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Jiang W, Sang R, Zhang C, Yin R, Ouyang Z, Wei Y. Application of small interfering RNA technology in cytochrome P450 gene modulation. Drug Metab Dispos 2025; 53:100040. [PMID: 40010050 DOI: 10.1016/j.dmd.2025.100040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/13/2025] [Accepted: 01/14/2025] [Indexed: 02/28/2025] Open
Abstract
Cytochrome P450 plays key roles in the biotransformation of endogenous and exogenous chemicals including drugs and environmental pollutants. The inhibition and downregulation of P450s can have therapeutic effects, and/or modulate drug metabolism. P450s are largely inhibited by small molecules; however, this strategy is often hampered by intrinsic toxicity and drug-drug interactions. Furthermore, it is challenging for small molecules to exhibit high selectivity and inhibitory efficiencies. Recently, small interfering RNA (siRNA) technology has demonstrated the potential for P450 modulation. Examples of recent applications of siRNAs in P450 gene modulation, in vitro and in vivo, are highlighted in this review. The necessity of siRNA techniques and their advantages as P450 modulators are discussed, along with a review of current obstacles and a perspective on future advancements. SIGNIFICANCE STATEMENT: This article reviews studies on the application of small interfering RNA technology to cytochrome P450 gene modulation. The necessity of siRNA methods and the benefits of their use as P450 modulators have been suggested by comparison with small-molecule drugs. Additionally, the challenges that presently limit the broader implementation of this topic are examined, and a perspective for future developments is proposed.
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Affiliation(s)
- Wenzhao Jiang
- School of Pharmacy, Jiangsu University, Zhenjiang, China
| | - Ruoyao Sang
- School of Pharmacy, Jiangsu University, Zhenjiang, China
| | - Cai Zhang
- School of Pharmacy, Jiangsu University, Zhenjiang, China
| | - Runting Yin
- School of Pharmacy, Jiangsu University, Zhenjiang, China
| | - Zhen Ouyang
- School of Pharmacy, Jiangsu University, Zhenjiang, China
| | - Yuan Wei
- School of Pharmacy, Jiangsu University, Zhenjiang, China.
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Lobato TB, Santos ESDS, Iser-Bem PN, Falcão HDS, Gimenes GM, Pauferro JRB, Rodrigues GT, Correa IS, Pereira ACG, Passos MEP, Borges JCDO, Alves ACDA, Santos CSD, Araújo MJLD, Diniz VLS, Levada-Pires AC, Pithon-Curi TC, Masi LN, Curi R, Hirabara SM, Gorjão R. Omega-3 Fatty Acids Weaken Lymphocyte Inflammatory Features and Improve Glycemic Control in Nonobese Diabetic Goto-Kakizaki Rats. Nutrients 2024; 16:4106. [PMID: 39683500 DOI: 10.3390/nu16234106] [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: 10/11/2024] [Revised: 10/30/2024] [Accepted: 11/03/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND/OBJECTIVES Goto-Kakizaki (GK) rats exhibit insulin resistance and type 2 diabetes mellitus (T2DM) without obesity. This study explored the effects of ω-3 fatty acid supplementation on T lymphocyte polarization in Wistar (WT) and GK rats. METHODS They were administered ω-3 fatty acid-rich fish oil (FO) containing eicosapentaenoic (540 mg/g) and docosahexaenoic acids (100 mg/g) by oral gavage at 2 g/kg, thrice a week for 8 weeks. The control groups (WT CT and GK CT) received the same volume of water. The following groups were investigated: GK CT, n = 14; GK ω-3, n = 15; Wistar CT, n = 15; and Wistar ω-3, n = 11. Glucose and insulin tolerance tests (GTT and ITT) were performed. Fasting plasma insulinemia and glycemia were measured. After euthanasia, the lymphocytes were extracted from the mesenteric lymph nodes. RESULTS The results showed that GK rats supplemented with FO had significantly improved glucose tolerance and insulin sensitivity (kITT). It also promoted greater polarization of lymphocytes toward T regulatory (Treg) features and a reduction in Th1 and Th17 profiles. Additionally, the GK ω-3 group exhibited lower cell proliferation, decreased pro-inflammatory cytokines, and increased IL-10 levels compared to the GK control. CONCLUSIONS In conclusion, FO supplementation benefited GK rats by improving glucose intolerance, suppressing insulin resistance, and modulating lymphocytes toward Treg polarization.
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Affiliation(s)
- Tiago Bertola Lobato
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | | | - Patrícia Nancy Iser-Bem
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
- National Commercial Learning Service (SENAC), São Paulo 01102-000, Brazil
| | - Henrique de Souza Falcão
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Gabriela Mandú Gimenes
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | | | - Glayce Tavares Rodrigues
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Ilana Souza Correa
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Ana Carolina Gomes Pereira
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | | | | | | | - Camila Soares Dos Santos
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | | | | | | | - Tânia Cristina Pithon-Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Laureane Nunes Masi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
- Department of Physiological Sciences, Multicenter Graduate Program in Physiological Sciences, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil
| | - Rui Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
- Educantion Center, Butantan Institute, São Paulo 05585-000, Brazil
| | - Sandro Massao Hirabara
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
| | - Renata Gorjão
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 01506-000, Brazil
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Skoczyńska A, Ołdakowska M, Dobosz A, Adamiec R, Gritskevich S, Jonkisz A, Lebioda A, Adamiec-Mroczek J, Małodobra-Mazur M, Dobosz T. PPARs in Clinical Experimental Medicine after 35 Years of Worldwide Scientific Investigations and Medical Experiments. Biomolecules 2024; 14:786. [PMID: 39062500 PMCID: PMC11275227 DOI: 10.3390/biom14070786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
This year marks the 35th anniversary of Professor Walter Wahli's discovery of the PPARs (Peroxisome Proliferator-Activated Receptors) family of nuclear hormone receptors. To mark the occasion, the editors of the scientific periodical Biomolecules decided to publish a special issue in his honor. This paper summarizes what is known about PPARs and shows how trends have changed and how research on PPARs has evolved. The article also highlights the importance of PPARs and what role they play in various diseases and ailments. The paper is in a mixed form; essentially it is a review article, but it has been enriched with the results of our experiments. The selection of works was subjective, as there are more than 200,000 publications in the PubMed database alone. First, all papers done on an animal model were discarded at the outset. What remained was still far too large to describe directly. Therefore, only papers that were outstanding, groundbreaking, or simply interesting were described and briefly commented on.
