the presence of 76 chemicals (negative controls, nuclear receptor ligands known to influence adipocyte biology, potential environmental PPARγ ligands). Differentiation was assessed by measuring lipid accumulation. mRNA expression was determined by RNA-sequencing (RNA-Seq) and validated by reverse transcription-quantitative polymerase chain reaction. A novel classification model was developed using an amended random forest procedure. A subset of environmental contaminants identified as strong PPARγ agonists were analyzed by their effects on lipid handling, mitochondrial biogenesis, and cellular respiration in 3T3-L1 cells and human preadipocytes. RESULTS We used lipid accumulation and RNA-Seq data to develop a classification system that a) identified PPARγ agonists; and b) sorted chemicals into likely white or brite adipogens. Expression of Cidec was the most efficacious indicator of strong PPARγ activation. 3T3-L1 cells treated with two known environmental PPARγ ligands, tetrabromobisphenol A and triphenyl phosphate, which sorted distinctly from therapeutic ligands, had higher expression of white adipocyte genes but no difference in Pgc1a and Ucp1 expression, and higher fatty acid uptake but not mitochondrial biogenesis. Moreover, cells treated with two chemicals identified as highly ranked PPARγ agonists, tonalide and quinoxyfen, induced white adipogenesis without the concomitant health-promoting characteristics of brite adipocytes in mouse and human preadipocytes. DISCUSSION A novel classification procedure accurately identified environmental chemicals as PPARγ ligands distinct from known PPARγ-activating therapeutics. CONCLUSION The computational and experimental framework has general applicability to the classification of as-yet uncharacterized chemicals. https://doi.org/10.1289/EHP6886.
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Affiliation(s)
- Stephanie Kim
- Boston University Superfund Research Program, Boston University, Massachusetts, USA
- Department of Environmental Health, Boston University School of Public Health, Massachusetts, USA
| | - Eric Reed
- Boston University Superfund Research Program, Boston University, Massachusetts, USA
- Section of Computational Biomedicine, Boston University School of Medicine, Massachusetts, USA
- Boston University Bioinformatics Program, Boston University, Massachusetts, USA
| | - Stefano Monti
- Boston University Superfund Research Program, Boston University, Massachusetts, USA
- Section of Computational Biomedicine, Boston University School of Medicine, Massachusetts, USA
- Boston University Bioinformatics Program, Boston University, Massachusetts, USA
| | - Jennifer J. Schlezinger
- Boston University Superfund Research Program, Boston University, Massachusetts, USA
- Department of Environmental Health, Boston University School of Public Health, Massachusetts, USA
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Xu H, Zhu B, Li H, Jiang B, Wang Y, Yin Q, Cai J, Glaser S, Francis H, Alpini G, Wu C. Adipocyte inducible 6-phosphofructo-2-kinase suppresses adipose tissue inflammation and promotes macrophage anti-inflammatory activation. J Nutr Biochem 2021; 95:108764. [PMID: 33964465 DOI: 10.1016/j.jnutbio.2021.108764] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 03/11/2021] [Accepted: 04/16/2021] [Indexed: 01/22/2023]
Abstract
Obesity-associated inflammation in white adipose tissue (WAT) is a causal factor of systemic insulin resistance. To better understand how adipocytes regulate WAT inflammation, the present study generated chimeric mice in which inducible 6-phosphofructo-2-kinase was low, normal, or high in WAT while the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3) was normal in hematopoietic cells, and analyzed changes in high-fat diet (HFD)-induced WAT inflammation and systemic insulin resistance in the mice. Indicated by proinflammatory signaling and cytokine expression, the severity of HFD-induced WAT inflammation in WT → Pfkfb3+/- mice, whose Pfkfb3 was disrupted in WAT adipocytes but not hematopoietic cells, was comparable with that in WT → WT mice, whose Pfkfb3 was normal in all cells. In contrast, the severity of HFD-induced WAT inflammation in WT → Adi-Tg mice, whose Pfkfb3 was over-expressed in WAT adipocytes but not hematopoietic cells, remained much lower than that in WT → WT mice. Additionally, HFD-induced insulin resistance was correlated with the status of WAT inflammation and comparable between WT → Pfkfb3+/- mice and WT → WT mice, but was significantly lower in WT → Adi-Tg mice than in WT → WT mice. In vitro, palmitoleate decreased macrophage phosphorylation states of Jnk p46 and Nfkb p65 and potentiated the effect of interleukin 4 on suppressing macrophage proinflammatory activation. Taken together, these results suggest that the Pfkfb3 in adipocytes functions to suppress WAT inflammation. Moreover, the role played by adipocyte Pfkfb3 is attributable to, at least in part, palmitoleate promotion of macrophage anti-inflammatory activation.
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Affiliation(s)
- Hang Xu
- Department of Nutrition, Texas A&M University, College Station, Texas, USA
| | - Bilian Zhu
- Department of Nutrition, Texas A&M University, College Station, Texas, USA; Department of VIP Medical Service Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Honggui Li
- Department of Nutrition, Texas A&M University, College Station, Texas, USA
| | - Boxiong Jiang
- Department of VIP Medical Service Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yina Wang
- Department of VIP Medical Service Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qiongli Yin
- Department of VIP Medical Service Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - James Cai
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA
| | - Shannon Glaser
- Medical Physiology, Texas A&M University College of Medicine, Bryan, Texas, USA
| | - Heather Francis
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana, USA; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana, USA; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, Texas, USA.
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Bao M, Zhang K, Wei Y, Hua W, Gao Y, Li X, Ye L. Therapeutic potentials and modulatory mechanisms of fatty acids in bone. Cell Prolif 2020; 53:e12735. [PMID: 31797479 PMCID: PMC7046483 DOI: 10.1111/cpr.12735] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 11/02/2019] [Accepted: 11/05/2019] [Indexed: 02/05/2023] Open
Abstract
Bone metabolism is a lifelong process that includes bone formation and resorption. Osteoblasts and osteoclasts are the predominant cell types associated with bone metabolism, which is facilitated by other cells such as bone marrow mesenchymal stem cells (BMMSCs), osteocytes and chondrocytes. As an important component in our daily diet, fatty acids are mainly categorized as long-chain fatty acids including polyunsaturated fatty acids (LCPUFAs), monounsaturated fatty acids (LCMUFAs), saturated fatty acids (LCSFAs), medium-/short-chain fatty acids (MCFAs/SCFAs) as well as their metabolites. Fatty acids are closely associated with bone metabolism and associated bone disorders. In this review, we summarized the important roles and potential therapeutic implications of fatty acids in multiple bone disorders, reviewed the diverse range of critical effects displayed by fatty acids on bone metabolism, and elucidated their modulatory roles and mechanisms on specific bone cell types. The evidence supporting close implications of fatty acids in bone metabolism and disorders suggests fatty acids as potential therapeutic and nutritional agents for the treatment and prevention of metabolic bone diseases.
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Affiliation(s)
- Minyue Bao
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Kaiwen Zhang
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Yangyini Wei
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Weihan Hua
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Yanzi Gao
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Xin Li
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Ling Ye
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesDepartment of Cariology and EndodonticsWest China Hospital of StomatologySichuan UniversityChengduChina
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10
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Lipid Accumulation and Chronic Kidney Disease. Nutrients 2019; 11:nu11040722. [PMID: 30925738 PMCID: PMC6520701 DOI: 10.3390/nu11040722] [Citation(s) in RCA: 257] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/25/2019] [Accepted: 03/26/2019] [Indexed: 12/12/2022] Open
Abstract
Obesity and hyperlipidemia are the most prevalent independent risk factors of chronic kidney disease (CKD), suggesting that lipid accumulation in the renal parenchyma is detrimental to renal function. Non-esterified fatty acids (also known as free fatty acids, FFA) are especially harmful to the kidneys. A concerted, increased FFA uptake due to high fat diets, overexpression of fatty acid uptake systems such as the CD36 scavenger receptor and the fatty acid transport proteins, and a reduced β-oxidation rate underlie the intracellular lipid accumulation in non-adipose tissues. FFAs in excess can damage podocytes, proximal tubular epithelial cells and the tubulointerstitial tissue through various mechanisms, in particular by boosting the production of reactive oxygen species (ROS) and lipid peroxidation, promoting mitochondrial damage and tissue inflammation, which result in glomerular and tubular lesions. Not all lipids are bad for the kidneys: polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) seem to help lag the progression of chronic kidney disease (CKD). Lifestyle interventions, especially dietary adjustments, and lipid-lowering drugs can contribute to improve the clinical outcome of patients with CKD.
