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1
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Latambale G, Juvale K. Thiazolidinedione derivatives: emerging role in cancer therapy. Mol Divers 2025:10.1007/s11030-024-11093-3. [PMID: 39899123 DOI: 10.1007/s11030-024-11093-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 12/19/2024] [Indexed: 02/04/2025]
Abstract
Cancer remains the leading cause of death worldwide, with the Globocan 2022 study reporting an estimated 9.7 million cancer deaths. Without the selectivity built for tumour cells, chemotherapeutic agents could be toxic to non-cancerous cells. Administration of such non-selective cytotoxic compounds causes severe side effects and could lead to death. Improved cancer treatments are required to overcome the limitations of the current cancer treatment. The potential of thiazolidinedione derivatives as anticancer drugs has recently drawn attention, despite their primary use as insulin sensitizers in the treatment of type 2 diabetes. The ability of thiazolidinedione derivatives to alter important molecular pathways implicated in carcinogenesis, such as cell proliferation, apoptosis, angiogenesis, Raf kinase, EGFR and HER-2 kinases, HDAC, COX-2 enzyme and metastasis, is highlighted in this review, which examines the growing relevance of these compounds in cancer treatment. Thiazolidinediones have anti-inflammatory, antioxidant, and antiproliferative properties in a variety of cancer types, including breast, colon, and prostate cancers, via activating the peroxisome proliferator-activated gamma receptor (PPARγ). In addition to examining the safety profile and difficulties in clinical translation, the paper looks at preclinical and clinical research that points to these medicines potential to improve the effectiveness of immunotherapy and chemotherapy. This review highlights the encouraging therapeutic possibilities and structure-activity relationship insight of TZDs for their anticancer activity and highlights the molecular level facets of the 'glitazone' pharmacophore for its anticancer activity.
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Affiliation(s)
- Ganesh Latambale
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, India
| | - Kapil Juvale
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, India.
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2
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Bar-Tana J. TorS - Reframing a rational for type 2 diabetes treatment. Diabetes Metab Res Rev 2024; 40:e3712. [PMID: 37615286 DOI: 10.1002/dmrr.3712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 05/11/2023] [Accepted: 08/04/2023] [Indexed: 08/25/2023]
Abstract
The mammalian target of rapamycin complex 1 syndrome (Tors), paradigm implies an exhaustive cohesive disease entity driven by a hyperactive mTORC1, and which includes obesity, type 2 diabetic hyperglycemia, diabetic dyslipidemia, diabetic cardiomyopathy, diabetic nephropathy, diabetic peripheral neuropathy, hypertension, atherosclerotic cardiovascular disease, non-alcoholic fatty liver disease, some cancers, neurodegeneration, polycystic ovary syndrome, psoriasis and other. The TorS paradigm may account for the efficacy of standard-of-care treatments of type 2 diabetes (T2D) in alleviating the glycaemic and non-glycaemic diseases of TorS in T2D and non-T2D patients. The TorS paradigm may generate novel treatments for TorS diseases.
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Iqbal S, Jabeen F, Kahwa I, Omara T. Suberosin Alleviates Thiazolidinedione-Induced Cardiomyopathy in Diabetic Rats by Inhibiting Ferroptosis via Modulation of ACSL4-LPCAT3 and PI3K-AKT Signaling Pathways. Cardiovasc Toxicol 2023; 23:295-304. [PMID: 37676618 DOI: 10.1007/s12012-023-09804-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/19/2023] [Indexed: 09/08/2023]
Abstract
Thiazolidinediones are useful antidiabetic medications. However, their use is associated with adverse side effects like edema, heart failure and bone fractures. In this study, we investigated the anti-ferroptosis effects of suberosin (SBR; a prenylated coumarin) in diabetic Sprague Dawley rats. Further, we assessed the effects of co-administration of SBR (30 and 90 mg/kg/day) with thiazolidinedione (TZ at 15 mg/kg) to mitigate TZ-induced cardiomyopathy in diabetic rats. Our results showed that cardiac output, stroke volume, left ventricle systolic and diastolic pressures were aggravated in diabetic rats treated with TZ alone after 4 weeks. TZ treatments induced ferroptosis as well as marked histoarchitecture disarrangements in rat cardiomyocytes. The study found that optimizing volume overload alleviated cardiac hypertrophy and mitigated left ventricular dysfunction in diabetic rats co-treated with SBR. SBR co-administration with TZ reduced MDA levels in heart tissue and serum iron concentration (biomarkers of ferroptosis), downregulated mRNA expressions of LOX, ACSL4, LPCAT3, and promoted GPX4 activity as well as upregulated mRNA levels of AKT/PI3K/GSK3β as compared to the group administered with TZ at 15 mg/kg. SBR co-administration also helped to retain the normal histoarchitecture of cardiomyocytes in diabetic rats. Hence, our results suggested that SBR is an effective supplement and could be prescribed to diabetic patients along with TZ but this requires further clinical trials.
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Affiliation(s)
- Shabnoor Iqbal
- Department of Zoology, Government College University Faisalabad, Pakistan Government College University, Faisalabad, Pakistan.
| | - Farhat Jabeen
- Department of Zoology, Government College University Faisalabad, Pakistan Government College University, Faisalabad, Pakistan
| | - Ivan Kahwa
- Pharma-Biotechnology and Traditional Medicine Center, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Timothy Omara
- Department of Chemistry and Biochemistry, School of Sciences and Aerospace Studies, Moi University, P.O. Box 3900, Eldoret, Kenya
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Souza-Tavares H, Miranda CS, Vasques-Monteiro IML, Sandoval C, Santana-Oliveira DA, Silva-Veiga FM, Fernandes-da-Silva A, Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas. World J Gastroenterol 2023; 29:4136-4155. [PMID: 37475842 PMCID: PMC10354577 DOI: 10.3748/wjg.v29.i26.4136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.
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Affiliation(s)
| | | | | | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Osorno 5310431, Chile
- Departamento de Ciencias Preclínicas, Universidad de la Frontera, Temuco 4780000, Chile
| | | | | | | | - Vanessa Souza-Mello
- Department of Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil
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5
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Chang CH, Fan KC, Cheng YP, Chen JC, Chen GS. Ultrasound Stimulation Potentiates Management of Diabetic Hyperglycemia. ULTRASOUND IN MEDICINE & BIOLOGY 2023; 49:1259-1267. [PMID: 36801179 DOI: 10.1016/j.ultrasmedbio.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 01/05/2023] [Accepted: 01/17/2023] [Indexed: 05/11/2023]
Abstract
OBJECTIVE Glucose homeostasis is the only way to manage diabetic progression as all medications used do not cure diabetes. This study was aimed at verifying the feasibility of lowering glucose with non-invasive ultrasonic stimulation. METHODS The ultrasonic device was homemade and controlled via a mobile application on the smartphone. Diabetes was induced in Sprague-Dawley rats through high-fat diets followed by streptozotocin injection. The treated acupoint CV12 was at the middle of the xiphoid and umbilicus of the diabetic rats. Parameters of ultrasonic stimulation were an operating frequency of 1 MHz, pulse repetition frequency of 15 Hz, duty cycle of 10% and sonication time of 30 min for a single treatment. DISCUSSION The diabetic rats exhibited a significant decrease of 11.5% ± 3.6% in blood glucose in 5 min of ultrasonic stimulation (p < 0.001). After the single treatment on the first day, third day and fifth day in the first week, the treated diabetic rats had a significantly small area under the curve of the glucose tolerance test (p < 0.05) compared with the untreated diabetic rats in the sixth week. Hematological analyses indicated that the serum concentrations of β-endorphin were significantly increased by 58% ± 71.9% (p < 0.05) and the insulin level was increased by 56% ± 88.2% (p = 0.15) without statistical significance after a single treatment. CONCLUSION Therefore, non-invasive ultrasound stimulation at an appropriate dose can produce a hypoglycemic effect and improve glucose tolerance for glucose homeostasis and may play a role as adjuvant therapy with diabetic medications in the future.