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Affiliation(s)
- Anna Skoczyńska
- Department of Internal and Occupational Medicine and Hypertension, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Monika Ołdakowska
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Agnieszka Dobosz
- Department of Basic Medical Sciences and Immunology, Division of Basic Medical Sciences, Wroclaw Medical University, Borowska 211, 50-556 Wrocław, Poland
| | - Rajmund Adamiec
- Department of Diabetology and Internal Medicine, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
- Department of Internal Medicine, Faculty of Medical and Technical Sciences, Karkonosze University of Applied Sciences, Lwówiecka 18, 58-506 Jelenia Góra, Poland
| | - Sofya Gritskevich
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Anna Jonkisz
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Arleta Lebioda
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Joanna Adamiec-Mroczek
- Department of Ophthalmology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Małgorzata Małodobra-Mazur
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Tadeusz Dobosz
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
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Biswas A, Choudhury AD, Agrawal S, Bisen AC, Sanap SN, Verma SK, Kumar M, Mishra A, Kumar S, Chauhan M, Bhatta RS. Recent Insights into the Etiopathogenesis of Diabetic Retinopathy and Its Management. J Ocul Pharmacol Ther 2024; 40:13-33. [PMID: 37733327 DOI: 10.1089/jop.2023.0068] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2023] Open
Abstract
Purpose: Diabetic retinopathy (DR) is a microvascular retinal disease associated with chronic diabetes mellitus, characterized by the damage of blood vessels in the eye. It is projected to become the leading cause of blindness, given the increasing burden of the diabetic population worldwide. The diagnosis and management of DR pose significant challenges for physicians because of the involvement of multiple biochemical pathways and the complexity of ocular tissues. This review aims to provide a comprehensive understanding of the molecular pathways implicated in the pathogenesis of DR, including the polyo pathway, hexosamine pathway, protein kinase C (PKC), JAK/STAT signaling pathways, and the renin-angiotensin system (RAS). Methods: Academic databases such as PubMed, Scopus, Google Scholar and Web of Science was systematically searched using a carefully constructed search strategy incorporating keywords like "Diabetic Retinopathy," "Molecular Pathways," "Pharmacological Treatments," and "Clinical Trials" to identify relevant literature for the comprehensive review. Results: In addition to activating other inflammatory cascades, these pathways contribute to the generation of oxidative stress within the retina. Furthermore, it aims to explore the existing pharmacotherapy options available for the treatment of DR. In addition to conventional pharmacological therapies such as corticosteroids, antivascular endothelial growth factors, and nonsteroidal anti-inflammatory drugs (NSAIDs), this review highlights the potential of repurposed drugs, phyto-pharmaceuticals, and novel pipeline drugs currently undergoing various stages of clinical trials. Conclusion: Overall, this review serves as a technical exploration of the complex nature of DR, highlighting both established and emerging molecular pathways implicated in its pathogenesis. Furthermore, it delves into the available pharmacological treatments, as well as the promising repurposed drugs, phyto-pharmaceuticals, and novel drugs currently being evaluated in clinical trials, with a focus on their specific mechanisms of action.
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Affiliation(s)
- Arpon Biswas
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Jawaharlal Nehru University, New Delhi, India
| | - Abhijit Deb Choudhury
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Jawaharlal Nehru University, New Delhi, India
| | - Sristi Agrawal
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, New Delhi, India
| | - Amol Chhatrapati Bisen
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, New Delhi, India
| | - Sachin Nashik Sanap
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, New Delhi, India
| | - Sarvesh Kumar Verma
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Jawaharlal Nehru University, New Delhi, India
| | - Mukesh Kumar
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Jawaharlal Nehru University, New Delhi, India
| | - Anjali Mishra
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, New Delhi, India
| | - Shivansh Kumar
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Mridula Chauhan
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Rabi Sankar Bhatta
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, India
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Tian JJ, Levy M, Zhang X, Sinnott R, Maddela R. Counteracting Health Risks by Modulating Homeostatic Signaling. Pharmacol Res 2022; 182:106281. [PMID: 35661711 DOI: 10.1016/j.phrs.2022.106281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/14/2022] [Accepted: 05/27/2022] [Indexed: 10/18/2022]
Abstract
Homeostasis was initially conceptualized by Bernard and Cannon around a century ago as a steady state of physiological parameters that vary within a certain range, such as blood pH, body temperature, and heart rate1,2. The underlying mechanisms that maintain homeostasis are explained by negative feedbacks that are executed by the neuronal, endocrine, and immune systems. At the cellular level, homeostasis, such as that of redox and energy steady state, also exists and is regulated by various cell signaling pathways. The induction of homeostatic mechanism is critical for human to adapt to various disruptive insults (stressors); while on the other hand, adaptation occurs at the expense of other physiological processes and thus runs the risk of collateral damages, particularly under conditions of chronic stress. Conceivably, anti-stress protection can be achieved by stressor-mimicking medicinals that elicit adaptive responses prior to an insult and thereby serve as health risk countermeasures; and in situations where maladaptation may occur, downregulating medicinals could be used to suppress the responses and prevent subsequent pathogenesis. Both strategies are preemptive interventions particularly suited for individuals who carry certain lifestyle, environmental, or genetic risk factors. In this article, we will define and characterize a new modality of prophylactic intervention that forestalls diseases via modulating homeostatic signaling. Moreover, we will provide evidence from the literature that support this concept and distinguish it from other homeostasis-related interventions such as adaptogen, hormesis, and xenohormesis.