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11
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Donat-Vargas C, Bergdahl IA, Tornevi A, Wennberg M, Sommar J, Kiviranta H, Koponen J, Rolandsson O, Åkesson A. Perfluoroalkyl substances and risk of type II diabetes: A prospective nested case-control study. ENVIRONMENT INTERNATIONAL 2019; 123:390-398. [PMID: 30622063 DOI: 10.1016/j.envint.2018.12.026] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 12/12/2018] [Accepted: 12/13/2018] [Indexed: 05/27/2023]
Abstract
BACKGROUND Perfluoroalkyl substances (PFAS) have drawn much attention due to bioaccumulation potential and their current omnipresence in human blood. We assessed whether plasma PFAS, suspected to induce endocrine-disrupting effects, were prospectively associated with clinical type 2 diabetes (T2D) risk. METHODS We established a nested case-control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Several PFAS were measured in plasma from a subset of 124 case-control pairs at baseline (during 1990-2003) and at 10-year follow-up. T2D cases were matched (1:1) according to gender, age and sample date with participants without T2D (controls). Conditional logistic regressions were used to prospectively assess risk of T2D by baseline PFAS plasma concentrations. Associations between long-term PFAS plasma levels (mean of baseline and follow-up) and insulin resistance (HOMA2-IR) and beta-cell function (HOMA2-B%) at follow-up were prospectively explored among 178 and 181 controls, respectively, by multivariable linear regressions. RESULTS After adjusting for gender, age, sample year, diet and body mass index, the odds ratio of T2D for the sum of PFAS (Σ z-score PFAS) was 0.52 (95% confidence interval, CI: 0.20, 1.36), comparing third with first tertile; and 0.92 (95% CI: 0.84, 1.00) per one standard deviation increment of sum of log-transformed PFAS. Among the controls, the adjusted β of HOMA2-IR and HOMA-B% for the sum of PFAS were -0.26 (95% CI: -0.52, -0.01) and -9.61 (95% CI: -22.60, 3.39) respectively comparing third with first tertile. CONCLUSIONS This prospective nested case-control study yielded overall inverse associations between individual PFAS and risk of T2D, although mostly non-significant. Among participants without T2D, long-term PFAS exposure was prospectively associated with lower insulin resistance.
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Affiliation(s)
- Carolina Donat-Vargas
- Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ingvar A Bergdahl
- Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine, Umeå University, Umeå, Sweden
| | - Andreas Tornevi
- Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine, Umeå University, Umeå, Sweden
| | - Maria Wennberg
- Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden
| | - Johan Sommar
- Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine, Umeå University, Umeå, Sweden
| | - Hannu Kiviranta
- Department for Health Security, Environmental Health Unit, National Institute for Health and Welfare, Kuopio, Finland
| | - Jani Koponen
- Department for Health Security, Environmental Health Unit, National Institute for Health and Welfare, Kuopio, Finland
| | - Olov Rolandsson
- Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden
| | - Agneta Åkesson
- Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
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12
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Matsubara T, Takakura N, Urata M, Muramatsu Y, Tsuboi M, Yasuda K, Addison WN, Zhang M, Matsuo K, Nakatomi C, Shigeyama-Tada Y, Kaneuji T, Nakamichi A, Kokabu S. Geranylgeraniol Induces PPARγ Expression and Enhances the Biological Effects of a PPARγ Agonist in Adipocyte Lineage Cells. In Vivo 2019; 32:1339-1344. [PMID: 30348686 DOI: 10.21873/invivo.11384] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 07/31/2018] [Accepted: 08/06/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND The global incidence of diabetes mellitus (DM) has risen precipitously, even in middle- and low-income countries. Peroxisome proliferator-activated receptor γ (PPARγ) plays an important role in the control of cellular glucose metabolism. Activation of PPARγ beneficially results in increased insulin sensitivity. However, the expression of PPARγ is reduced by obesity and several nutritional factors. Here we examined the effect of geranylgeraniol (GGOH), a bioactive compound found naturally in fruits, vegetables, and grains, on the expression and activation of PPARγ. MATERIALS AND METHODS C3H10T1/2 mouse embryonic fibroblasts and 3T3-L1 pre-adipocytes were used as in vitro models of adipocyte differentiation and function. Quantitative reverse-transcriptase polymerase chain reaction, western blotting, Oil Red O staining, and luciferase assay were performed to respectively assess mRNA expression, protein levels, lipid droplet formation and transcriptional activity. RESULTS GGOH increased the expression of PPARγ in adipocyte lineage cells. GGOH also enhanced adipogenesis induced by rosiglitazone, a thiazolidinedione class PPARγ agonist. CONCLUSION GGOH induces PPARγ expression and enhances the biological effects of a PPARγ agonist in adipocyte lineage cells.
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Affiliation(s)
- Takuma Matsubara
- Division of Molecular Signaling and Biochemistry, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
| | - Nana Takakura
- Division of Molecular Signaling and Biochemistry, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
| | - Mariko Urata
- Division of Molecular Signaling and Biochemistry, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
| | - Yuya Muramatsu
- Division of Molecular Signaling and Biochemistry, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
| | - Makoto Tsuboi
- Division of Molecular Signaling and Biochemistry, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
| | - Kazuma Yasuda
- Division of Molecular Signaling and Biochemistry, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
| | - William N Addison
- Research Unit, Shriners Hospitals for Children-Canada, Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Min Zhang
- Division of Oral Pathology, Department of Health Promotion, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
| | - Kou Matsuo
- Division of Oral Pathology, Department of Health Promotion, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
| | - Chihiro Nakatomi
- Division of Molecular Signaling and Biochemistry, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
| | - Yukiyo Shigeyama-Tada
- Division of Dental Anesthesiology, Department of Control of Physical Functions, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
| | - Takeshi Kaneuji
- Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Atsuko Nakamichi
- Department of Oral Functional Management, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
| | - Shoichiro Kokabu
- Division of Molecular Signaling and Biochemistry, School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan
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13
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Kim D, Ahn BN, Kim Y, Hur DY, Yang JW, Park GB, Jang JE, Lee EJ, Kwon MJ, Kim TN, Kim MK, Park JH, Rhee BD, Lee SH. High Glucose with Insulin Induces Cell Cycle Progression and Activation of Oncogenic Signaling of Bladder Epithelial Cells Cotreated with Metformin and Pioglitazone. J Diabetes Res 2019; 2019:2376512. [PMID: 30729133 PMCID: PMC6343135 DOI: 10.1155/2019/2376512] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 11/25/2018] [Indexed: 12/13/2022] Open
Abstract
Metformin and pioglitazone are two commonly prescribed oral hypoglycemic agents for diabetes. Recent evidence suggests that these drugs may contribute to bladder cancer. This study investigated molecular mechanism underlying effects of metformin and pioglitazone in bladder epithelial carcinogenesis in type 2 diabetes. The cells derived from human bladder epithelial cells (HBlEpCs) were treated with metformin or pioglitazone with high glucose and insulin. Cell viability and proliferation were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and a bromodeoxyuridine incorporation assay, respectively, while cell cycle regulatory factors and oncogene expression were analyzed using western blotting. Metformin or pioglitazone suppressed cell viability concentration and time dependently, which was reversed by exposure to high glucose with or without insulin. Prolonged exposure to high glucose and insulin enhanced cyclin D, cyclin-dependent kinase 4 (Cdk4), and Cdk2 expression and suppressed cyclin-dependent kinase inhibitors p21 and p15/16 in HBlEpC cotreated with pioglitazone and metformin. Levels of tumor suppressor proteins p53 and cav-1 were downregulated while those of the oncogenic protein as c-Myc were upregulated under high glucose and insulin supplementation in HBlEpC cotreated with pioglitazone and metformin. Prolonged exposure to high glucose with or without insulin downregulated B cell lymphoma 2-associated X (Bax) and failed to enhance the expression of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) in drug-treated cells. These results suggest that hyperglycemic and insulinemic conditions promote cell cycle progression and oncogenic signaling in drug-treated bladder epithelial cells and uncontrolled hyperglycemia and hyperinsulinemia are probably greater cancer risk factors than diabetes drugs.
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Affiliation(s)
- Daejin Kim
- Department of Anatomy, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Byul-Nim Ahn
- T2B Infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - YeongSeok Kim
- Department of Anatomy, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Dae Young Hur
- Department of Anatomy, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Jae Wook Yang
- T2B Infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, Busan, Republic of Korea
- Department of Ophthalmology, Inje University College of Medicine, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - Ga Bin Park
- Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea
| | - Jung Eun Jang
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Eun Ju Lee
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Min Jeong Kwon
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Tae Nyun Kim
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Mi Kyung Kim
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Jeong Hyun Park
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Byoung Doo Rhee
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Soon Hee Lee
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
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14
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Dutta D, Lai KY, Reyes-Ordoñez A, Chen J, van der Donk WA. Lanthionine synthetase C-like protein 2 (LanCL2) is important for adipogenic differentiation. J Lipid Res 2018; 59:1433-1445. [PMID: 29880530 DOI: 10.1194/jlr.m085274] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 06/01/2018] [Indexed: 01/13/2023] Open
Abstract
Adipogenic differentiation is a highly regulated process that is necessary for metabolic homeostasis and nutrient sensing. The expression of PPARγ and the subsequent activation of adipogenic genes is critical for the process. In this study, we identified lanthionine synthetase C-like protein 2 (LanCL2) as a positive regulator of adipogenesis in 3T3-L1 cells. Knockdown of LanCL2, but not LanCL1, inhibited adipogenic differentiation, and this effect was not mediated through cAMP or Akt signaling pathways. The expression of early adipogenic markers CCAAT enhancer binding protein β (C/EBPβ) and C/EBPδ remained intact in LanCL2 knockdown cells, but levels of late adipogenic markers PPARγ and C/EBPα were suppressed. The addition of the naturally occurring PPARγ activator 15-deoxy-Δ12,14-prostaglandin J2 or conditioned medium from differentiating cells did not restore differentiation, implying that LanCL2 may not be involved in the production of a secreted endogenous PPARγ ligand. Pulldown assays demonstrated a direct physical interaction between LanCL2 and PPARγ. Consistent with a regulatory role of LanCL2, luciferase reporter assays revealed that full transcriptional activation by PPARγ was dependent on LanCL2. Taken together, our study reveals a novel role of LanCL2 in adipogenesis, specifically involved in PPARγ-mediated transactivation of downstream adipogenic genes.