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Affiliation(s)
- Chia-Hsuan Chang
- Graduate Degree Program of the College of Electrical and Computer Engineering, National Yang Ming Chiao Tung University, Hsinchu City, Taiwan; Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County, Taiwan
| | - Kang-Chih Fan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - Yuan-Pin Cheng
- Electronic Systems Research Division, National Chung-Shan Institute of Technology, Taoyuan City, Taiwan
| | - Jung-Chih Chen
- Institute of Biomedical Engineering, National Yang Ming Chiao Tung University, Hsinchu City, Taiwan; Department of Electrical and Computer Engineering, National Yang Ming Chiao Tung University, Hsinchu City, Taiwan; Catholic Mercy Hospital, Catholic Mercy Medical Foundation, Hsinchu County, Taiwan; Medical Device Innovation & Translation Center, National Yang Ming Chiao Tung University, Hsinchu City, Taiwan
| | - Gin-Shin Chen
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County, Taiwan; Institute of Biomedical Engineering, National Yang Ming Chiao Tung University, Hsinchu City, Taiwan.
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Ballav S, Biswas B, Sahu VK, Ranjan A, Basu S. PPAR-γ Partial Agonists in Disease-Fate Decision with Special Reference to Cancer. Cells 2022; 11:3215. [PMID: 36291082 PMCID: PMC9601205 DOI: 10.3390/cells11203215] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/03/2022] [Accepted: 10/09/2022] [Indexed: 11/16/2023] Open
Abstract
Peroxisome proliferator-activated receptor-γ (PPAR-γ) has emerged as one of the most extensively studied transcription factors since its discovery in 1990, highlighting its importance in the etiology and treatment of numerous diseases involving various types of cancer, type 2 diabetes mellitus, autoimmune, dermatological and cardiovascular disorders. Ligands are regarded as the key determinant for the tissue-specific activation of PPAR-γ. However, the mechanism governing this process is merely a contradictory debate which is yet to be systematically researched. Either these receptors get weakly activated by endogenous or natural ligands or leads to a direct over-activation process by synthetic ligands, serving as complete full agonists. Therefore, fine-tuning on the action of PPAR-γ and more subtle modulation can be a rewarding approach which might open new avenues for the treatment of several diseases. In the recent era, researchers have sought to develop safer partial PPAR-γ agonists in order to dodge the toxicity induced by full agonists, akin to a balanced activation. With a particular reference to cancer, this review concentrates on the therapeutic role of partial agonists, especially in cancer treatment. Additionally, a timely examination of their efficacy on various other disease-fate decisions has been also discussed.
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Affiliation(s)
- Sangeeta Ballav
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Bini Biswas
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Vishal Kumar Sahu
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Amit Ranjan
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Soumya Basu
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
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Zainal AA, Merkhan MM. IMPACT OF ANTIDIABETIC DRUGS ON RISK AND OUTCOME OF COVID-19 INFECTION: A REVIEW. MILITARY MEDICAL SCIENCE LETTERS 2022; 91:140-160. [DOI: 10.31482/mmsl.2022.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Chen M, Zhu H, Zhu Q, Wu X, Zhou Y, Gao R, Shi M, Zhang T, Yin T, Zhang H, Shang H, Li X. Citri Reticulatae Pericarpium alleviates postmyocardial infarction heart failure by upregulating PPARγ expression. Clin Exp Pharmacol Physiol 2022; 49:661-673. [PMID: 35278230 DOI: 10.1111/1440-1681.13642] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 01/24/2022] [Accepted: 03/07/2022] [Indexed: 11/30/2022]
Abstract
Heart failure after myocardial infarction (MI) is the leading cause of death worldwide. Citri Reticulatae Pericarpium (CRP) is a traditional Chinese herbal medicine that has been used in the clinic for centuries. In this study, we aimed to investigate the roles of CRP in cardiac remodeling and heart failure after MI, as well as the molecular mechanisms involved. Male C57BL/6 mice aged 8 weeks were subjected to coronary artery ligation to mimic the clinical situation in vivo. Echocardiography was used to assess the systolic function of the mouse heart. Masson trichrome staining and Wheat germ agglutinin (WGA) staining were utilized to determine the fibrotic area and cross-sectional area of the mouse heart, respectively. Cardiomyocytes and fibroblasts were isolated from neonatal rats aged 0-3 days in vitro using enzyme digestion. TUNEL staining and EdU staining were performed to evaluate apoptosis and proliferation, respectively. Gene expression changes were analyzed by qRT-PCR, and protein expression changes were assessed by Western blotting. Our findings revealed that CRP attenuated cardiac hypertrophy, fibrosis and apoptosis and alleviated heart failure after MI in vivo. Furthermore, CRP mitigated cardiomyocyte apoptosis and fibroblast proliferation and differentiation into myofibroblasts. In addition, the PPARγ inhibitor T0070907 completely abolished the abovementioned beneficial effects of CRP, and the PPARγ activator rosiglitazone failed to further ameliorate cardiac apoptosis and fibrosis in vitro. CRP alleviates cardiac hypertrophy, fibrosis, and apoptosis and can ameliorate heart failure after MI via activation of PPARγ. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Mengli Chen
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hongyan Zhu
- Department of Pediatric Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qingqing Zhu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaodong Wu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yufei Zhou
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Rongrong Gao
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mengsha Shi
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ting Zhang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ting Yin
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haifeng Zhang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University
| | - Hongcai Shang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xinli Li
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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9
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Mizuno T, Satoh N, Horita S, Tsukada H, Takagi M, Sato Y, Kume H, Nangaku M, Nakamura M. Oxidized alkyl phospholipids stimulate sodium transport in proximal tubules via a non-genomic PPARγ-dependent pathway. J Biol Chem 2022; 298:101681. [PMID: 35124009 PMCID: PMC8892145 DOI: 10.1016/j.jbc.2022.101681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/29/2022] [Accepted: 02/01/2022] [Indexed: 11/22/2022] Open
Abstract
Oxidized phospholipids have been shown to exhibit pleiotropic effects in numerous biological contexts. For example, 1-O-hexadecyl-2-azelaoyl-sn-glycero-3-phosphocholine (azPC), an oxidized phospholipid formed from alkyl phosphatidylcholines, is a peroxisome proliferator–activated receptor gamma (PPARγ) nuclear receptor agonist. Although it has been reported that PPARγ agonists including thiazolidinediones can induce plasma volume expansion by enhancing renal sodium and water retention, the role of azPC in renal transport functions is unknown. In the present study, we investigated the effect of azPC on renal proximal tubule (PT) transport using isolated PTs and kidney cortex tissues and also investigated the effect of azPC on renal sodium handling in vivo. We showed using a microperfusion technique that azPC rapidly stimulated Na+/HCO3− cotransporter 1 (NBCe1) and luminal Na+/H+ exchanger (NHE) activities in a dose-dependent manner at submicromolar concentrations in isolated PTs from rats and humans. The rapid effects (within a few minutes) suggest that azPC activates NBCe1 and NHE via nongenomic signaling. The stimulatory effects were completely blocked by specific PPARγ antagonist GW9662, ERK kinase inhibitor PD98059, and CD36 inhibitor sulfosuccinimidyl oleate. Treatment with an siRNA against PPAR gamma completely blocked the stimulation of both NBCe1 and NHE by azPC. Moreover, azPC induced ERK phosphorylation in rat and human kidney cortex tissues, which were completely suppressed by GW9662 and PD98059 treatments. These results suggest that azPC stimulates renal PT sodium-coupled bicarbonate transport via a CD36/PPARγ/mitogen-activated protein/ERK kinase/ERK pathway. We conclude that the stimulatory effects of azPC on PT transport may be partially involved in volume expansion.