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Affiliation(s)
- Junqiang J Tian
- USANA Health Science, Inc., 3838 Parkway Blvd, Salt Lake City, UT 84121, USA.
| | - Mark Levy
- USANA Health Science, Inc., 3838 Parkway Blvd, Salt Lake City, UT 84121, USA
| | - Xuekai Zhang
- Beijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Chaoyang District, Beijing100029, China; US Center for Chinese Medicine, 14801 Physicians lane, 171 A 2nd Floor, #281, Rockville MD 20850, USA
| | - Robert Sinnott
- USANA Health Science, Inc., 3838 Parkway Blvd, Salt Lake City, UT 84121, USA
| | - Rolando Maddela
- USANA Health Science, Inc., 3838 Parkway Blvd, Salt Lake City, UT 84121, USA
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Imig JD. Diabetes risk associated with plasma epoxylipid levels. EBioMedicine 2021; 66:103331. [PMID: 33857907 PMCID: PMC8050865 DOI: 10.1016/j.ebiom.2021.103331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 03/22/2021] [Indexed: 11/20/2022] Open
Affiliation(s)
- John D Imig
- Drug Discovery Center, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
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Li BJ, Zhu ZX, Qin H, Meng ZN, Lin HR, Xia JH. Genome-Wide Characterization of Alternative Splicing Events and Their Responses to Cold Stress in Tilapia. Front Genet 2020; 11:244. [PMID: 32256528 PMCID: PMC7093569 DOI: 10.3389/fgene.2020.00244] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 02/28/2020] [Indexed: 12/15/2022] Open
Abstract
Alternative splicing (AS) is an important post-transcriptional regulatory mechanism for cells to generate transcript variability and proteome diversity. No systematic investigation of AS events among different tissues in response to stressors is available for tilapia currently. In this study, AS among different tissues was identified and the cold stress-related AS events were explored in a Nile tilapia (Oreochromis niloticus) line based on 42 RNA-seq datasets using a bioinformatics pipeline. 14,796 (82.76%; SD = 2,840) of the expression genes showed AS events. The two most abundant AS types were alternative transcription start site (TSS) and terminal site (TTS) in tilapia. Testis, brain and kidney possess the most abundant AS gene number, while the blood, muscle and liver possess the least number in each tissue. Furthermore, 208 differentially alternative splicing (DAS) genes in heart and 483 DAS in brain in response to cold stress. The number of AS types for alternative exon end, exon skipping and retention of single intron increased significantly under cold stress. GO enrichment and pathway overrepresentation analysis indicated that many DAS genes, e.g., genes in circadian clock pathway, may influence expression of downstream genes under cold stress. Our study revealed that AS exists extensively in tilapia and plays an important role in cold adaption.
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Affiliation(s)
| | | | | | | | | | - Jun Hong Xia
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, College of Life Sciences, Sun Yat-sen University, Guangzhou, China
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PPARγ provides anti-inflammatory and protective effects in intrahepatic cholestasis of pregnancy through NF-κB pathway. Biochem Biophys Res Commun 2018; 504:834-842. [PMID: 30219229 DOI: 10.1016/j.bbrc.2018.09.035] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 09/07/2018] [Indexed: 12/11/2022]
Abstract
AIMS Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific hepatic disorder with potentially deleterious consequences of fetuses. Although the intimate relationship between ICP and peroxisome proliferator-activated receptor γ (PPARγ) has been previously reported in physiological and pathological conditions, the detailed mechanisms in the process of intrahepatic cholestasis of pregnancy has been unclear. The aims of this study are to assess the role of PPARγ regulating the reactive oxygen species (ROS) and inflammation in the process of the ICP. METHODS Clinical data of the pregnant women were collected. And the serum of cytokines, hepatic function, the expression of PPARγ and NF-κB were measured. The rat and fetal rat ICP model were constructed and detection of the expression of PPARγ and NF-κB, evaluation the level of ROS and inflammation. RESULTS The clinical data showed that the new-born information in severe ICP group were significantly different as compared to that in control group (P < 0.05), and part of information in mild ICP group were also difference to that in control group (P < 0.05). The expression of PPARγ and NF-κB were significantly higher in clinical pregnant women, rat, fetal rat ICP model groups and taurocholate acid (TCA) treated HTR-8/SVneo cell (P < 0.01). PPARγ inhibited the production of ROS and decreased the level of inflammation. PPARγ down-regulated the NF-κB pathway. CONCLUSIONS PPARγ provides the anti-inflammatory and protective effects in intrahepatic cholestasis of pregnancy through NF-κB pathway, which might be a probably one of the mechanisms of ICP.