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Affiliation(s)
- Debapriya Dutta
- Department of Chemistry and Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL
| | - Kuan-Yu Lai
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL
| | - Adriana Reyes-Ordoñez
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL
| | - Jie Chen
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL
| | - Wilfred A van der Donk
- Department of Chemistry and Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL .,Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL
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15
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Abushouk AI, El-Husseny MWA, Bahbah EI, Elmaraezy A, Ali AA, Ashraf A, Abdel-Daim MM. Peroxisome proliferator-activated receptors as therapeutic targets for heart failure. Biomed Pharmacother 2017; 95:692-700. [PMID: 28886529 DOI: 10.1016/j.biopha.2017.08.083] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 08/05/2017] [Accepted: 08/23/2017] [Indexed: 01/06/2023] Open
Abstract
Heart failure (HF) is a common clinical syndrome that affects more than 23 million individuals worldwide. Despite the marked advances in its management, the mortality rates in HF patients have remained unacceptably high. Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription regulators, involved in the regulation of fatty acid and glucose metabolism. PPAR agonists are currently used for the treatment of type II diabetes mellitus and hyperlipidemia; however, their role as therapeutic agents for HF remains under investigation. Preclinical studies have shown that pharmacological modulation of PPARs can upregulate the expression of fatty acid oxidation genes in cardiomyocytes. Moreover, PPAR agonists were proven able to improve ventricular contractility and reduce cardiac remodelling in animal models through their anti-inflammatory, anti-oxidant, anti-fibrotic, and anti-apoptotic activities. Whether these effects can be replicated in humans is yet to be proven. This article reviews the interactions of PPARs with the pathophysiological mechanisms of HF and how the pharmacological modulation of these receptors can be of benefit for HF patients.
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Affiliation(s)
| | | | - Eshak I Bahbah
- Faculty of Medicine, Al-Azhar University, Damietta, Egypt
| | - Ahmed Elmaraezy
- NovaMed Medical Research Association, Cairo, Egypt; Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Aya Ashraf Ali
- Faculty of Medicine, Minia University, Minia, Egypt; Minia Medical Research Society, Minia University, Minia, Egypt
| | - Asmaa Ashraf
- Faculty of Medicine, Minia University, Minia, Egypt; Minia Medical Research Society, Minia University, Minia, Egypt
| | - Mohamed M Abdel-Daim
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt; Department of Ophthalmology and Micro-Technology, Yokohama City University, Yokohama, Japan.
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16
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Paramasivam D, Safi SZ, Qvist R, Abidin IBZ, Hairi NNM, Chinna K. Role of PPARG (Pro12Ala) in Malaysian type 2 diabetes mellitus patients. Int J Diabetes Dev Ctries 2016; 36:449-456. [DOI: 10.1007/s13410-015-0462-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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17
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Panebianco C, Oben JA, Vinciguerra M, Pazienza V. Senescence in hepatic stellate cells as a mechanism of liver fibrosis reversal: a putative synergy between retinoic acid and PPAR-gamma signalings. Clin Exp Med 2016; 17:269-280. [PMID: 27655446 DOI: 10.1007/s10238-016-0438-x] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 09/08/2016] [Indexed: 12/16/2022]
Abstract
Hepatic stellate cells (HSCs), also known as perisinusoidal cells, are pericytes found in the perisinusoidal space of the liver. HSCs are the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage. When the liver is damaged, stellate cells can shift into an activated state, characterized by proliferation, contractility and chemotaxis. The activated HSCs secrete collagen scar tissue, which can lead to cirrhosis. Recent studies have shown that in vivo activation of HSCs by fibrogenic agents can eventually lead to senescence of these cells, which would contribute to reversal of fibrosis although it may also favor the insurgence of liver cancer. HSCs in their non-active form store huge amounts of retinoic acid derivatives in lipid droplets, which are progressively depleted upon cell activation in injured liver. Retinoic acid is a metabolite of vitamin A (retinol) that mediates the functions of vitamin A, generally required for growth and development. The precise function of retinoic acid and its alterations in HSCs has yet to be elucidated, and nonetheless in various cell types retinoic acid and its receptors (RAR and RXR) are known to act synergistically with peroxisome proliferator-activated receptor gamma (PPAR-gamma) signaling through the activity of transcriptional heterodimers. Here, we review the recent advancements in the understanding of how retinoic acid signaling modulates the fibrogenic potential of HSCs and proposes a synergistic combined action with PPAR-gamma in the reversal of liver fibrosis.
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Affiliation(s)
- Concetta Panebianco
- Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, Viale dei Cappuccini, 1, San Giovanni Rotondo, FG, Italy
| | - Jude A Oben
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London (UCL), London, UK
| | - Manlio Vinciguerra
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London (UCL), London, UK.,Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne's University Hospital, Brno, Czech Republic.,Centro Studi Fegato (CSF)-Liver Research Center, Fondazione Italiana Fegato, Trieste, Italy
| | - Valerio Pazienza
- Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, Viale dei Cappuccini, 1, San Giovanni Rotondo, FG, Italy.
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18
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Laurenzana EM, Coslo DM, Vigilar MV, Roman AM, Omiecinski CJ. Activation of the Constitutive Androstane Receptor by Monophthalates. Chem Res Toxicol 2016; 29:1651-1661. [PMID: 27551952 DOI: 10.1021/acs.chemrestox.6b00186] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Humans in industrialized areas are continuously exposed to phthalate plasticizers, prompting concerns of their potential toxicities. Previous studies from our laboratory and others have shown that various phthalates activate several mammalian nuclear receptors, in particular the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the peroxisomal proliferator-activated receptors (PPARs), although often at concentration levels of questionable relevance to human exposure. We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). These diphthalates undergo rapid metabolism in mammalian systems, initially to their major monophthalate derivatives MEHP and MiNP. Although MEHP and MiNP are reported activators of the rodent PPARs, with lower affinities for the corresponding human PPARs, it remains unclear whether these monophthalate metabolites activate hCAR2 or hPXR. In this investigation, we assessed the relative activation potential of selected monophthalates and other low molecular weight phthalates against hCAR, the most prominent hCAR splice variants, as well as hPXR and human PPAR. Using transactivation and mammalian two-hybrid protein interaction assays, we demonstrate that these substances indeed activate hCARs and hPXR but to varying degrees. MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. Results from primary hepatocyte experiments also reflect the MEHP and MiNP upregulation of the respective human target genes. We conclude that both di- and monophthalates are potently selective hCAR2 activators and effective hPXR activators. These results implicate these targets as important mediators of selective phthalate effects in humans. The striking differential affinities for these compounds between human and rodent nuclear receptors further implies that biological results obtained from rodent models may be of only limited relevance for interpolating phthalate-mediated effects in humans.
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Affiliation(s)
- Elizabeth M Laurenzana
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University , 101 Life Sciences Building, University Park, Pennsylvania 16802, United States
| | - Denise M Coslo
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University , 101 Life Sciences Building, University Park, Pennsylvania 16802, United States
| | - M Veronica Vigilar
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University , 101 Life Sciences Building, University Park, Pennsylvania 16802, United States
| | - Anthony M Roman
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University , 101 Life Sciences Building, University Park, Pennsylvania 16802, United States
| | - Curtis J Omiecinski
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University , 101 Life Sciences Building, University Park, Pennsylvania 16802, United States
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19
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Singh S, Usman K, Banerjee M. Pharmacogenetic studies update in type 2 diabetes mellitus. World J Diabetes 2016; 7:302-315. [PMID: 27555891 PMCID: PMC4980637 DOI: 10.4239/wjd.v7.i15.302] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 05/30/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment.
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20
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Röder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med 2016; 48:e219. [PMID: 26964835 PMCID: PMC4892884 DOI: 10.1038/emm.2016.6] [Citation(s) in RCA: 544] [Impact Index Per Article: 60.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 12/03/2015] [Accepted: 12/06/2015] [Indexed: 12/11/2022] Open
Abstract
In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.
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Affiliation(s)
- Pia V Röder
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore. E-mail: or
| | - Bingbing Wu
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Singapore
| | - Yixian Liu
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Singapore
| | - Weiping Han
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Singapore
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore. E-mail: or
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21
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Silva JC, César FA, de Oliveira EM, Turato WM, Tripodi GL, Castilho G, Machado-Lima A, de Las Heras B, Boscá L, Rabello MM, Hernandes MZ, Pitta MGR, Pitta IR, Passarelli M, Rudnicki M, Abdalla DSP. New PPARγ partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr(-/-) mice. Pharmacol Res 2016; 104:49-60. [PMID: 26706782 DOI: 10.1016/j.phrs.2015.12.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Revised: 12/01/2015] [Accepted: 12/08/2015] [Indexed: 02/07/2023]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) regulates multiple pathways involved in the pathogenesis of obesity and atherosclerosis. Here, we evaluated the therapeutic potential of GQ-177, a new thiazolidinedione, on diet-induced obesity and atherosclerosis. The intermolecular interaction between PPARγ and GQ-177 was examined by virtual docking and PPAR activation was determined by reporter gene assay identifying GQ-177 as a partial and selective PPARγ agonist. For the evaluation of biological activity of GQ-177, low-density lipoprotein receptor-deficient (LDLr(-/-)) C57/BL6 mice were fed either a high fat diabetogenic diet (diet-induced obesity), or a high fat atherogenic diet, and treated with vehicle, GQ-177 (20mg/kg/day), pioglitazone (20mg/kg/day, diet-induced obesity model) or rosiglitazone (15mg/kg/day, atherosclerosis model) for 28 days. In diet-induced obesity mice, GQ-177 improved insulin sensitivity and lipid profile, increased plasma adiponectin and GLUT4 mRNA in adipose tissue, without affecting body weight, food consumption, fat accumulation and bone density. Moreover, GQ-177 enhanced hepatic mRNA levels of proteins involved in lipid metabolism. In the atherosclerosis mice, GQ-177 inhibited atherosclerotic lesion progression, increased plasma HDL and mRNA levels of PPARγ and ATP-binding cassette A1 in atherosclerotic lesions. GQ-177 acts as a partial PPARγ agonist that improves obesity-associated insulin resistance and dyslipidemia with atheroprotective effects in LDLr(-/-) mice.