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10
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Frkic RL, Richter K, Bruning JB. The therapeutic potential of inhibiting PPARγ phosphorylation to treat type 2 diabetes. J Biol Chem 2021; 297:101030. [PMID: 34339734 PMCID: PMC8387755 DOI: 10.1016/j.jbc.2021.101030] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 11/30/2022] Open
Abstract
A promising approach for treating type 2 diabetes mellitus (T2DM) is to target the Peroxisome Proliferator-Activated Receptor γ (PPARγ) transcription factor, which regulates the expression of proteins critical for T2DM. Mechanisms involved in PPARγ signaling are poorly understood, yet globally increasing T2DM prevalence demands improvements in drug design. Synthetic, nonactivating PPARγ ligands can abolish the phosphorylation of PPARγ at Ser273, a posttranslational modification correlated with obesity and insulin resistance. It is not understood how these ligands prevent phosphorylation, and the lack of experimental mechanistic information can be attributed to previous ambiguity in the field as well as to limitations in experimental approaches; in silico modeling currently provides the only insight into how ligands block Ser273 phosphorylation. The future availability of experimental evidence is critical for clarifying the mechanism by which ligands prevent phosphorylation and should be the priority of future T2DM-focused research. Following this, the properties of ligands that enable them to block phosphorylation can be improved upon to generate ligands tailored for blocking phosphorylation and therefore restoring insulin sensitivity. This would represent a significant step forward for treating T2DM. This review summarizes current knowledge of the roles of PPARγ in T2DM as well as the effects of synthetic ligands on the modulation of these roles. We hypothesize potential factors that contribute to the reduction in recent developments and summarize what has currently been done to shed light on this critical field of research.
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Affiliation(s)
- Rebecca L Frkic
- The Institute for Photonics and Advanced Sensing, and School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Katharina Richter
- Richter Lab, Department of Surgery, Basil Hetzel Institute for Translational Health Research, The University of Adelaide, Adelaide, South Australia, Australia
| | - John B Bruning
- The Institute for Photonics and Advanced Sensing, and School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
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Effects of SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone on fluid retention in type 2 diabetic mice with NASH. Eur J Pharmacol 2021; 901:174076. [PMID: 33798599 DOI: 10.1016/j.ejphar.2021.174076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/22/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022]
Abstract
Several antidiabetic agents, including thiazolidinediones and sodium-glucose cotransporter (SGLT) 2 inhibitors, attenuate the symptoms of nonalcoholic steatohepatitis (NASH). However, thiazolidinediones have serious side effects such as fluid retention and increased risk of congestive heart failure. We examined the effects of SGLT2 inhibitor ipragliflozin, pioglitazone, and ipragliflozin + pioglitazone on fluid retention in type 2 diabetic mice with NASH. Four-week repeated administration of pioglitazone caused significant increases in heart weight (31% increase in 30 mg/kg pioglitazone-treated group compared to vehicle-treated group) concomitant with fluid retention, as estimated by a decrease in plasma osmolality and increase in water intake/urine volume ratio. In addition, pioglitazone significantly increased (by 1.5 to 2-fold) mRNA expression of α, β, and γ subtypes of ENaC and AQP2 and 3 subtypes in the renal medulla. Thus, pioglitazone-induced fluid retention may arise from enhanced reabsorption of sodium and water associated with increased expression of these channels in the kidney. In contrast, ipragliflozin alone did not induce these symptoms and did not affect ENaC or AQP expression. Combination treatment with ipragliflozin + pioglitazone attenuated these symptoms by ipragliflozin-induced osmotic diuresis. These findings demonstrate that treatment with ipragliflozin monotherapy or coadministered with pioglitazone may be a potential therapeutic option for the treatment of type 2 diabetes with NASH without fluid retention as a side effect.
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12
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Pessoa EDA, Convento MB, Castino B, Leme AM, de Oliveira AS, Aragão A, Fernandes SM, Carbonel A, Dezoti C, Vattimo MDF, Schor N, Borges FT. Beneficial Effects of Isoflavones in the Kidney of Obese Rats Are Mediated by PPAR-Gamma Expression. Nutrients 2020; 12:nu12061624. [PMID: 32492810 PMCID: PMC7352183 DOI: 10.3390/nu12061624] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/29/2020] [Accepted: 05/29/2020] [Indexed: 12/17/2022] Open
Abstract
Several studies have demonstrated an important association between altered lipid metabolism and the development of kidney injury because of a high-fat diet. Fructose is also closely associated with renal injury. We opted for a combination of fructose and saturated fats in a diet (DH) that is a model known to induce renal damage in order to evaluate whether soy isoflavones could have promising use in the treatment of renal alterations. After two months of ingestion, there was an expansion of visceral fat, which was associated with long-term metabolic disorders, such as sustained hyperglycemia, insulin resistance, polyuria, dyslipidemia, and hypertension. Additionally, we found a decrease in renal blood flow and an increase in renal vascular resistance. Biochemical markers of chronic kidney disease were detected; there was an infiltration of inflammatory cells with an elevated expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-6, and IL-1β), the activation of the renin–angiotensin system, and oxidative/nitrosative stress. Notably, in rats exposed to the DH diet for 120 days, the concomitant treatment with isoflavones after 60 days was able to revert metabolic parameters, renal alterations, and oxidative/nitrosative stress. The beneficial effects of isoflavones in the kidney of the obese rats were found to be mediated by expression of peroxisome proliferator-activated receptor gamma (PPAR-γ).