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Wang S, Chen X, Wang M, Yao D, Yan Q, Lu W. SiRNA-Cyp4a14 and diabetic nephropathy: silencing of Cyp4a14 by siRNA inhibits proliferation and fibrosis of mesangial cells. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:11909-11917. [PMID: 31966555 PMCID: PMC6966019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 05/03/2017] [Indexed: 06/10/2023]
Abstract
Diabetic nephropathy (DN) is one of the most common complications of diabetes, which increases mortality of diabetic patients. In recent years, many studies have confirmed that patients with diabetes are often accompanied by lipid metabolism disorders. Peroxisome proliferator-activated receptor (PPARs) is known to play pivotal roles in the regulation of insulin signaling, glucose and lipid metabolism. Cyp4a14 was confirmed to be the PPARα-target marker genes. We attempt to explore the biological role of Cyp4a14 in diabetic nephropathy. In our previous study, lncRNA microarray analysis showed us Cyp4a29-ps, Cyp4a14, Cyp4a12a and Cyp4a12b were the nearby mRNAs of lncRNA CYP4B1-PS1-001, we chose Cyp4a14 as our candidate. Renal cortical tissues were collected from db/db and db/m mice, and the mRNA expression of Cyp4a14 in diabetic tissue was significantly higher than that in normal tissue. And the expression of Cyp4a14 in mesangial cells cultured in high glucose was higher than that in low glucose by qualitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis. By Cell Counting Kit-8 (CCK8) and colony- forming ability, it is found that siRNA-Cyp4a14 treatment effectively suppressed the proliferation of mesangial cells. From our results, the protein expression of proliferating cell nuclear antigen (PCNA), Cyclin D1, Collagen I, and Fibronectin were all regulated dramatically in siRNA-Cyp4a14 group compared with the negative control group. Our data indicated that siRNA-Cyp4a14 inhibits proliferation and fibrosis of mesangial cells, which can be considered as a therapeutic target for diabetic nephropathy.
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Affiliation(s)
- Suyu Wang
- Department of Endocrinology and Metabolism, Huai’an First People’s Hospital, Nanjing Medical University6 Beijing Road West, Huai’an, Jiangsu, P. R. China
| | - Xin Chen
- Department of Endocrinology and Metabolism, Huai’an First People’s Hospital, Nanjing Medical University6 Beijing Road West, Huai’an, Jiangsu, P. R. China
| | - Min Wang
- Department of Endocrinology and Metabolism, Huai’an First People’s Hospital, Nanjing Medical University6 Beijing Road West, Huai’an, Jiangsu, P. R. China
| | - Di Yao
- Department of Endocrinology and Metabolism, Huai’an First People’s Hospital, Nanjing Medical University6 Beijing Road West, Huai’an, Jiangsu, P. R. China
| | - Qin Yan
- Department of Microbiology, Nanjing Medical UniversityNanjing, Jiangsu, P. R. China
| | - Weiping Lu
- Department of Endocrinology and Metabolism, Huai’an First People’s Hospital, Nanjing Medical University6 Beijing Road West, Huai’an, Jiangsu, P. R. China
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Igami K, Shimojo Y, Ito H, Miyazaki T, Nakano F, Kashiwada Y. Fermented Ginseng Contains an Agonist of Peroxisome Proliferator Activated Receptors α and γ. J Med Food 2017; 19:817-22. [PMID: 27627700 DOI: 10.1089/jmf.2016.3673] [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] [Indexed: 11/13/2022] Open
Abstract
Peroxisome proliferator activated receptor (PPAR) is a nuclear receptor that is one of the transcription factors regulating lipid and glucose metabolism. Fermented ginseng (FG) is a ginseng fermented by Lactobacillus paracasei A221 containing minor ginsenosides and metabolites of fermentation. DNA microarray analysis of rat liver treated with FG indicated that FG affects on lipid metabolism are mediated by PPAR-α. To identify a PPAR-α agonist in FG, PPAR-α transcription reporter assay-guided fractionation was performed. The fraction obtained from the MeOH extract of FG, which showed potent transcription activity of PPAR-α, was fractionated by silica gel column chromatography into 16 subfractions, and further separation and crystallization gave compound 1 together with four known constituents of ginseng, including 20(R)- and 20(S)-protopanaxadiol, and 20(R)- and 20(S)-ginsenoside Rh1. The structure of compound 1 was identified as 10-hydroxy-octadecanoic acid by (1)H- and (13)C-NMR spectra and by EI-MS analysis of the methyl ester of 1. Compound 1 demonstrated much higher transcription activity of PPAR-α than the other isolated compounds. In addition, compound 1 also showed 5.5-fold higher transcription activity of PPAR-γ than vehicle at the dose of 20 μg/mL. In the present study, we identified 10-hydroxy-octadecanoic acid as a dual PPAR-α/γ agonist in FG. Our study suggested that metabolites of fermentation, in addition to ginsenosides, contribute to the health benefits of FG.