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Affiliation(s)
- Jacqueline C Silva
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Fernanda A César
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Edson M de Oliveira
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Walter M Turato
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Gustavo L Tripodi
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Gabriela Castilho
- Lipids Laboratory (LIM-10), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Adriana Machado-Lima
- Lipids Laboratory (LIM-10), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Beatriz de Las Heras
- Department of Pharmacology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
| | - Marcelo M Rabello
- Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife, PE, Brazil
| | - Marcelo Z Hernandes
- Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife, PE, Brazil
| | - Marina G R Pitta
- Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil
| | - Ivan R Pitta
- Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil
| | - Marisa Passarelli
- Lipids Laboratory (LIM-10), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Martina Rudnicki
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Dulcineia S P Abdalla
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
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22
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Effects of Thiazolidinediones on metabolism and cancer: Relative influence of PPARγ and IGF-1 signaling. Eur J Pharmacol 2015; 768:217-25. [DOI: 10.1016/j.ejphar.2015.10.057] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Revised: 10/13/2015] [Accepted: 10/30/2015] [Indexed: 12/31/2022]
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23
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Sharma MC. Prospective QSAR-Based Prediction Models with Pharmacophore Studies of Oxadiazole-Substituted α-Isopropoxy Phenylpropanoic Acids with Dual Activators of PPARα and PPARγ. Interdiscip Sci 2015; 7:335-45. [PMID: 26178333 DOI: 10.1007/s12539-015-0009-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 11/22/2013] [Accepted: 12/05/2013] [Indexed: 10/23/2022]
Abstract
A series of oxadiazole-substituted [Formula: see text]-isopropoxy phenylpropanoic acids with dual activators of PPARα and PPARγ derivatives were subjected to two-dimensional and k-Nearest Neighbors molecular field analysis. The statistically significant best 2D-QSAR (PPARα ) model having good predictive ability with statistical values of r(2) = 0:8725; q(2) = 0:7957and pred_r(2) = 0:8136 was developed by GA-PLS with the descriptors like SsClcount, SddsN (nitro) count and SsOHcount that contribute significantly to the biological activity. The best 3D-QSAR studies (PPARα ) were performed using the genetic algorithm selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q(2) = 0:7188 and predicate activity pred_r(2) = 0.7508 were obtained. The influences of steric and electrostatic field effects generated by the contribution plots are discussed. The best pharmacophore model includes three features, viz. hydrogen bond donor, hydrogen bond acceptor and aromatic features. The information rendered by 2D-QSAR and 3D-QSAR models may lead to a better understanding of structural requirements of substituted α-isopropoxy phenylpropanoic derivatives and also aid in designing novel potent PPARα and PPARγ for antihyperglycemic molecules.
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Affiliation(s)
- Mukesh C Sharma
- Drug Design and Development Laboratory, School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshila Campus, Khandwa Road, Indore, 452 001, MP, India.
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24
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Wauquier F, Léotoing L, Philippe C, Spilmont M, Coxam V, Wittrant Y. Pros and cons of fatty acids in bone biology. Prog Lipid Res 2015; 58:121-45. [PMID: 25835096 DOI: 10.1016/j.plipres.2015.03.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 03/06/2015] [Accepted: 03/23/2015] [Indexed: 12/12/2022]
Abstract
Despite the growing interest in deciphering the causes and consequences of obesity-related disorders, the mechanisms linking fat intake to bone behaviour remain unclear. Since bone fractures are widely associated with increased morbidity and mortality, most notably in elderly and obese people, bone health has become a major social and economic issue. Consistently, public health system guidelines have encouraged low-fat diets in order to reduce associated complications. However, from a bone point of view, mechanisms linking fat intake to bone alteration remain quite controversial. Thus, after more than a decade of dedicated studies, this timely review offers a comprehensive overview of the relationships between bone and fatty acids. Using clinical evidences as a starting-point to more complex molecular elucidation, this work highlights the complexity of the system and reveals that bone alteration that cannot be solved simply by taking ω-3 pills. Fatty acid effects on bone metabolism can be both direct and indirect and require integrated investigations. Furthermore, even at the level of a single cell, one fatty acid is able to trigger several different independent pathways (receptors, metabolites…) which may all have a say in the final cellular metabolic response.
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Affiliation(s)
- Fabien Wauquier
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France
| | - Laurent Léotoing
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France
| | - Claire Philippe
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France
| | - Mélanie Spilmont
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France
| | - Véronique Coxam
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France
| | - Yohann Wittrant
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France.
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25
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Vaidya H, Cheema SK. Arachidonic acid has a dominant effect to regulate lipogenic genes in 3T3-L1 adipocytes compared to omega-3 fatty acids. Food Nutr Res 2015; 59:25866. [PMID: 25797050 PMCID: PMC4369559 DOI: 10.3402/fnr.v59.25866] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 01/12/2015] [Accepted: 01/14/2015] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The effects of long-chain n-3 and n-6 polyunsaturated fatty acids (PUFA) on the regulation of adipocytes metabolism are well known. These fatty acids are generally consumed together in our diets; however, the metabolic regulation of adipocytes in the presence of these fatty acids when given together is not known. OBJECTIVE To investigate the effects of n-3 PUFA and arachidonic acid (AA), an n-6 PUFA, on the regulation of adipogenic and lipogenic genes in mature 3T3-L1 adipocytes. METHODS 3T3-L1 adipocytes were incubated in the presence or absence of 100 µM of eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA; docosapentaenoic acid, DPA and AA, either alone or AA+n-3 PUFA; control cells received bovine serum albumin alone. The mRNA expression of adipogenic and lipogenic genes was measured. The fatty acid composition of adipocytes was analyzed using gas chromatography. RESULTS Individual n-3 PUFA or AA had no effect on the mRNA expression of peroxisome-proliferator-activated receptor-γ; however, AA+EPA and AA+DPA significantly increased (P<0.05) the expression compared to control cells (38 and 42%, respectively). AA and AA+EPA increased the mRNA expression of acetyl-CoA carboxylase 1 (P<0.05). AA treatment decreased the mRNA expression of stearoyl-CoA desaturase (SCD1) (P<0.01), while n-3 PUFA, except EPA, had no effect compared to control cells. AA+DHA and AA+DPA inhibited SCD1 gene expression (P<0.05) suggesting a dominant effect of AA. Fatty acids analysis of adipocytes revealed a higher accretion of AA compared to n-3 PUFA. CONCLUSIONS Our findings reveal that AA has a dominant effect on the regulation of lipogenic genes in adipocytes.
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Affiliation(s)
- Hitesh Vaidya
- Department of Biochemistry, Memorial University, St. John's, NL, Canada
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26
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Laghezza A, Montanari R, Lavecchia A, Piemontese L, Pochetti G, Iacobazzi V, Infantino V, Capelli D, De Bellis M, Liantonio A, Pierno S, Tortorella P, Conte Camerino D, Loiodice F. On the metabolically active form of metaglidasen: improved synthesis and investigation of its peculiar activity on peroxisome proliferator-activated receptors and skeletal muscles. ChemMedChem 2015; 10:555-65. [PMID: 25641779 DOI: 10.1002/cmdc.201402462] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Indexed: 01/27/2023]
Abstract
Metaglidasen is a fibrate-like drug reported as a selective modulator of peroxisome proliferator-activated receptor γ (PPARγ), able to lower plasma glucose levels in the absence of the side effects typically observed with thiazolidinedione antidiabetic agents in current use. Herein we report an improved synthesis of metaglidasen's metabolically active form halofenic acid (R)-2 and that of its enantiomer (S)-2. The activity of the two stereoisomers was carefully examined on PPARα and PPARγ subtypes. As expected, both showed partial agonist activity toward PPARγ; the investigation of PPARα activity, however, led to unexpected results. In particular, (S)-2 was found to act as a partial agonist, whereas (R)-2 behaved as an antagonist. X-ray crystallographic studies with PPARγ were carried out to gain more insight on the molecular-level interactions and to propose a binding mode. Given the adverse effects provoked by fibrate drugs on skeletal muscle function, we also investigated the capacity of (R)-2 and (S)-2 to block conductance of the skeletal muscle membrane chloride channel. The results showed a more beneficial profile for (R)-2, the activity of which on skeletal muscle function, however, should not be overlooked in the ongoing clinical trials studying its long-term effects.