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Affiliation(s)
- Edson de Andrade Pessoa
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo SP 04023-900, Brazil; (E.d.A.P.); (M.B.C.); (A.M.L.); (A.S.d.O.); (N.S.)
| | - Márcia Bastos Convento
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo SP 04023-900, Brazil; (E.d.A.P.); (M.B.C.); (A.M.L.); (A.S.d.O.); (N.S.)
| | - Bianca Castino
- Interdisciplinary Postgraduate Program in Health Sciences, Universidade Cruzeiro do Sul, São Paulo SP 01506-000, Brazil; (B.C.); (A.A.)
| | - Ala Moana Leme
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo SP 04023-900, Brazil; (E.d.A.P.); (M.B.C.); (A.M.L.); (A.S.d.O.); (N.S.)
| | - Andréia Silva de Oliveira
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo SP 04023-900, Brazil; (E.d.A.P.); (M.B.C.); (A.M.L.); (A.S.d.O.); (N.S.)
| | - Alef Aragão
- Interdisciplinary Postgraduate Program in Health Sciences, Universidade Cruzeiro do Sul, São Paulo SP 01506-000, Brazil; (B.C.); (A.A.)
| | - Sheila Marques Fernandes
- Experimentation Laboratory in Animal Model, School of Nursing, Universidade de São Paulo, São Paulo SP 05403-000, Brazil; (S.M.F.); (C.D.)
| | - Adriana Carbonel
- Histology and Structural Biology Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo SP 04039-032, Brazil;
| | - Cassiane Dezoti
- Experimentation Laboratory in Animal Model, School of Nursing, Universidade de São Paulo, São Paulo SP 05403-000, Brazil; (S.M.F.); (C.D.)
| | - Maria de Fátima Vattimo
- Department Medical-Surgical Nursing, School of Nursing, Universidade de São Paulo, São Paulo SP 05403-000, Brazil;
| | - Nestor Schor
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo SP 04023-900, Brazil; (E.d.A.P.); (M.B.C.); (A.M.L.); (A.S.d.O.); (N.S.)
| | - Fernanda Teixeira Borges
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo SP 04023-900, Brazil; (E.d.A.P.); (M.B.C.); (A.M.L.); (A.S.d.O.); (N.S.)
- Interdisciplinary Postgraduate Program in Health Sciences, Universidade Cruzeiro do Sul, São Paulo SP 01506-000, Brazil; (B.C.); (A.A.)
- Correspondence: ; Tel.: +55-11-5576-4242
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Xue J, Liu W, Shi F, Zheng J, Ma J. Pleural Effusion Due to Use of Pioglitazone: A Case Report. Metab Syndr Relat Disord 2020; 18:168-171. [PMID: 32250209 DOI: 10.1089/met.2019.0109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Affiliation(s)
- Jinhui Xue
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Wei Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Fanghong Shi
- Department of Pharmacy, Shanghai Jiao Tong University School of Medicine, Affiliated Renji Hospital, Shanghai, China
| | - Jun Zheng
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Jing Ma
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
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Identification and Characterization of Cannabimovone, a Cannabinoid from Cannabis sativa, as a Novel PPARγ Agonist via a Combined Computational and Functional Study. Molecules 2020; 25:molecules25051119. [PMID: 32138197 PMCID: PMC7179127 DOI: 10.3390/molecules25051119] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 02/28/2020] [Accepted: 03/01/2020] [Indexed: 12/28/2022] Open
Abstract
Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and CBD are also well-known agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor involved in energy homeostasis and lipid metabolism. In the search of new pCBs potentially acting as PPARγ agonists, we identified cannabimovone (CBM), a structurally unique abeo-menthane pCB, as a novel PPARγ modulator via a combined computational and experimental approach. The ability of CBM to act as dual PPARγ/α agonist was also evaluated. Computational studies suggested a different binding mode toward the two isoforms, with the compound able to recapitulate the pattern of H-bonds of a canonical agonist only in the case of PPARγ. Luciferase assays confirmed the computational results, showing a selective activation of PPARγ by CBM in the low micromolar range. CBM promoted the expression of PPARγ target genes regulating the adipocyte differentiation and prevented palmitate-induced insulin signaling impairment. Altogether, these results candidate CBM as a novel bioactive compound potentially useful for the treatment of insulin resistance-related disorders.
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15
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Impact of discontinuation of fish oil after pioglitazone–fish oil combination therapy in diabetic KK mice. J Nutr Biochem 2020; 76:108265. [DOI: 10.1016/j.jnutbio.2019.108265] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 10/05/2019] [Accepted: 10/29/2019] [Indexed: 12/12/2022]
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16
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Packer M. Do most patients with obesity or type 2 diabetes, and atrial fibrillation, also have undiagnosed heart failure? A critical conceptual framework for understanding mechanisms and improving diagnosis and treatment. Eur J Heart Fail 2019; 22:214-227. [PMID: 31849132 DOI: 10.1002/ejhf.1646] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 09/14/2019] [Accepted: 09/20/2019] [Indexed: 02/06/2023] Open
Abstract
Obesity and diabetes can lead to heart failure with preserved ejection fraction (HFpEF), potentially because they both cause expansion and inflammation of epicardial adipose tissue and thus lead to microvascular dysfunction and fibrosis of the underlying left ventricle. The same process also causes an atrial myopathy, which is clinically evident as atrial fibrillation (AF); thus, AF may be the first manifestation of HFpEF. Many patients with apparently isolated AF have latent HFpEF or subsequently develop HFpEF. Most patients with obesity or diabetes who have AF and exercise intolerance have increased left atrial pressures at rest or during exercise, even in the absence of diagnosed HFpEF. Among patients with AF, those who also have latent HFpEF have increased risk for systemic thromboembolism and death. The identification of HFpEF in patients with obesity or diabetes alters the risk-to-benefit relationship of commonly prescribed treatments. Bariatric surgery and statins can ameliorate AF and reduce the risk for HFpEF. Conversely, antihyperglycaemic drugs that promote adipogenesis or cause sodium retention (insulin and thiazolidinediones) may increase the risk for heart failure in patients with an underlying ventricular myopathy. Patients with obesity and diabetes who undergo catheter ablation for AF are at increased risk for AF recurrence and for post-ablation increases in pulmonary venous pressures and worsening heart failure, especially if HFpEF coexists. Therefore, AF may be the earliest indicator of HFpEF in patients with obesity or type 2 diabetes, and recognition of HFpEF alters the management of these patients.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA.,Imperial College London, London, UK
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17
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Drugs That Ameliorate Epicardial Adipose Tissue Inflammation May Have Discordant Effects in Heart Failure With a Preserved Ejection Fraction as Compared With a Reduced Ejection Fraction. J Card Fail 2019; 25:986-1003. [DOI: 10.1016/j.cardfail.2019.09.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 08/28/2019] [Accepted: 09/03/2019] [Indexed: 02/08/2023]
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Abstract
PURPOSE OF REVIEW Thiazolidinediones (TZDs) are the only pharmacologic agents that specifically treat insulin resistance. The beneficial effects of TZDs on the cardiovascular risk factors associated with insulin resistance have been well documented. TZD use has been limited because of concern about safety issues and side effects. RECENT FINDINGS Recent studies indicate that cardiovascular toxicity with rosiglitazone and increase in bladder cancer with pioglitazone are no longer significant issues. There are new data which show that pioglitazone treatment reduces myocardial infarctions and ischemic strokes. New data concerning TZD-mediated edema, congestive heart failure, and bone fractures improves the clinician's ability to select patients that will have minimal significant side effects. Thiazolidinediones are now generic and less costly than pharmaceutical company-promoted therapies. Better understanding of the side effects coupled with clear benefits on the components of the insulin resistance syndrome should promote TZD use in treating patients with type 2 diabetes.