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Affiliation(s)
- Kentaro Igami
- 1 Research & Development Center, Nagase and Co., Ltd. , Kobe, Japan .,2 Graduate School of Pharmaceutical Sciences, Tokushima University , Tokushima, Japan
| | - Yosuke Shimojo
- 1 Research & Development Center, Nagase and Co., Ltd. , Kobe, Japan
| | - Hisatomi Ito
- 1 Research & Development Center, Nagase and Co., Ltd. , Kobe, Japan
| | | | - Fusako Nakano
- 2 Graduate School of Pharmaceutical Sciences, Tokushima University , Tokushima, Japan
| | - Yoshiki Kashiwada
- 2 Graduate School of Pharmaceutical Sciences, Tokushima University , Tokushima, Japan
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Hatami M, Saidijam M, Yadegarzari R, Borzuei S, Soltanian A, Arian MS, Goodarzi MT. Peroxisome Proliferator-Activated Receptor-γGene Expression and Its Association with Oxidative Stress in Patients with Metabolic Syndrome. Chonnam Med J 2016; 52:201-6. [PMID: 27689030 PMCID: PMC5040769 DOI: 10.4068/cmj.2016.52.3.201] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 05/02/2016] [Accepted: 05/10/2016] [Indexed: 12/11/2022] Open
Abstract
Regulation of the peroxisome proliferator-activated receptor-γ (PPAR-γ) gene plays an important role in controlling the metabolism of lipids and inflammatory processes. Therefore, it can be associated with the pathogenesis of metabolic syndrome (MetS). The purpose of this study was to determine the expression of this gene in peripheral blood mononuclear cells (PBMC) in patients with metabolic syndrome. Using real-time polymerase chain reaction (PCR), mRNA expression of PPAR-γ was found in PBMC from 37 subjects with MetS and 30 healthy controls. Serum levels of glucose and lipid profiles were measured. The total antioxidant capacity (TAC) was measured using the ferric reducing ability of plasma (FRAP) test. Malondialdehyde (MDA) was determined using a fluorimetric method. Total oxidant status (TOS) in serum was assayed according to oxidation of ferric to ferrous in the presence of methyl orange. Super oxide dismutase (SOD) activity was measured using a Randox kit. Expression of PPAR-γ gene was significantly increased in patients with MetS compared to the control subjects (p=0.002). There was no difference in serum levels of TAC, MDA and SOD between the two study groups, but a significant difference was observed in the TOS (p=0.03). Serum levels of triglycerides and glucose were significantly higher in subjects with MetS. According to the results of our study, an increase in the expression of PPAR-γ in subjects with MetS indicated a possible role of PPAR-γ in the pathogenesis of this disease.
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Affiliation(s)
- Mehdi Hatami
- Department of Clinical Biochemistry, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Reza Yadegarzari
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Shiva Borzuei
- Department of Internal Medicine, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Alireza Soltanian
- Department of Biostatistics, Health School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Marzieh Safi Arian
- Department of Clinical Biochemistry, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammad Taghi Goodarzi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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12
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Fernandes-Lima F, Monte TLRG, Nascimento FADM, Gregório BM. Short Exposure to a High-Sucrose Diet and the First 'Hit' of Nonalcoholic Fatty Liver Disease in Mice. Cells Tissues Organs 2016; 201:464-472. [PMID: 27318725 DOI: 10.1159/000446514] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2016] [Indexed: 11/19/2022] Open
Abstract
High-sucrose and high-fat diets induce deregulation in the metabolism of lipids and carbohydrates. This study aimed to detect the initial consequences on lipogenesis, gluconeogenesis and insulin signaling in the livers of rodents fed high-fat and/or high-sucrose diets for a short period of time. Male mice received a standard chow (SC), high-fat (HF), high-sucrose (HSu) or high-fat, high-sucrose (HFHSu) diet for 4 weeks. At euthanasia, blood was collected and the liver was removed for histomorphometrical and molecular analysis. The HF, HSu and HFHSu groups presented glucose intolerance, hepatomegaly, liver steatosis and lipid profile alteration when compared to the SC group (p < 0.0005). Additionally, there was an elevation in protein levels involved in lipogenesis (SREBP-1c), gluconeogenesis (PEPCK and G6Pase) and insulin signaling (IRS-1 and Akt) in the livers from the experimental groups compared to the SC group (p < 0.0005). Thus, we conclude that a short-term HF and/or HSu diet promotes glucose intolerance and liver damage in adult male mice. Surprisingly, the short exposure to excess sucrose in the diet promoted glucose intolerance and liver damage even in the absence of an increase in body mass or changes in serum insulin, cholesterol and triacylglycerol levels.
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Affiliation(s)
- Flavia Fernandes-Lima
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
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13
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Yasutake Y, Mizokami A, Kawakubo-Yasukochi T, Chishaki S, Takahashi I, Takeuchi H, Hirata M. Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet. Am J Physiol Endocrinol Metab 2016; 310:E662-E675. [PMID: 26884384 DOI: 10.1152/ajpendo.00334.2015] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 02/05/2016] [Indexed: 01/13/2023]
Abstract
Uncarboxylated osteocalcin (GluOC), a bone-derived hormone, regulates energy metabolism by stimulating insulin secretion, pancreatic β-cell proliferation, and adiponectin expression in adipocytes. Previously, we showed that long-term intermittent or daily oral administration of GluOC reduced the fasting blood glucose level, improved glucose tolerance, and increased the fasting serum insulin concentration as well as pancreatic β-cell area in female mice fed a normal or high-fat, high-sucrose diet. We have now performed similar experiments with male mice and found that such GluOC administration induced glucose intolerance, insulin resistance, and adipocyte hypertrophy in those fed a high-fat, high-sucrose diet. In addition, GluOC increased the circulating concentration of testosterone and reduced that of adiponectin in such mice. These phenotypes were not observed in male mice fed a high-fat, high-sucrose diet after orchidectomy, but they were apparent in orchidectomized male mice or intact female mice that were fed such a diet and subjected to continuous testosterone supplementation. Our results thus reveal a sex difference in the effects of GluOC on glucose homeostasis. Given that oral administration of GluOC has been considered a potentially safe and convenient option for the treatment or prevention of metabolic disorders, this sex difference will need to be taken into account in further investigations.