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Affiliation(s)
- Antonio Laghezza
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", 70126 Bari (Italy)
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27
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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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28
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Sharma MC. Prospective QSAR-based prediction models with pharmacophore studies of oxadiazole-substituted α-isopropoxy phenylpropanoic acids on with dual activators of PPARα and PPARγ. Interdiscip Sci 2014. [PMID: 25183350 DOI: 10.1007/s12539-013-0051-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 11/22/2013] [Accepted: 12/05/2013] [Indexed: 11/26/2022]
Abstract
A series of oxadiazole-substituted α-isopropoxy phenylpropanoic acids with dual activators of PPARα and PPARγ derivatives were subjected to two dimensional and k-nearest neighbour Molecular field analysis. The statistically significant best 2D-QSAR (PPARα) model having good predictive ability with statistical values of r2 = 0.8725, q2 = 0.7957 and pred_r2 = 0.8136, was developed by GA-PLS with the descriptors like SsClcount, SddsN (nitro) count and SsOHcount contribute significantly to the biological activity. The best 3D-QSAR studies (PPARα) were performed using the genetic algorithm selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q2=0.7188 and predicate activity pred_r2 =0.7508 were obtained. The influences of steric and electrostatic field effects generated by the contribution plots are discussed. The best pharmacophore model includes three features viz. hydrogen bond donor, hydrogen bond acceptor, and aromatic features were developed. The information rendered by 2D, 3D QSAR models may lead to a better understanding of structural requirements of substituted α-isopropoxy phenylpropanoic derivatives and also aid in designing novel potent PPARα and PPARγ for antihyperglycemic molecules.
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Affiliation(s)
- Mukesh C Sharma
- Drug Design and Development Laboratory, School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshila Campus, Khandwa Road, Indore, M.P, 452 001, India,
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29
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Yang C, Li Q, Li Y. Targeting nuclear receptors with marine natural products. Mar Drugs 2014; 12:601-35. [PMID: 24473166 PMCID: PMC3944506 DOI: 10.3390/md12020601] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 12/20/2013] [Accepted: 01/07/2014] [Indexed: 02/07/2023] Open
Abstract
Nuclear receptors (NRs) are important pharmaceutical targets because they are key regulators of many metabolic and inflammatory diseases, including diabetes, dyslipidemia, cirrhosis, and fibrosis. As ligands play a pivotal role in modulating nuclear receptor activity, the discovery of novel ligands for nuclear receptors represents an interesting and promising therapeutic approach. The search for novel NR agonists and antagonists with enhanced selectivities prompted the exploration of the extraordinary chemical diversity associated with natural products. Recent studies involving nuclear receptors have disclosed a number of natural products as nuclear receptor ligands, serving to re-emphasize the translational possibilities of natural products in drug discovery. In this review, the natural ligands of nuclear receptors will be described with an emphasis on their mechanisms of action and their therapeutic potentials, as well as on strategies to determine potential marine natural products as nuclear receptor modulators.
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Affiliation(s)
- Chunyan Yang
- State Key Laboratory of Cellular Stress Biology, Innovation Center of Cell Biology Research, School of Life Sciences, Xiamen University, Xiamen 361102, China.
| | - Qianrong Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center of Cell Biology Research, School of Life Sciences, Xiamen University, Xiamen 361102, China.
| | - Yong Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center of Cell Biology Research, School of Life Sciences, Xiamen University, Xiamen 361102, China.
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30
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Lai MC, Teng TH, Yang C. The natural PPAR agonist linoleic acid stimulated insulin release in the rat pancreas. J Vet Med Sci 2013; 75:1449-54. [PMID: 23832628 PMCID: PMC3942972 DOI: 10.1292/jvms.13-0189] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Free fatty acids play an important role in regulating animal insulin secretion response.
Acute elevated free fatty acids increased animal insulin secretion and glucose-stimulated
insulin secretion. In the present study, we perfused the rat pancreas to explore the
effect of unsaturated fatty acids on insulin secretion. The results showed that linoleic
acid, γ-linolenic acid and arachidonic acid significantly stimulated insulin secretion.
Glucose (10 mM) alone induced a biphasic insulin secretion response. The peak effluent
insulin concentrations increased by 444% and 800% compared with the baseline in the first
and second insulin secretion phases, respectively. Based on comparison of the percentage
increases, arachidonic acid, γ-linolenic acid or linoleic acid increased glucose-induced
insulin release by 555% and 934%, 522% and 995% and 463% and 1,105% in the first and
second insulin secretion phases, respectively. However, the percentage increases of
insulin secretion decreased significantly to 402% and 564% in the first and second phases
in the rats fed a high-fat diet for 13 weeks. Linoleic acid alone stimulated a 391%
increase in the peak insulin concentration compared with the baseline in the rats fed a
normal diet. The peak insulin concentration decreased significantly to183% in the rats fed
a long-term high-fat diet. All the results suggested that unsaturated fatty acids
stimulated insulin secretion and additively increased glucose-induced insulin secretion in
the perfused rat pancreas. However, the rats fed a high-fat diet had a decreased linoleic
acid-induced insulin secretion response.
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Affiliation(s)
- Min-Chuan Lai
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, No.250, Kuo Kuang Road, Taichung City, Taiwan 402, R.O.C
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31
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Lanuza-Masdeu J, Arévalo MI, Vila C, Barberà A, Gomis R, Caelles C. In vivo JNK activation in pancreatic β-cells leads to glucose intolerance caused by insulin resistance in pancreas. Diabetes 2013; 62:2308-17. [PMID: 23349497 PMCID: PMC3712047 DOI: 10.2337/db12-1097] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Insulin resistance is a key condition in the development of type 2 diabetes. It is well established that exacerbated Jun NH2-terminal kinase (JNK) activity is involved in promoting insulin resistance in peripheral insulin-target tissues; however, this involvement is less documented in pancreatic β-cells. Using a transgenic mouse model, here we show that JNK activation in β-cells led to glucose intolerance as a result of impaired capacity to increase insulinemia in response to hyperglycemia. Pancreatic islets from these mice showed no obvious morphostructural abnormalities or decreased insulin content. In contrast, these islets failed to secrete insulin in response to glucose or insulin but were competent in succinate-, ketoisocaproate-, 3-isobutyl-1-methylxanthine (IBMX-), KCl-, and tolbutamide-induced insulin secretion. At the molecular level, JNK activation in β-cells inhibited insulin-induced Akt phosphorylation, pancreatic and duodenal homeobox 1 nucleocytoplasmic shuttling, and transcription of insulin-target genes. Remarkably, rosiglitazone restored insulin secretion in response to hyperglycemia in mice and insulin-induced insulin secretion and signaling in isolated islets. In conclusion, the mere activation of JNK suffices to induce insulin resistance in pancreatic β-cells by inhibition of insulin signaling in these cells, but it is not sufficient to elicit β-cell death. In addition, we provide the first evidence that thiazolidinediones exert insulin-sensitizing action directly on pancreatic β-cells.
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Affiliation(s)
- Jordi Lanuza-Masdeu
- Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Barcelona, Spain
- Cell Signaling Research Group, Institute for Research in Biomedicine, Barcelona, Spain
| | - M. Isabel Arévalo
- Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Barcelona, Spain
- Cell Signaling Research Group, Institute for Research in Biomedicine, Barcelona, Spain
| | - Cristina Vila
- Cell Signaling Research Group, Institute for Research in Biomedicine, Barcelona, Spain
| | - Albert Barberà
- Diabetes and Obesity Laboratory, IDIBAPS-Hospital Clínic, University of Barcelona, Barcelona, Spain
- CIBERDEM, Spain
| | - Ramon Gomis
- Diabetes and Obesity Laboratory, IDIBAPS-Hospital Clínic, University of Barcelona, Barcelona, Spain
- CIBERDEM, Spain
| | - Carme Caelles
- Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Barcelona, Spain
- Cell Signaling Research Group, Institute for Research in Biomedicine, Barcelona, Spain
- Corresponding author: Carme Caelles,
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32
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Avior Y, Bomze D, Ramon O, Nahmias Y. Flavonoids as dietary regulators of nuclear receptor activity. Food Funct 2013; 4:831-44. [PMID: 23598551 PMCID: PMC3781338 DOI: 10.1039/c3fo60063g] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Metabolic diseases such as obesity, type II diabetes, and dyslipidemia are a rising cause of mortality worldwide. The progression of many metabolic diseases is fundamentally regulated on the transcriptional level by a family of ligand-activated transcription factors, called nuclear receptors, which detect and respond to metabolic changes. Their role in maintaining metabolic homeostasis makes nuclear receptors an important pharmaceutical and dietary target. This review will present the growing evidence that flavonoids, natural secondary plant metabolites, are important regulators of nuclear receptor activity. Structural similarities between flavonoids and cholesterol derivatives combined with the promiscuous nature of most nuclear receptors provide a wealth of possibilities for pharmaceutical and dietary modulation of metabolism. While the challenges of bringing flavonoid-derived therapeutics to the market are significant, we consider this rapidly growing field to be an essential aspect of the functional food initiative and an important mine for pharmaceutical compounds.
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Affiliation(s)
- Yishai Avior
- School of Computer Science and Engineering, Center for Bioengineering, The Hebrew University of Jerusalem, Edmond J. Safra Campus (Givat Ram), Silberman 3-512, Jerusalem 91904, Israel.
| | - David Bomze
- Department of Cell and Developmental Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Ory Ramon
- School of Computer Science and Engineering, Center for Bioengineering, The Hebrew University of Jerusalem, Edmond J. Safra Campus (Givat Ram), Silberman 3-512, Jerusalem 91904, Israel.
| | - Yaakov Nahmias
- School of Computer Science and Engineering, Center for Bioengineering, The Hebrew University of Jerusalem, Edmond J. Safra Campus (Givat Ram), Silberman 3-512, Jerusalem 91904, Israel.