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Affiliation(s)
- Harold E Lebovitz
- SUNY Downstate Medical Center, 450 Clarkson Avenue, Box 1205, Brooklyn, NY, 11203, USA.
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19
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Reddy MR, Hemaiswarya S, Kommidi H, Aidhen IS, Doble M. Acyl and Benzyl-C-
β-D-
Glucosides: Synthesis and Biostudies for Glucose-Uptake-Promoting Activity in C2C12 Mytotubes. European J Org Chem 2019. [DOI: 10.1002/ejoc.201901037] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
| | - Shanmugam Hemaiswarya
- Department of Biotechnology; Indian Institute of Technology Madras; 600036 Chennai India
| | - Harikrishna Kommidi
- Department of Chemistry; Indian Institute of Technology Madras; 600036 Chennai India
| | - Indrapal Singh Aidhen
- Department of Chemistry; Indian Institute of Technology Madras; 600036 Chennai India
| | - Mukesh Doble
- Department of Biotechnology; Indian Institute of Technology Madras; 600036 Chennai India
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20
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Cardiac Insulin Resistance in Heart Failure: The Role of Mitochondrial Dynamics. Int J Mol Sci 2019; 20:ijms20143552. [PMID: 31330848 PMCID: PMC6678249 DOI: 10.3390/ijms20143552] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 07/12/2019] [Accepted: 07/18/2019] [Indexed: 12/15/2022] Open
Abstract
Heart failure (HF) frequently coexists with conditions associated with glucose insufficiency, such as insulin resistance and type 2 diabetes mellitus (T2DM), and patients with T2DM have a significantly high incidence of HF. These two closely related diseases cannot be separated on the basis of their treatment. Some antidiabetic drugs failed to improve cardiac outcomes in T2DM patients, despite lowering glucose levels sufficiently. This may be, at least in part, due to a lack of understanding of cardiac insulin resistance. Basic investigations have revealed the significant contribution of cardiac insulin resistance to the pathogenesis and progression of HF; however, there is no clinical evidence of the definition or treatment of cardiac insulin resistance. Mitochondrial dynamics play an important role in cardiac insulin resistance and HF because they maintain cellular homeostasis through energy production, cell survival, and cell proliferation. The innovation of diagnostic tools and/or treatment targeting mitochondrial dynamics is assumed to improve not only the insulin sensitivity of the myocardium and cardiac metabolism, but also the cardiac contraction function. In this review, we summarized the current knowledge on the correlation between cardiac insulin resistance and progression of HF, and discussed the role of mitochondrial dynamics on the pathogenesis of cardiac insulin resistance and HF. We further discuss the possibility of mitochondria-targeted intervention to improve cardiac metabolism and HF.
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21
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Vallée A, Lecarpentier Y, Vallée JN. Targeting the Canonical WNT/β-Catenin Pathway in Cancer Treatment Using Non-Steroidal Anti-Inflammatory Drugs. Cells 2019; 8:cells8070726. [PMID: 31311204 PMCID: PMC6679009 DOI: 10.3390/cells8070726] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 07/11/2019] [Accepted: 07/14/2019] [Indexed: 12/19/2022] Open
Abstract
Chronic inflammation and oxidative stress are common and co-substantial pathological processes accompanying and contributing to cancers. Numerous epidemiological studies have indicated that non-steroidal anti-inflammatory drugs (NSAIDs) could have a positive effect on both the prevention of cancer and tumor therapy. Numerous hypotheses have postulated that NSAIDs could slow tumor growth by acting on both chronic inflammation and oxidative stress. This review takes a closer look at these hypotheses. In the cancer process, one of the major signaling pathways involved is the WNT/β-catenin pathway, which appears to be upregulated. This pathway is closely associated with both chronic inflammation and oxidative stress in cancers. The administration of NSAIDs has been observed to help in the downregulation of the WNT/β-catenin pathway and thus in the control of tumor growth. NSAIDs act as PPARγ agonists. The WNT/β-catenin pathway and PPARγ act in opposing manners. PPARγ agonists can promote cell cycle arrest, cell differentiation, and apoptosis, and can reduce inflammation, oxidative stress, proliferation, invasion, and cell migration. In parallel, the dysregulation of circadian rhythms (CRs) contributes to cancer development through the upregulation of the canonical WNT/β-catenin pathway. By stimulating PPARγ expression, NSAIDs can control CRs through the regulation of many key circadian genes. The administration of NSAIDs in cancer treatment would thus appear to be an interesting therapeutic strategy, which acts through their role in regulating WNT/β-catenin pathway and PPARγ activity levels.
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Affiliation(s)
- Alexandre Vallée
- Diagnosis and Therapeutic Center, Hypertension and Cardiovascular Prevention Unit, Hotel-Dieu Hospital, AP-HP, Université Paris Descartes, 75004 Paris, France.
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), 6-8 rue Saint-fiacre, 77100 Meaux, France
| | - Jean-Noël Vallée
- Centre Hospitalier Universitaire (CHU) Amiens Picardie, Université Picardie Jules Verne (UPJV), 80054 Amiens, France
- Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, 86000 Poitiers, France
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22
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He J, Qi D, Tang XM, Deng W, Deng XY, Zhao Y, Wang DX. Rosiglitazone promotes ENaC-mediated alveolar fluid clearance in acute lung injury through the PPARγ/SGK1 signaling pathway. Cell Mol Biol Lett 2019; 24:35. [PMID: 31160894 PMCID: PMC6540532 DOI: 10.1186/s11658-019-0154-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 04/29/2019] [Indexed: 02/06/2023] Open
Abstract
Background Pulmonary edema is one of the pathological characteristics of acute respiratory distress syndrome (ARDS). The epithelial sodium channel (ENaC) is thought to be the rate-limiting factor for alveolar fluid clearance (AFC) during pulmonary edema. The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone was shown to stimulate ENaC-mediated salt absorption in the kidney. However, its role in the lung remains unclear. Here, we investigated the role of the PPARγ agonist in the lung to find out whether it can regulate AFC during acute lung injury (ALI). We also attempted to elucidate the mechanism for this. Methods Our ALI model was established through intratracheal instillation of lipopolysaccharide (LPS) in C57BL/6 J mice. The mice were randomly divided into 4 groups of 10. The control group underwent a sham operation and received an equal quantity of saline. The three experimental groups underwent intratracheal instillation of 5 mg/kg LPS, followed by intraperitoneal injection of 4 mg/kg rosiglitazone, 4 mg/kg rosiglitazone plus 1 mg/kg GW9662, or only equal quantity of saline. The histological morphology of the lung, the levels of TNF-α and IL-1β in the bronchoalveolar lavage fluid (BALF), the level of AFC, and the expressions of αENaC and serum and glucocorticoid-induced kinase-1 (SGK1) were determined. Type 2 alveolar (AT II) cells were incubated with rosiglitazone (15 μM) with or without GW9662 (10 μM). The expressions of αENaC and SGK1 were determined 24 h later. Results A mouse model of ALI was successfully established. Rosiglitazone significantly ameliorated the lung injury, decreasing the TNF-α and IL-1β levels in the BALF, enhancing AFC, and promoting the expressions of αENaC and SGK1 in ALI mice, which were abolished by the specific PPARγ blocker GW9662. In vitro, rosiglitazone increased the expressions of αENaC and SGK1. This increase was prevented by GW9662. Conclusions Rosiglitazone ameliorated the lung injury and promoted ENaC-mediated AFC via a PPARγ/SGK1-dependent signaling pathway, alleviating pulmonary edema in a mouse model of ALI.