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Affiliation(s)
- Yu Yasutake
- Laboratory of Molecular and Cellular Biochemistry
- Division of Orthodontics, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Akiko Mizokami
- Laboratory of Molecular and Cellular Biochemistry
- OBT Research Center, and
| | - Tomoyo Kawakubo-Yasukochi
- Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; and
| | | | - Ichiro Takahashi
- Division of Orthodontics, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Hiroshi Takeuchi
- Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu, Japan
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14
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Radosinska J, Kurahara LH, Hiraishi K, Viczenczova C, Egan Benova T, Szeiffova Bacova B, Dosenko V, Navarova J, Obsitnik B, Imanaga I, Soukup T, Tribulova N. Modulation of cardiac connexin-43 by omega-3 fatty acid ethyl-ester supplementation demonstrated in spontaneously diabetic rats. Physiol Res 2015; 64:795-806. [PMID: 26447526 DOI: 10.33549/physiolres.933075] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Previous data suggest that type 1 diabetes mellitus leads to the deterioration of myocardial intercellular communication mediated by connexin-43 (Cx43) channels. We therefore aimed to explore Cx43, PKC signaling and ultrastructure in non-treated and omega-3 fatty acid (omega-3) treated spontaneously diabetic Goto-Kakizaki (GK) rats considered as type 2 diabetes model. Four-week-old GK and non-diabetic Wistar-Clea rats were fed omega-3 (200 mg/kg/day) for 2 months and compared with untreated rats. Real-time PCR and immunoblotting were performed to determine Cx43, PKC-epsilon and PKC-delta expression. In situ Cx43 was examined by immunohistochemistry and subcellular alterations by electron microscopy. Omega-3 intake reduced blood glucose, triglycerides, and cholesterol in diabetic rats and this was associated with improved integrity of cardiomyocytes and capillaries in the heart. Myocardial Cx43 mRNA and protein levels were higher in diabetic versus non-diabetic rats and were further enhanced by omega-3. The ratio of phosphorylated (functional) to non-phosphorylated Cx43 was lower in diabetic compared to non-diabetic rats but was increased by omega-3, in part due to up-regulation of PKC-epsilon. In addition, pro-apoptotic PKC-delta expression was decreased. In conclusion, spontaneously diabetic rats at an early stage of disease benefit from omega-3 intake due to its hypoglycemic effect, upregulation of myocardial Cx43, and preservation of cardiovascular ultrastructure. These findings indicates that supplementation of omega-3 may be beneficial also in the management of diabetes in humans.
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Affiliation(s)
- J Radosinska
- Institute of Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia, Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia.
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15
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Dong C, Zhou H, Shen C, Yu LG, Ding Y, Zhang YH, Guo ZR. Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome. World J Diabetes 2015; 6:654-661. [PMID: 25987964 PMCID: PMC4434087 DOI: 10.4239/wjd.v6.i4.654] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/27/2014] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are the serious public health problems worldwide. Moreover, it is estimated that MetS patients have about five-fold greater risk of the T2DM development compared with people without the syndrome. Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2DM. All three members of the peroxisome proliferator-activated receptor (PPAR) nuclear receptor subfamily, PPARα, PPARβ/δ and PPARγ are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, and blood pressure. Recently, more and more studies indicated that the gene polymorphism of PPARs, such as Leu162Val and Val227Ala of PPARα, +294T > C of PPARβ/δ, Pro12Ala and C1431T of PPARγ, are significantly associated with the onset and progressing of MetS and T2DM in different population worldwide. Furthermore, a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes. However, given the complexity pathogenesis of metabolic disease, it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes. Thus, gene-gene interactions and gene-environment interactions associated with T2DM and MetS need future comprehensive studies.
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16
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Gao D, Zhang YL, Xu P, Lin YX, Yang FQ, Liu JH, Zhu HW, Xia ZN. In vitro evaluation of dual agonists for PPARγ/β from the flower of Edgeworthia gardneri (wall.) Meisn. JOURNAL OF ETHNOPHARMACOLOGY 2015; 162:14-19. [PMID: 25557029 DOI: 10.1016/j.jep.2014.12.034] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 09/17/2014] [Accepted: 12/22/2014] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE In Tibet, the flower of Edgeworthia gardneri (Wall.) Meisn., locally named "Lvluohua, [symbols: see text]", has been traditionally used to treat diabetes mellitus for many years. AIM OF THIS STUDY To evaluate the activity of dual agonists for PPARγ/β from the flower of E.gardneri in vitro. MATERIALS AND METHODS HeLa cells were transiently co-transfected with the re-constructed plasmids of pBIND-PPARγ-LBD or pBIND-PPARβ-LBD and rL4.35. The activities of crude extracts, secondary fractions and compounds from the flower of E.gardneri were evaluated with the transfected cells. Rosiglitazone (at 0.5 μg/mL) and L-165041 (at 0.5 μg/mL) were used as the positive controls for PPARγ and PPARβ respectively. RESULTS The results demonstrated that n-hexane, ethyl acetate and n-butanol extracts from the flower of E.gardneri were able to significantly activate PPARγ and PPARβ respectively, and the activity of ethyl acetate extract was much better. We further observed that, among the 11 secondary fractions of ethyl acetate extract, the fr. 9 could activate PPARγ and PPARβ significantly. Moreover, umbelliferone (from fr.9) and pentadecanoic acid could activate PPARγ and PPARβ at the same time. CONCLUSIONS The extracts from the flower of E.gardneri could significantly activate PPARγ and PPARβ. Besides, umbelliferone and pentadecanoic acid isolated from the flower of E.gardneri were the new agonists for PPARγ and PPARβ.
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Affiliation(s)
- Die Gao
- College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400030, China
| | - Yong-lan Zhang
- College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400030, China
| | - Pan Xu
- College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400030, China
| | - Ye-xin Lin
- College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400030, China
| | - Feng-qing Yang
- College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400030, China
| | - Jian-hui Liu
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Hai-wen Zhu
- College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400030, China
| | - Zhi-ning Xia
- College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400030, China.