- Department of Cell and Developmental Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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33
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Effect of Opuntia humifusa supplementation and acute exercise on insulin sensitivity and associations with PPAR-γ and PGC-1α protein expression in skeletal muscle of rats. Int J Mol Sci 2013; 14:7140-54. [PMID: 23538842 PMCID: PMC3645680 DOI: 10.3390/ijms14047140] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 03/21/2013] [Accepted: 03/25/2013] [Indexed: 12/15/2022] Open
Abstract
This study examined whether Opuntia humifusa (O. humifusa), which is a member of the Cactaceae family, supplementation and acute swimming exercise affect insulin sensitivity and associations with PPAR-γ and PGC-1α protein expression in rats. Thirty-two rats were randomly divided into four groups (HS: high fat diet sedentary group, n = 8; HE: high fat diet acute exercise group, n = 8; OS: 5% O. humifusa supplemented high fat diet sedentary group, n = 8; OE: 5% O. humifusa supplemented high fat diet acute exercise group, n = 8). Rats in the HE and OE swam for 120 min. before being sacrificed. Our results indicated that serum glucose level, fasting insulin level and homeostasis model assessment of insulin resistance (HOMA-IR) in OS were significantly lower compared to those of the HS (p < 0.01, p < 0.05, p < 0.05). In addition, PPAR-γ protein expression in the OS and OE was significantly higher than that of the HS and HE, respectively (p < 0.05, p < 0.01). PGC-1α and GLUT-4 protein expressions in the OS were significantly higher compared to those of the HS (p < 0.05, p < 0.05). From these results, O. humifusa supplementation might play an important role for improving insulin sensitivity through elevation of PPAR-γ, PGC-1α, and GLUT-4 protein expression in rat skeletal muscle.
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Sakharkar MK, Shashni B, Sharma K, Dhillon SK, Ranjekar PR, Sakharkar KR. Therapeutic implications of targeting energy metabolism in breast cancer. PPAR Res 2013; 2013:109285. [PMID: 23431283 PMCID: PMC3575613 DOI: 10.1155/2013/109285] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Accepted: 12/23/2012] [Indexed: 12/12/2022] Open
Abstract
PPARs are ligand activated transcription factors. PPARγ agonists have been reported as a new and potentially efficacious treatment of inflammation, diabetes, obesity, cancer, AD, and schizophrenia. Since cancer cells show dysregulation of glycolysis they are potentially manageable through changes in metabolic environment. Interestingly, several of the genes involved in maintaining the metabolic environment and the central energy generation pathway are regulated or predicted to be regulated by PPARγ. The use of synthetic PPARγ ligands as drugs and their recent withdrawal/restricted usage highlight the lack of understanding of the molecular basis of these drugs, their off-target effects, and their network. These data further underscores the complexity of nuclear receptor signalling mechanisms. This paper will discuss the function and role of PPARγ in energy metabolism and cancer biology in general and its emergence as a promising therapeutic target in breast cancer.
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Affiliation(s)
- Meena K. Sakharkar
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba 305-8572, Japan
| | - Babita Shashni
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba 305-8572, Japan
| | - Karun Sharma
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba 305-8572, Japan
| | - Sarinder K. Dhillon
- Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | | | - Kishore R. Sakharkar
- Omicsvista, Singapore 120417
- Rajiv Gandhi Institute of Information Technology and Biotechnology, Bharati Vidyapeeth University, Pune 411046, India
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Abstract
Recent advances demonstrate peroxisome proliferator-activated receptors gamma (PPARγ) agonist, pioglitazone, as an anti-inflammatory drug. We investigated the effect of pioglitazone on experimental autoimmune neuritis (EAN) rats. Pioglitazone was given once daily (10 mg/kg) by oral gavage feeding from day 1-24 (suppressive group) and day 11-24 (therapeutic group). Pioglitazone ameliorated the clinical score of EAN, decreased expression of TNF-α, IFN-γ, and the activation of NF-κB, while increasing the expression of PPARγ and IL-4. Furthermore, we observed higher expression of PPARγ and IL-4 and lower expression of TNF-α, IFN-γ and reduced activation of NF-κB in suppressive group than those in the therapeutic group, which corresponds to lower clinical score and earlier disease recovery. Our data effectively demonstrate the anti-inflammatory properties of pioglitazone in EAN by inhibition of NF-κB signaling pathway.
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Wauquier F, Philippe C, Léotoing L, Mercier S, Davicco MJ, Lebecque P, Guicheux J, Pilet P, Miot-Noirault E, Poitout V, Alquier T, Coxam V, Wittrant Y. The free fatty acid receptor G protein-coupled receptor 40 (GPR40) protects from bone loss through inhibition of osteoclast differentiation. J Biol Chem 2013; 288:6542-51. [PMID: 23335512 DOI: 10.1074/jbc.m112.429084] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The mechanisms linking fat intake to bone loss remain unclear. By demonstrating the expression of the free fatty acid receptor G-coupled protein receptor 40 (GPR40) in bone cells, we hypothesized that this receptor may play a role in mediating the effects of fatty acids on bone remodeling. Using micro-CT analysis, we showed that GPR40(-/-) mice exhibit osteoporotic features suggesting a positive role of GPR40 on bone density. In primary cultures of bone marrow, we showed that GW9508, a GRP40 agonist, abolished bone-resorbing cell differentiation. This alteration of the receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation occurred via the inhibition of the nuclear factor κB (NF-κB) signaling pathway as demonstrated by decrease in gene reporter activity, inhibitor of κB kinase (IKKα/β) activation, inhibitor of κB (IkBα) phosphorylation, and nuclear factor of activated T cells 1 (NFATc1) expression. The GPR40-dependent effect of GW9508 was confirmed using shRNA interference in osteoclast precursors and GPR40(-/-) primary cell cultures. In addition, in vivo administration of GW9508 counteracted ovariectomy-induced bone loss in wild-type but not GPR40(-/-) mice, enlightening the obligatory role of the GPR40 receptor. Then, in a context of growing prevalence of metabolic and age-related bone disorders, our results demonstrate for the first time in translational approaches that GPR40 is a relevant target for the design of new nutritional and therapeutic strategies to counter bone complications.
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Affiliation(s)
- Fabien Wauquier
- Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1019, Unité de Nutrition Humaine, Centre de Recherche en Nutrition Humaine Auvergne, F-63009 Clermont-Ferrand, France
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Youngson NA, Morris MJ. What obesity research tells us about epigenetic mechanisms. Philos Trans R Soc Lond B Biol Sci 2013; 368:20110337. [PMID: 23166398 PMCID: PMC3539363 DOI: 10.1098/rstb.2011.0337] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The pathophysiology of obesity is extremely complex and is associated with extensive gene expression changes in tissues throughout the body. This situation, combined with the fact that all gene expression changes are thought to have associated epigenetic changes, means that the links between obesity and epigenetics will undoubtedly be vast. Much progress in identifying epigenetic changes induced by (or inducing) obesity has already been made, with candidate and genome-wide approaches. These discoveries will aid the clinician through increasing our understanding of the inheritance, development and treatment of obesity. However, they are also of great value for epigenetic researchers, as they have revealed mechanisms of environmental interactions with epigenetics that can produce or perpetuate a disease state. Here, we will review the evidence for four mechanisms through which epigenetics contributes to obesity: as downstream effectors of environmental signals; through abnormal global epigenetic state driving obesogenic expression patterns; through facilitating developmental programming and through transgenerational epigenetic inheritance.
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Affiliation(s)
| | - Margaret J. Morris
- Department of Pharmacology, School of Medical Sciences, University of New South Wales, High Street, Kensington, New South Wales 2052, Australia
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Song EK, Lee YR, Kim YR, Yeom JH, Yoo CH, Kim HK, Park HM, Kang HS, Kim JS, Kim UH, Han MK. NAADP mediates insulin-stimulated glucose uptake and insulin sensitization by PPARγ in adipocytes. Cell Rep 2012. [PMID: 23177620 DOI: 10.1016/j.celrep.2012.10.018] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Insulin stimulates glucose uptake through the membrane translocation of GLUT4 and GLUT1. Peroxisome proliferator-activated receptor γ (PPARγ) enhances insulin sensitivity. Here, we demonstrate that insulin stimulates GLUT4 and GLUT1 translocation, and glucose uptake, by activating the signaling pathway involving nicotinic acid adenine dinucleotide phosphate (NAADP), a calcium mobilizer, in adipocytes. We also demonstrate that PPARγ mediates insulin sensitization by enhancing NAADP production through upregulation of CD38, the only enzyme identified for NAADP synthesis. Insulin produced NAADP by both CD38-dependent and -independent pathways, whereas PPARγ produced NAADP by CD38-dependent pathway. Blocking the NAADP signaling pathway abrogated both insulin-stimulated and PPARγ-induced GLUT4 and GLUT1 translocation, thereby inhibiting glucose uptake. CD38 knockout partially inhibited insulin-stimulated glucose uptake. However, CD38 knockout completely blocked PPARγ-induced glucose uptake in adipocytes and PPARγ-mediated amelioration of glucose tolerance in diabetic mice. These results demonstrated that the NAADP signaling pathway is a critical molecular target for PPARγ-mediated insulin sensitization.