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Affiliation(s)
- Jing He
- Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010 China
| | - Di Qi
- Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010 China
| | - Xu-Mao Tang
- Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010 China
| | - Wang Deng
- Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010 China
| | - Xin-Yu Deng
- Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010 China
| | - Yan Zhao
- Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010 China
| | - Dao-Xin Wang
- Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010 China
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23
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Shinozuka T, Tsukada T, Fujii K, Tokumaru E, Shimada K, Onishi Y, Matsui Y, Wakimoto S, Kuroha M, Ogata T, Araki K, Ohsumi J, Sawamura R, Watanabe N, Yamamoto H, Fujimoto K, Tani Y, Mori M, Tanaka J. Discovery of DS-6930, a potent selective PPARγ modulator. Part I: Lead identification. Bioorg Med Chem 2018; 26:5079-5098. [PMID: 30241907 DOI: 10.1016/j.bmc.2018.09.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/03/2018] [Accepted: 09/05/2018] [Indexed: 01/05/2023]
Abstract
The lead identification of a novel potent selective PPARγ agonist, DS-6930 is reported. To avoid PPARγ-related adverse effects, a partial agonist was designed to prevent the direct interaction with helix 12 of PPARγ-LBD. Because the TZD group is known to interact with helix 12, the TZD in efatutazone (CS-7017) was replaced to discover novel PPARγ intermediate partial agonist 8i. The optimization of 8i yielded 13ac with high potency in vitro. Compound 13ac exhibited robust plasma glucose lowering effects comparable to those of rosiglitazone (3 mg/kg) in Zucker diabetic fatty rats. Upon toxicological evaluation, compound 13ac (300 mg/kg) induced hemodilution to a lower extent than rosiglitazone; however, 13ac elevated liver enzyme activities. X-ray crystallography revealed no direct interaction of 13ac with helix 12, and the additional lipophilic interactions are also suggested to be related to the maximum transcriptional activity of 13ac.
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Affiliation(s)
- Tsuyoshi Shinozuka
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
| | - Tomoharu Tsukada
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Kunihiko Fujii
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Eri Tokumaru
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Kousei Shimada
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Yoshiyuki Onishi
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Yumi Matsui
- Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan
| | - Satoko Wakimoto
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Masanori Kuroha
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Tsuneaki Ogata
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Kazushi Araki
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Jun Ohsumi
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Ryoko Sawamura
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Nobuaki Watanabe
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Hideki Yamamoto
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Kazunori Fujimoto
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Yoshiro Tani
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Makoto Mori
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Jun Tanaka
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
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Kim TH, Lee JH, Chae YN, Jung IH, Kim MK. Additive effects of evogliptin in combination with pioglitazone on fasting glucose control through direct and indirect hepatic effects in diabetic mice. Eur J Pharmacol 2018; 830:95-104. [DOI: 10.1016/j.ejphar.2018.04.033] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 04/26/2018] [Accepted: 04/30/2018] [Indexed: 01/24/2023]
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Interplay between the renin-angiotensin system, the canonical WNT/β-catenin pathway and PPARγ in hypertension. Curr Hypertens Rep 2018; 20:62. [PMID: 29884931 DOI: 10.1007/s11906-018-0860-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Heterogeneous causes can determinate hypertension. RECENT FINDINGS The renin-angiotensin system (RAS) has a major role in the pathophysiology of blood pressure. Angiotensin II and aldosterone are overexpressed during hypertension and lead to hypertension development and its cardiovascular complications. In several tissues, the overactivation of the canonical WNT/β-catenin pathway leads to inactivation of peroxisome proliferator-activated receptor gamma (PPARγ), while PPARγ stimulation induces a decrease of the canonical WNT/β-catenin pathway. In hypertension, the WNT/β-catenin pathway is upregulated, whereas PPARγ is decreased. The WNT/β-catenin pathway and RAS regulate positively each other during hypertension, whereas PPARγ agonists can decrease the expression of both the WNT/β-catenin pathway and RAS. We focus this review on the hypothesis of an opposite interplay between PPARγ and both the canonical WNT/β-catenin pathway and RAS in regulating the molecular mechanism underlying hypertension. The interactions between PPARγ and the canonical WNT/β-catenin pathway through the regulation of the renin-angiotensin system in hypertension may be an interesting way to better understand the actions and the effects of PPARγ agonists as antihypertensive drugs.
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Abstract
PURPOSE OF REVIEW In addition to their effects on glycemic control, two specific classes of relatively new anti-diabetic drugs, namely the sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have demonstrated reduced rates of major adverse cardiovascular events (MACE) in subjects with type 2 diabetes (T2D) at high risk for cardiovascular disease (CVD). This review summarizes recent experimental results that inform putative molecular mechanisms underlying these benefits. RECENT FINDINGS SGLT2i and GLP-1RA exert cardiovascular effects by targeting in both common and distinctive ways (A) several mediators of macro- and microvascular pathophysiology: namely (A1) inflammation and atherogenesis, (A2) oxidative stress-induced endothelial dysfunction, (A3) vascular smooth muscle cell reactive oxygen species (ROS) production and proliferation, and (A4) thrombosis. These agents also exhibit (B) hemodynamic effects through modulation of (B1) natriuresis/diuresis and (B2) the renin-angiotensin-aldosterone system. This review highlights that while GLP-1RA exert direct effects on vascular (endothelial and smooth muscle) cells, the effects of SGLT2i appear to include the activation of signaling pathways that prevent adverse vascular remodeling. Both SGLT2i and GLP-1RA confer hemodynamic effects that counter adverse cardiac remodeling.
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Affiliation(s)
- Dorrin Zarrin Khat
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
| | - Mansoor Husain
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
- Department of Medicine, University of Toronto, Toronto, Canada.
- Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.
- Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada.
- Ted Rogers Centre for Heart Research, University Health Network, Toronto, Canada.
- Peter Munk Cardiac Centre, University Health Network, Toronto, Canada.
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Motohashi Y, Kemmochi Y, Maekawa T, Tadaki H, Sasase T, Tanaka Y, Kakehashi A, Yamada T, Ohta T. Diabetic macular edema-like ocular lesions in male spontaneously diabetic torii fatty rats. Physiol Res 2018. [PMID: 29527913 DOI: 10.33549/physiolres.933709] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Diabetic macular edema (DME) is a major factor contributing to visual disabilities in diabetic patients, and the number of patients is increasing. Animal models play a key role in the development of novel therapies. In this study, pathophysiological analyses of ocular lesions in Spontaneously Diabetic Torii (SDT) fatty rats were performed. First, vascular endothelial growth factor (VEGF) concentrations in vitreous humor, retinal vascular permeability and retinal thickness were measured in SDT fatty rats (Experiment 1). Furthermore, the pharmacological effects of two anti-diabetic drugs, phlorizin and pioglitazone, on retinal lesions were evaluated (Experiment 2). As results, the SDT fatty rats exhibited VEGF increase in vitreous humor at 8 and 16 weeks of age, and both retinal vascular hyperpermeability and retinal thickening at 16 weeks of age. In particular, the layers between the retinal internal limiting membrane and the outer nuclear layer were thickened. Phlorizin treatment from 4 to 16 weeks of age improved hyperglycemia and normalized retinal thickness; however, the effect of pioglitazone on retinal thickness was not strong despite the normalization of hyperglycemia. These data demonstrate that the male SDT fatty rat is a useful model for developing new therapeutic approaches in DME.