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17
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Demir R, Cadirci E, Akpinar E, Cayir Y, Atmaca HT, Un H, Kunak CS, Yayla M, Bayraktutan Z, Demir I. Does bosentan protect diabetic brain alterations in rats? The role of endothelin-1 in the diabetic brain. Basic Clin Pharmacol Toxicol 2015; 116:236-243. [PMID: 25200216 DOI: 10.1111/bcpt.12318] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 08/25/2014] [Indexed: 10/15/2024]
Abstract
Diabetes mellitus (DM) is a major problem all over the world, affecting more people in recent years. Individuals with diabetes are more prone to disease than non-diabetics, especially vascular complications. The aim of this study was to examine the roles of the endothelin (ET)-1 in brain damage formed in a streptozocin (STZ)-induced diabetes model, and the effect of bosentan, which is the non-specific ET1 receptor blocker in the prevention of the diabetes-induced brain damage. To examine the effects of bosentan (50 mg/kg and 100 mg/kg) in this study, the rats were given the drug for 3 months. The rats were divided into four groups: the sham group (n = 10), the diabetic control group (n = 10), the group of diabetic rats given bosentan 50 mg/kg (n = 10) and the group of diabetic rats given bosentan 100 mg/kg (n = 10). Diabetes was induced in the rats by STZ (60 mg/kg i.p.). On day 91, all rats were killed. Brain tissues of the rats were measured by molecular, biochemical and histopathological methods. Antioxidant levels in the therapy groups were observed as quite near to the values in the healthy group. In this study, while the brain eNOS levels in the diabetic groups decreased, the ET1 and iNOS levels were found to be increased. However, in the diabetes group, hippocampus and cerebellum, pericellular oedema and a number of neuronal cytoretraction were increased in neuropiles, whereas these results were decreased in the therapy group. Based on all of these results, ET1 will not be ignored in diabetes-induced cerebral complications.
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Affiliation(s)
- Recep Demir
- Faculty of Medicine, Department of Neurology, Ataturk University, Erzurum, Turkey
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18
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Wang XJ, Zhang J, Wang SQ, Xu WR, Cheng XC, Wang RL. Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone. DRUG DESIGN DEVELOPMENT AND THERAPY 2014; 8:2255-62. [PMID: 25422585 PMCID: PMC4232041 DOI: 10.2147/dddt.s70383] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research.
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Affiliation(s)
- Xue-Jiao Wang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China
| | - Jun Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China
| | - Shu-Qing Wang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China
| | - Wei-Ren Xu
- Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, People's Republic of China
| | - Xian-Chao Cheng
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China
| | - Run-Ling Wang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China
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19
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Lu YF, Xu YY, Jin F, Wu Q, Shi JS, Liu J. Icariin is a PPARα activator inducing lipid metabolic gene expression in mice. Molecules 2014; 19:18179-91. [PMID: 25383754 PMCID: PMC6270773 DOI: 10.3390/molecules191118179] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 10/12/2014] [Accepted: 10/13/2014] [Indexed: 01/06/2023] Open
Abstract
Icariin is effective in the treatment of hyperlipidemia. To understand the effect of icariin on lipid metabolism, effects of icariin on PPARα and its target genes were investigated. Mice were treated orally with icariin at doses of 0, 100, 200, and 400 mg/kg, or clofibrate (500 mg/kg) for five days. Liver total RNA was isolated and the expressions of PPARα and lipid metabolism genes were examined. PPARα and its marker genes Cyp4a10 and Cyp4a14 were induced 2-4 fold by icariin, and 4-8 fold by clofibrate. The fatty acid (FA) binding and co-activator proteins Fabp1, Fabp4 and Acsl1 were increased 2-fold. The mRNAs of mitochondrial FA β-oxidation enzymes (Cpt1a, Acat1, Acad1 and Hmgcs2) were increased 2-3 fold. The mRNAs of proximal β-oxidation enzymes (Acox1, Ech1, and Ehhadh) were also increased by icariin and clofibrate. The expression of mRNAs for sterol regulatory element-binding factor-1 (Srebf1) and FA synthetase (Fasn) were unaltered by icariin. The lipid lysis genes Lipe and Pnpla2 were increased by icariin and clofibrate. These results indicate that icariin is a novel PPARα agonist, activates lipid metabolism gene expressions in liver, which could be a basis for its lipid-lowering effects and its beneficial effects against diabetes.
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Affiliation(s)
- Yuan-Fu Lu
- Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical College, Zunyi 563003, China.
| | - Yun-Yan Xu
- Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical College, Zunyi 563003, China.
| | - Feng Jin
- Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical College, Zunyi 563003, China.
| | - Qin Wu
- Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical College, Zunyi 563003, China.
| | - Jing-Shan Shi
- Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical College, Zunyi 563003, China.
| | - Jie Liu
- Key Lab for Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical College, Zunyi 563003, China.