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Affiliation(s)
- Eun-Kyung Song
- Department of Microbiology, Chonbuk National University Medical School, Jeonju 561-756, Korea
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Marion V, Mockel A, De Melo C, Obringer C, Claussmann A, Simon A, Messaddeq N, Durand M, Dupuis L, Loeffler JP, King P, Mutter-Schmidt C, Petrovsky N, Stoetzel C, Dollfus H. BBS-induced ciliary defect enhances adipogenesis, causing paradoxical higher-insulin sensitivity, glucose usage, and decreased inflammatory response. Cell Metab 2012; 16:363-77. [PMID: 22958920 DOI: 10.1016/j.cmet.2012.08.005] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Revised: 06/13/2012] [Accepted: 08/16/2012] [Indexed: 01/11/2023]
Abstract
Studying ciliopathies, like the Bardet-Biedl syndrome (BBS), allow the identification of signaling pathways potentially involved in common diseases, sharing phenotypic features like obesity or type 2 diabetes. Given the close association between obesity and insulin resistance, obese BBS patients would be expected to be insulin resistant. Surprisingly, we found that a majority of obese BBS patients retained normal glucose tolerance and insulin sensitivity. Patient's adipose tissue biopsies revealed upregulation of adipogenic genes and decrease of inflammatory mediators. In vitro studies on human primary mesenchymal stem cells (MSCs) showed that BBS12 inactivation facilitated adipogenesis, increased insulin sensitivity, and glucose utilization. We generated a Bbs12(-/-) mouse model to assess the impact of Bbs12 inactivation on adipocyte biology. Despite increased obesity, glucose tolerance was increased with specific enhanced insulin sensitivity in the fat. This correlated with an active recruitment of MSCs resulting in adipose tissue hyperplasia and decreased in inflammation.
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Affiliation(s)
- Vincent Marion
- Laboratoire de Physiopathologie des Syndromes Rares Héréditaires, AVENIR-Inserm, EA3949, Université de Strasbourg, 11 rue Humann, 67085 Strasbourg, France.
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40
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Disruption of inducible 6-phosphofructo-2-kinase impairs the suppressive effect of PPARγ activation on diet-induced intestine inflammatory response. J Nutr Biochem 2012; 24:770-5. [PMID: 22841546 DOI: 10.1016/j.jnutbio.2012.04.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 04/11/2012] [Accepted: 04/16/2012] [Indexed: 12/25/2022]
Abstract
PFKFB3 is a target gene of peroxisome proliferator-activated receptor gamma (PPARγ) and encodes for inducible 6-phosphofructo-2-kinase (iPFK2). As a key regulatory enzyme that stimulates glycolysis, PFKFB3/iPFK2 links adipocyte metabolic and inflammatory responses. Additionally, PFKFB3/iPFK2 is involved in the effect of active PPARγ on suppressing overnutrition-induced adipose tissue inflammatory response, which accounts for the insulin-sensitizing and antidiabetic effects of PPARγ activation. Using PFKFB3/iPFK2-disrupted mice, the present study investigated the role of PFKFB3/iPFK2 in regulating overnutrition-associated intestine inflammatory response and in mediating the effects of PPARγ activation. In wild-type mice, intestine PFKFB3/iPFK2 was increased in response to high-fat diet (HFD) feeding compared with that in mice fed a low-fat diet. However, intestine PFKFB3/iPFK2 was decreased in PFKFB3/iPFK2-disrupted mice and did not respond to HFD feeding. Furthermore, on an HFD, PFKFB3/iPFK2-disrupted mice displayed a significant increase in major intestine proinflammatory indicators such as toll-like receptor 4 expression, c-Jun N-terminal kinase 1 and nuclear factor kappa B phosphorylation, and proinflammatory cytokine expression compared with wild-type littermates. Upon treatment with rosiglitazone, an agonist of PPARγ, intestine proinflammatory indicators were markedly decreased in wild-type mice, but to a much lesser degree in PFKFB3/iPFK2-disrupted mice. Overall, the status of HFD-induced intestine inflammatory response in all treated mice correlated inversely with systemic insulin sensitivity, indicated by the homeostasis model assessment of insulin resistance data. Together, these results suggest that PFKFB3/iPFK2 is critically involved in the effect of PPARγ activation on suppressing diet-induced intestine inflammatory response.
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Tabe Y, Konopleva M, Andreeff M, Ohsaka A. Effects of PPARγ Ligands on Leukemia. PPAR Res 2012; 2012:483656. [PMID: 22685453 PMCID: PMC3364693 DOI: 10.1155/2012/483656] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2012] [Accepted: 03/21/2012] [Indexed: 12/18/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) and retinoic acid receptors (RARs), members of the nuclear receptor superfamily, are transcription factors that regulate a variety of important cellular functions. PPARs form heterodimers retinoid X receptor (RXR), an obligate heterodimeric partner for other nuclear receptors. Several novel links between retinoid metabolism and PPAR responses have been identified, and activation of PPAR/RXR expression has been shown to increase response to retinoids. PPARγ has emerged as a key regulator of cell growth and survival, whose activity is modulated by a number of synthetic and natural ligands. While clinical trials in cancer patients with thiazolidinediones (TZD) have been disappointing, novel structurally different PPARγ ligands, including triterpenoids, have entered clinical arena as therapeutic agents for epithelial and hematopoietic malignancies. Here we shall review the antitumor advances of PPARγ, alone and in combination with RARα ligands in control of cell proliferation, differentiation, and apoptosis and their potential therapeutic applications in hematological malignancies.
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Affiliation(s)
- Yoko Tabe
- Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Marina Konopleva
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Michael Andreeff
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Akimichi Ohsaka
- Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan
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FSP27 promotes lipid droplet clustering and then fusion to regulate triglyceride accumulation. PLoS One 2011; 6:e28614. [PMID: 22194867 PMCID: PMC3237475 DOI: 10.1371/journal.pone.0028614] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 11/11/2011] [Indexed: 02/08/2023] Open
Abstract
Fat Specific Protein 27 (FSP27), a lipid droplet (LD) associated protein in adipocytes, regulates triglyceride (TG) storage. In the present study we demonstrate that FSP27 plays a key role in LD morphology to accumulate TGs. We show here that FSP27 promotes clustering of the LDs which is followed by their fusion into fewer and enlarged droplets. To map the domains of FSP27 responsible for these events, we generated GFP-fusion constructs of deletion mutants of FSP27. Microscopic analysis revealed that amino acids 173–220 of FSP27 are necessary and sufficient for both the targeting of FSP27 to LDs and the initial clustering of the droplets. Amino acids 120–140 are essential but not sufficient for LD enlargement, whereas amino acids 120–210 are necessary and sufficient for both clustering and fusion of LDs to form enlarged droplets. In addition, we found that FSP27-mediated enlargement of LDs, but not their clustering, is associated with triglyceride accumulation. These results suggest a model in which FSP27 facilitates LD clustering and then promotes their fusion to form enlarged droplets in two discrete, sequential steps, and a subsequent triglyceride accumulation.
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Liu W, Lau F, Liu K, Wood HB, Zhou G, Chen Y, Li Y, Akiyama TE, Castriota G, Einstein M, Wang C, McCann ME, Doebber TW, Wu M, Chang CH, McNamara L, McKeever B, Mosley RT, Berger JP, Meinke PT. Benzimidazolones: a new class of selective peroxisome proliferator-activated receptor γ (PPARγ) modulators. J Med Chem 2011; 54:8541-54. [PMID: 22070604 DOI: 10.1021/jm201061j] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPARγ modulators (SPPARγMs) as potential therapeutic agents for the treatment of type II diabetes mellitus (T2DM) with improved safety profiles relative to rosiglitazone and pioglitazone, the currently marketed PPARγ full agonist drugs. Structure-activity relationships of these potent and highly selective SPPARγMs were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPARγ transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPARγ receptor in comparison to full agonists. In rodent models of T2DM, benzimidazolone analogues such as (5R)-5-(3-{[3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl]methyl}phenyl)-5-methyloxazolidinedione (51) demonstrated efficacy equivalent to that of rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPARγ full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.
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Affiliation(s)
- Weiguo Liu
- Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States.
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Saraf N, Sharma PK, Mondal SC, Garg VK, Singh AK. Role of PPARg2 transcription factor in thiazolidinedione-induced insulin sensitization. ACTA ACUST UNITED AC 2011; 64:161-71. [PMID: 22221092 DOI: 10.1111/j.2042-7158.2011.01366.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Adipose tissue is the key regulator of energy balance, playing an active role in lipid storage and metabolism and may be a dynamic buffer to control fatty acid flux. Peroxisome proliferator-activated receptor gamma isoform-2 (PPARg2), an isoform of the nuclear hormone receptor superfamily, has been implicated in almost all aspects of human metabolic alterations such as obesity, insulin resistance, type-2 diabetes and dyslipidaemia. The PPARg2 isoform is highly present in adipose tissue where it functions as a thrifty phenotype, which promotes adipocyte differentiation and triglyceride storage. Thiazolidinediones, antidiabetic drugs, induce insulin sensitivity by controlling adipokines. The thiazolidinediones bind with PPARg2 in adipocytes and exert an agonist effect by enhancing adipogenesis and fatty acid uptake. Thiazolidinediones stimulate PPARg2, by which they down-regulate tumour necrosis factor-α, leptin, interleukin-6 and plasminogen and also enhance insulin sensitivity. The aim of this work is to define role of PPARg2 transcription factor in thiazolidinedione-induced insulin sensitization. KEY FINDINGS The PPARg2 alters the transcription of the target gene. This altered gene transcription results in the up-regulation of insulin-sensitizing factors and down-regulation of insulin-resistant factors. The variant Pro12Ala of the PPARg2 gene is an important modulator in metabolic control in the body. Thiazolidinediones stimulate PPARg2 transcription factor by which PPARg2 binds to responsive elements located in the promoter regions of many genes and modulates their transcriptive activity. There is a strong mutual relationship between receptor binding and agonism, which is evidence of the insulin-sensitizing target of thiazolidinediones in PPARg2. This evidently increases the biological potency of the glucose-lowering effect of thiazolidinediones in vivo as well as their antidiabetic activity. CONCLUSIONS PPARg2 transcription factor plays an important role in treatment of type-2 diabetes with thiazolidindiones. The variant Pro12Ala of the PPARg2 gene promotes the activity of thiazolidinediones in minimizing insulin resistance. Transcriptional activity of Pro12Ala variant improves the activity of insulin. Thus thiazolidinediones promote the phosphorylation of PPARg2 to induce insulin sensitivity.