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Affiliation(s)
- Y Motohashi
- Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Takatsuki, Osaka, Japan.
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Abstract
Over the past two decades, therapeutics for diabetes have evolved from drugs with known heart failure risk to classes with potential benefit for patients with heart failure. As many as 25 to 35 % of patients with heart failure carry a diagnosis of type 2 diabetes mellitus. Therefore, newer drug classes including dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GIP-1) agonists, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors are being examined for cardiovascular safety as well as their effects on left ventricular function, quality of life, and other measures of disease progression. The purpose of this review is to summarize the existing evidence on these classes of anti-diabetic agents in patients with heart failure.
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Elaidy SM, Hussain MA, El-Kherbetawy MK. Time-dependent therapeutic roles of nitazoxanide on high-fat diet/streptozotocin-induced diabetes in rats: effects on hepatic peroxisome proliferator-activated receptor-gamma receptors. Can J Physiol Pharmacol 2017; 96:485-497. [PMID: 29244961 DOI: 10.1139/cjpp-2017-0533] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Targeting peroxisome proliferator-activated receptor-gamma (PPAR-γ) is an approved strategy in facing insulin resistance (IR) for diabetes mellitus (DM) type 2. The PPAR-γ modulators display improvements in the insulin-sensitizing and adverse effects of the traditional thiazolidinediones. Nitazoxanide (NTZ) is proposed as a PPAR-γ receptor ligand with agonistic post-transcriptional effects. Currently, NTZ antidiabetic activities versus pioglitazone (PIO) in a high-fat diet/streptozotocin rat model of type 2 diabetes was explored. Diabetic adult male Wistar rats were treated orally with either PIO (2.7 mg·kg-1·day-1) or NTZ (200 mg·kg-1·day-1) for 14, 21, and 28 days. Body masses, fasting blood glucose, IR, lipid profiles, and liver and kidney functions of rats were assayed. Hepatic glucose metabolism and PPAR-γ protein expression levels as well as hepatic, pancreatic, muscular, and renal histopathology were evaluated. Significant time-dependent euglycemic and insulin-sensitizing effects with preservation of liver and kidney functions were offered by NTZ. Higher hepatic levels of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase enzymes and PPAR-γ protein expressions were acquired by NTZ and PIO, respectively. NTZ could be considered an oral therapeutic strategy for DM type 2. Further systematic NTZ/PPAR-γ receptor subtype molecular activations are recommended. Simultaneous use of NTZ with other approved antidiabetics should be explored.
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Affiliation(s)
- Samah M Elaidy
- a Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Mona A Hussain
- b Department of Physiology, Faculty of Medicine, Portsaid University, Portsaid, Egypt
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Rajapaksha H, Bhatia H, Wegener K, Petrovsky N, Bruning JB. X-ray crystal structure of rivoglitazone bound to PPARγ and PPAR subtype selectivity of TZDs. Biochim Biophys Acta Gen Subj 2017; 1861:1981-1991. [DOI: 10.1016/j.bbagen.2017.05.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 04/28/2017] [Accepted: 05/08/2017] [Indexed: 01/08/2023]
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Chamarthi B, Cincotta AH. Effect of bromocriptine-QR therapy on glycemic control in subjects with type 2 diabetes mellitus whose dysglycemia is inadequately controlled on insulin. Postgrad Med 2017; 129:446-455. [DOI: 10.1080/00325481.2017.1315290] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Bindu Chamarthi
- VeroScience LLC, Tiverton, RI, USA
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
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Gangopadhyay KK, Singh P. Consensus Statement on Dose Modifications of Antidiabetic Agents in Patients with Hepatic Impairment. Indian J Endocrinol Metab 2017; 21:341-354. [PMID: 28459036 PMCID: PMC5367241 DOI: 10.4103/ijem.ijem_512_16] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver disease is an important cause of mortality in type 2 diabetes mellitus (T2DM). It is estimated that diabetes is the most common cause of liver disease in the United States. Virtually, entire spectrum of liver disease is seen in T2DM including abnormal liver enzymes, nonalcoholic fatty liver disease, cirrhosis, hepatocellular carcinoma, and acute liver failure. The treatment of diabetes mellitus (DM) in cirrhotic patients has particular challenges as follows: (1) about half the patients have malnutrition; (2) patients already have advanced liver disease when clinical DM is diagnosed; (3) most of the oral antidiabetic agents (ADAs) are metabolized in the liver; (4) patients often have episodes of hypoglycemia. The aim of this consensus group convened during the National Insulin Summit 2015, Puducherry, was to focus on the challenges with glycemic management, with particular emphasis to safety of ADAs across stages of liver dysfunction. Published literature, product labels, and major clinical guidelines were reviewed and summarized. The drug classes included are biguanides (metformin), the second- or third-generation sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and currently available insulins. Consensus recommendations have been drafted for glycemic targets and dose modifications of all ADAs. These can aid clinicians in managing patients with diabetes and liver disease.
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Affiliation(s)
| | - Parminder Singh
- Division of Endocrinology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
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Deciphering the Roles of Thiazolidinediones and PPAR γ in Bladder Cancer. PPAR Res 2017; 2017:4810672. [PMID: 28348577 PMCID: PMC5350343 DOI: 10.1155/2017/4810672] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/12/2017] [Indexed: 12/17/2022] Open
Abstract
The use of thiazolidinedione (TZD) therapy in type II diabetic patients has proven useful in the lowering of blood glucose levels. However, recent investigations have shown that there may be potential health concerns associated, including the risk of developing bladder cancer as well as complications in the cardiovasculature. TZDs are ligands for the nuclear receptor PPARγ, and activation causes lipid uptake and insulin sensitization, both of which are critical processes for diabetic patients whose bodies are unable to utilize insulin effectively. Several studies have shown that PPARγ/TZDs decrease IGF-1 levels and, thus, reduce cancer growth in carcinomas such as the pancreas, colon, liver, and prostate. However, other studies have shed light on the potential of the receptor as a biomarker for uroepithelial carcinomas, particularly due to its stimulatory effect on migration of bladder cancer cells. Furthermore, PPARγ may provide the tumor-promoting microenvironment by de novo synthesis of nutrients that are needed for bladder cancer development. In this review, we closely examine the TZD class of drugs and their effects on PPARγ in patient studies along with additional molecular factors that are positive modulators, such as protein phosphatase 5 (PP5), which may have considerable implications for bladder cancer therapy.
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Toffoli B, Gilardi F, Winkler C, Soderberg M, Kowalczuk L, Arsenijevic Y, Bamberg K, Bonny O, Desvergne B. Nephropathy in Pparg-null mice highlights PPARγ systemic activities in metabolism and in the immune system. PLoS One 2017; 12:e0171474. [PMID: 28182703 PMCID: PMC5300244 DOI: 10.1371/journal.pone.0171474] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 01/20/2017] [Indexed: 01/10/2023] Open
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor involved in many aspects of metabolism, immune response, and development. Total-body deletion of the two Pparg alleles provoked generalized lipoatrophy along with severe type 2 diabetes. Herein, we explore the appearance and development of structural and functional alterations of the kidney, comparing Pparg null-mice to their littermate controls (carrying Pparg floxed alleles). We show that renal hypertrophy and functional alterations with increased glucosuria and albuminuria are already present in 3 weeks-old Pparg null-mice. Renal insufficiency with decreased creatinine clearance progress at 7 weeks of age, with the advance of the type 2 diabetes. At 52 weeks of age, these alterations are accompanied by signs of fibrosis and mesangial expansion. More intriguingly, aged Pparg null-mice concomitantly present an anti-phospholipid syndrome (APS), characterized by the late appearance of microthrombi and a mesangioproliferative pattern of glomerular injury, associated with significant plasmatic levels of anti-β2- glycoprotein1 antibodies and renal deposition of IgG, IgM, and C3. Thus, in line with the role of PPARγ in metabolic homeostasis, Pparg null-mice first represent a potent model for studying the initiation and the development of diabetic nephropathy. Second, and in relation with the important PPARγ activity in inflammation and in immune system, these mice also highlight a new role for PPARγ signaling in the promotion of APS, a syndrome whose pathogenesis is poorly known and whose current treatment is limited to prevention of thrombosis events.
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Affiliation(s)
- Barbara Toffoli
- Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Federica Gilardi
- Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Carine Winkler
- Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | | | - Laura Kowalczuk
- Unit of Gene Therapy & Stem Cell Biology, University of Lausanne, Department of Ophthalmology, Fondation Asile des Aveugles, Jules-Gonin Eye Hospital, Lausanne, Switzerland
| | - Yvan Arsenijevic
- Unit of Gene Therapy & Stem Cell Biology, University of Lausanne, Department of Ophthalmology, Fondation Asile des Aveugles, Jules-Gonin Eye Hospital, Lausanne, Switzerland
| | | | - Olivier Bonny
- Service of Nephrology, Lausanne University Hospital and Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
| | - Béatrice Desvergne
- Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- * E-mail:
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Zamaninour N, Mirzaei K, Keshavarz SA, Ansar H, Hossein-Nezhad A. New insight into determining indicators of metabolic status in women: Expression of PPARγ and FABP4 in PBMCs. Women Health 2016; 57:905-918. [PMID: 27563749 DOI: 10.1080/03630242.2016.1222330] [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] [Indexed: 12/21/2022]
Abstract
Adiposity and its metabolic disturbances could be regulated by adipocyte-specific peroxisome proliferator-activated receptor gamma and fatty acid-binding protein4. Although these two proteins are mainly expressed in adipose tissues, they can also be expressed in peripheral blood mononuclear cells, which could be useful for predicting body composition and blood parameters. Thus, this cross-sectional study was performed during January 2013-January 2014 with 229 women (age range, 22-52 years) who were classified as obese or nonobese. Serum glucose, insulin, lipids, and body composition were measured in the fasting state. Peripheral blood mononuclear cells were isolated to extract ribonucleic acid (RNA) and to determine gene expression by real time polymerase chain reaction (PCR). All serum parameters and components of body composition were significantly higher in obese than in nonobese women. Gene expression analysis showed that serum levels of glucose and lipids, except high-density lipoprotein (HDL), were higher in the group that expressed high fatty acid-binding protein4. Increased expression of the peroxisome proliferator-activated receptor gamma was associated with a significant reduction of blood sugar and increased HDL and other lipids and visceral fat. Therefore, it seems that the level of expression of these genes in peripheral blood mononuclear cells may indicate metabolic status.
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Affiliation(s)
- Negar Zamaninour
- a Department of Community Nutrition, School of Nutritional Sciences and Dietetics , Tehran University of Medical Sciences (TUMS) , Tehran , Iran
| | - Khadijeh Mirzaei
- a Department of Community Nutrition, School of Nutritional Sciences and Dietetics , Tehran University of Medical Sciences (TUMS) , Tehran , Iran
| | - Seyed Ali Keshavarz
- b Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics , Tehran University of Medical Sciences (TUMS) , Tehran , Iran
| | - Hastimansooreh Ansar
- c Osteoporosis Research Center, Endocrinology and Metabolism Clinical Sciences Institute , Tehran University of Medical Sciences (TUMS) , Tehran , Iran
| | - Arash Hossein-Nezhad
- c Osteoporosis Research Center, Endocrinology and Metabolism Clinical Sciences Institute , Tehran University of Medical Sciences (TUMS) , Tehran , Iran.,d Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin, and Bone Research Laboratory , Boston University Medical Center , Boston , Massachusetts , USA
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Current Advances in the Biochemical and Physiological Aspects of the Treatment of Type 2 Diabetes Mellitus with Thiazolidinediones. PPAR Res 2016; 2016:7614270. [PMID: 27313601 PMCID: PMC4893583 DOI: 10.1155/2016/7614270] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 04/24/2016] [Indexed: 12/19/2022] Open
Abstract
The present review summarizes the current advances in the biochemical and physiological aspects in the treatment of type 2 diabetes mellitus (DM2) with thiazolidinediones (TZDs). DM2 is a metabolic disorder characterized by hyperglycemia, triggering the abnormal activation of physiological pathways such as glucose autooxidation, polyol's pathway, formation of advance glycation end (AGE) products, and glycolysis, leading to the overproduction of reactive oxygen species (ROS) and proinflammatory cytokines, which are responsible for the micro- and macrovascular complications of the disease. The treatment of DM2 has been directed toward the reduction of hyperglycemia using different drugs such as insulin sensitizers, as the case of TZDs, which are able to lower blood glucose levels and circulating triglycerides by binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) as full agonists. When TZDs interact with PPARγ, the receptor regulates the transcription of different genes involved in glucose homeostasis, insulin resistance, and adipogenesis. However, TZDs exhibit some adverse effects such as fluid retention, weight gain, hepatotoxicity, plasma-volume expansion, hemodilution, edema, bone fractures, and congestive heart failure, which limits their use in DM2 patients.
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Affiliation(s)
- Ningjun Li
- Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
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Review of the Structural and Dynamic Mechanisms of PPARγ Partial Agonism. PPAR Res 2015; 2015:816856. [PMID: 26435709 PMCID: PMC4578752 DOI: 10.1155/2015/816856] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 08/19/2015] [Indexed: 01/02/2023] Open
Abstract
PPARγ (peroxisome proliferator activated receptor γ) is a ligand activated transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. While endogenous ligands of PPARγ include fatty acids and eicosanoids, synthetic full agonists of the receptor, including members of the thiazolidinedione (TZD) class, have been widely prescribed for the treatment of type II diabetes mellitus (T2DM). Unfortunately, the use of full agonists has been hampered by harsh side effects with some removed from the market in many countries. In contrast, partial agonists of PPARγ have been shown to retain favourable insulin sensitizing effects while exhibiting little to no side effects and thus represent a new potential class of therapeutics for the treatment of T2DM. Partial agonists have been found to not only display differences in transcriptional and cellular outcomes, but also act through distinct structural and dynamic mechanisms within the ligand binding cavity compared to full agonists.
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