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Affiliation(s)
- Neha Saraf
- Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut (UP), India.
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Transcriptional Control of Vascular Smooth Muscle Cell Proliferation by Peroxisome Proliferator-Activated Receptor-gamma: Therapeutic Implications for Cardiovascular Diseases. PPAR Res 2011; 2008:429123. [PMID: 18288288 PMCID: PMC2225465 DOI: 10.1155/2008/429123] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2007] [Accepted: 10/24/2007] [Indexed: 12/14/2022] Open
Abstract
Proliferation of vascular smooth muscle cells (SMCs) is a critical process for the development of atherosclerosis and complications of procedures used to treat atherosclerotic diseases, including postangioplasty restenosis, vein graft failure, and transplant vasculopathy. Peroxisome proliferator-activated receptor (PPAR) gamma is a member of the nuclear hormone receptor superfamily and the molecular target for the thiazolidinediones (TZD), used clinically to treat insulin resistance in patients with type 2 diabetes. In addition to their efficacy to improve insulin sensitivity, TZD exert a broad spectrum of pleiotropic beneficial effects on vascular gene expression programs. In SMCs, PPARgamma is prominently upregulated during neointima formation and suppresses the proliferative response to injury of the arterial wall. Among the molecular target genes regulated by PPARgamma in SMCs are genes encoding proteins involved in the regulation of cell-cycle progression, cellular senescence, and apoptosis. This inhibition of SMC proliferation is likely to contribute to the prevention of atherosclerosis and postangioplasty restenosis observed in animal models and proof-of-concept clinical studies. This review will summarize the transcriptional target genes regulated by PPARgamma in SMCs and outline the therapeutic implications of PPARgamma activation for the treatment and prevention of atherosclerosis and its complications.
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Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and ligand-activated transcription factors. PPARγ plays an important role in adipocyte differentiation, lipid storage and energy dissipation in adipose tissue, and is involved in the control of inflammatory reactions as well as in glucose metabolism through the improvement of insulin sensitivity. Growing evidence has demonstrated that activation of PPARγ has an antineoplastic effect in tumors, including colorectal cancer. High expression of PPARγ is detected in human colon cancer cell lines and adenocarcinoma. This review describes the molecular mechanisms by which PPARγ regulates tumorigenesis in colorectal cancer, and examines current clinical trials evaluating PPARγ agonists as therapeutic agents for colorectal cancer.
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Affiliation(s)
- Yun Dai
- Yun Dai, Wei-Hong Wang, Department of Gastroenterology, Peking University First Hospital, Beijing 100034, China
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48
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Szentandrássy N, Harmati G, Bárándi L, Simkó J, Horváth B, Magyar J, Bányász T, Lorincz I, Szebeni A, Kecskeméti V, Nánási PP. Effects of rosiglitazone on the configuration of action potentials and ion currents in canine ventricular cells. Br J Pharmacol 2011; 163:499-509. [PMID: 21232044 PMCID: PMC3101613 DOI: 10.1111/j.1476-5381.2011.01215.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2010] [Revised: 10/21/2010] [Accepted: 10/28/2010] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND PURPOSE In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the antidiabetic drug rosiglitazone in larger experimental animals. In the present study therefore concentration-dependent effects of rosiglitazone on action potential morphology and the underlying ion currents were studied in dog hearts. EXPERIMENTAL APPROACH Standard microelectrode techniques, conventional whole cell patch clamp and action potential voltage clamp techniques were applied in enzymatically dispersed ventricular cells from dog hearts. KEY RESULTS At concentrations ≥10 µM rosiglitazone decreased the amplitude of phase-1 repolarization, reduced the maximum velocity of depolarization and caused depression of the plateau potential. These effects developed rapidly and were readily reversible upon washout. Rosiglitazone suppressed several transmembrane ion currents, concentration-dependently, under conventional voltage clamp conditions and altered their kinetic properties. The EC(50) value for this inhibition was 25.2 ± 2.7 µM for the transient outward K(+) current (I(to)), 72.3 ± 9.3 µM for the rapid delayed rectifier K(+) current (I(Kr)) and 82.5 ± 9.4 µM for the L-type Ca(2+) current (I(Ca) ) with Hill coefficients close to unity. The inward rectifier K(+) current (I(K1)) was not affected by rosiglitazone up to concentrations of 100 µM. Suppression of I(to), I(Kr), and I(Ca) was confirmed also under action potential voltage clamp conditions. CONCLUSIONS AND IMPLICATIONS Alterations in the densities and kinetic properties of ion currents may carry serious pro-arrhythmic risk in case of overdose with rosiglitazone, especially in patients having multiple cardiovascular risk factors, like elderly diabetic patients.
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Stopponi S, Somaini L, Cippitelli A, Cannella N, Braconi S, Kallupi M, Ruggeri B, Heilig M, Demopulos G, Gaitanaris G, Massi M, Ciccocioppo R. Activation of nuclear PPARγ receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking. Biol Psychiatry 2011; 69:642-9. [PMID: 21276964 DOI: 10.1016/j.biopsych.2010.12.010] [Citation(s) in RCA: 117] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Revised: 12/01/2010] [Accepted: 12/01/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pioglitazone and rosiglitazone belong to the class of thiazolidinediones (TZDs). They were first developed as antioxidants and then approved for the clinical treatment of insulin resistance and Type 2 diabetes. TZDs bind with high affinity and activate peroxisome proliferator-activated receptor-gamma (PPARγ) receptors, which in the brain are expressed both in neurons and in glia. METHODS We evaluated the effect of PPARγ activation by TZDs on alcohol drinking, relapse-like behavior, and withdrawal in the rat. We also tested the effect of TZDs on alcohol and saccharin self-administration. RESULTS We showed that activation of PPARγ receptors by pioglitazone (0, 10, and 30 mg/kg) and rosiglitazone (0, 10 and 30 mg/kg) given orally selectively reduced alcohol drinking. The effect was blocked by pretreatment with the selective PPARγ antagonist GW9662 (5 μg/rat) given into the lateral cerebroventricle, suggesting that this TZD's effect is mediated by PPARγ receptors in the central nervous system. Pioglitazone abolished reinstatement of alcohol seeking, a relapse-like behavior, induced by yohimbine, a pharmacologic stressor, but did not affect cue-induced relapse. In the self-administration experiments, pioglitazone reduced lever pressing for alcohol but not for saccharin. Finally, pioglitazone prevented the expression of somatic signs of alcohol withdrawal. CONCLUSIONS These findings provide new information about the role of brain PPARγ receptors and identify pioglitazone as candidate treatments for alcoholism and possibly other addictions.
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Affiliation(s)
- Serena Stopponi
- School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy
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Regulation of dectin-1–mediated dendritic cell activation by peroxisome proliferator–activated receptor-gamma ligand troglitazone. Blood 2011; 117:3569-74. [DOI: 10.1182/blood-2010-08-302224] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Abstract
Dectin-1 is the major receptor for fungal β-glucans. The activation of Dectin-1 leads to the up-regulation of surface molecules on dendritic cells (DCs) and cytokine secretion. Furthermore, Dectin-1 is important for the recruitment of leukocytes and the production of inflammatory mediators. Peroxisome proliferator–activated receptor-γ (PPAR-γ) and its ligands, cyclopentenone prostaglandins or thiazolidinediones, have modulatory effects on B-cell, T-cell, and DC function. In the present study, we analyzed the effects of troglitazone (TGZ), a high-affinity synthetic PPAR-γ ligand, on the Dectin-1–mediated activation of monocyte-derived human DCs. Dectin-1–mediated activation of DCs was inhibited by TGZ, as shown by down-regulation of costimulatory molecules and reduced secretion of cytokines and chemokines involved in T-lymphocyte activation. Furthermore, TGZ inhibited the T-cell–stimulatory capacity of DCs. These effects were not due to a diminished expression of Dectin-1 or to a reduced phosphorylation of spleen tyrosine kinase; they were mediated by the inhibition of downstream signaling molecules such as mitogen-activated protein kinases and nuclear factor-κB. Furthermore, curdlan-mediated accumulation of caspase recruitment domain 9 (CARD9) in the cytosol was inhibited by TGZ. Our data demonstrate that the PPAR-γ ligand TGZ inhibits Dectin-1–mediated activation by interfering with CARD9, mitogen-activated protein kinase, and nuclear factor-κB signaling pathways. This confirms their important role as negative-feedback regulators of potentially harmful inflammatory responses.
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