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20
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Penna-de-Carvalho A, Graus-Nunes F, Rabelo-Andrade J, Mandarim-de-Lacerda CA, Souza-Mello V. Enhanced pan-peroxisome proliferator-activated receptor gene and protein expression in adipose tissue of diet-induced obese mice treated with telmisartan. Exp Physiol 2014; 99:1663-78. [PMID: 25326526 DOI: 10.1113/expphysiol.2014.081596] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Telmisartan has previously been used to target obesity, showing peroxisome proliferator-activated receptor (PPAR) β/δ-related effects in white adipose tissue (WAT). We sought to evaluate whether telmisartan enhances gene and protein expression of all PPAR isoforms in WAT and brown adipose tissue (BAT), as well as their downstream effects upon insulin resistance, adipokine profile and adaptive thermogenesis. Male C57BL/6 mice were fed standard chow (SC; 10% lipids) or high-fat diet (HF; 50% lipids) for 10 weeks. Animals were then randomly allocated into the following four groups: SC, SC-T, HF and HF-T. Telmisartan [10 mg (kg diet)(-1)] was administered for 4 weeks in the diet. Animals in the HF group were overweight and exhibited hypertension, insulin resistance, decreased energy expenditure, a pro-inflammatory adipokine profile and abnormal fat pad mass distribution. Animals in the HF group showed decreased expression of PPARα, β/δ and γ in WAT and BAT, resulting in impaired glucose uptake and insufficient thermogenesis. Due to the improvement in the adipokine profile and enhanced insulin sensitivity with adequate insulin-stimulated glucose uptake after treatment with telmisartan, the activation of all PPAR isoforms in WAT was beneficial. In BAT, telmisartan induced sustained sympathetic activation, because the β3-adrenergic receptor was induced by PPARβ/δ, while uncoupling protein 1 was induced by PPARα to promote thermogenesis. Telmisartan exerted anti-obesity effects through higher pan-PPAR gene and protein expression. Upon PPARα, β/δ and γ (pan-PPAR) agonism in adipose tissue of obese mice, telmisartan ameliorates inflammation and insulin resistance, as well as inducing non-shivering thermogenesis. Our results point to new therapeutic targets for the control of obesity and comorbidities through pan-PPAR-related effects.
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Affiliation(s)
- Aline Penna-de-Carvalho
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Francielle Graus-Nunes
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Júlia Rabelo-Andrade
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Carlos Alberto Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
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21
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Xuan AG, Chen Y, Long DH, Zhang M, Ji WD, Zhang WJ, Liu JH, Hong LP, He XS, Chen WL. PPARα Agonist Fenofibrate Ameliorates Learning and Memory Deficits in Rats Following Global Cerebral Ischemia. Mol Neurobiol 2014; 52:601-9. [DOI: 10.1007/s12035-014-8882-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 08/27/2014] [Indexed: 01/01/2023]
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22
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Pan ZQ, Xie D, Choudhary V, Seremwe M, Tsai YY, Olala L, Chen X, Bollag WB. The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells. Mol Cell Endocrinol 2014; 394:119-28. [PMID: 25038520 PMCID: PMC4237224 DOI: 10.1016/j.mce.2014.07.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Revised: 06/16/2014] [Accepted: 07/08/2014] [Indexed: 01/27/2023]
Abstract
Pioglitazone belongs to the class of drugs called thiazolidinediones (TZDs), which are widely used as insulin sensitizers in the treatment of diabetes. A major side effect of TZDs is fluid retention. The steroid hormone aldosterone also promotes sodium and fluid retention; however, the effect of pioglitazone on aldosterone production is controversial. We analyzed the effect of pioglitazone alone and in combination with angiotensin II (AngII) on the late rate-limiting step of adrenocortical steroidogenesis in human adrenocortical carcinoma HAC15 cells. Treatment with pioglitazone for 24 h significantly increased the expression of CYP11B2 and enhanced AngII-induced CYP11B2 expression. Despite the observed changes in mRNA levels, pioglitazone significantly inhibited AngII-induced aldosterone production and CYP11B2 protein levels. On the other hand, pioglitazone stimulated the expression of the unfolded protein response (UPR) marker DDIT3, with this effect occurring at early times and inhibitable by the PPARγ antagonist GW9962. The levels of DDIT3 (CHOP) and phospho-eIF2α (Ser51), a UPR-induced event that inhibits protein translation, were also increased. Thus, pioglitazone promotes CYP11B2 expression but nevertheless inhibits aldosterone production in AngII-treated HAC15 cells, likely by blocking global protein translation initiation through DDIT3 and phospho-eIF2α. In contrast, pioglitazone promoted AngII-induced CYP11B1 expression and cortisol production. Since cortisol enhances lipolysis, this result suggests the possibility that PPARs, activated by products of fatty acid oxidation, stimulate cortisol secretion to promote utilization of fatty acids during fasting. In turn, the ability of pioglitazone to stimulate cortisol production could potentially underlie the effects of this drug on fluid retention.
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Affiliation(s)
- Zhi-qiang Pan
- Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA; School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ding Xie
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA
| | - Vivek Choudhary
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA
| | - Mutsa Seremwe
- Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA
| | - Ying-Ying Tsai
- Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA
| | - Lawrence Olala
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA
| | - Xunsheng Chen
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA
| | - Wendy B Bollag
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA; Department of Physiology, Georgia Regents University (Medical College of Georgia), 1120 15th Street, Augusta, GA 30912, USA.
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He XQ, Cichello SA, Duan JL, Zhou J. Canola oil influence on azoxymethane-induced colon carcinogenesis, hypertriglyceridemia and hyperglycemia in Kunming mice. Asian Pac J Cancer Prev 2014; 15:2477-83. [PMID: 24761850 DOI: 10.7314/apjcp.2014.15.6.2477] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Azoxymethane (AOM) is a potent genotoxic carcinogen which specifically induces colon cancer. Hyperlipidemia and diabetes have several influences on colon cancer development, with genetic and environmental exposure aspects. Here, we investigated plasma lipid and glucose concentrations in Kunming mice randomized into four groups; control (no AOM or oil exposure), AOM control, AOM + pork oil, and AOM + canola oil. Aberrant crypt foci (ACF), plasma cholesterol, plasma triglyceride, plasma glucose and organ weight were examined 32 weeks after AOM injection. Results revealed that AOM exposure significantly increased ACF number, plasma triglyceride and glucose level. Further, male mice displayed a much higher plasma triglyceride level than female mice in the AOM control group. Dietary fat significantly inhibited AOM-induced hypertriglyceridemia, and canola oil had stronger inhibitory effect than pork oil. AOM-induced hyperglycemia had no sex-difference and was not significantly modified by dietary fat. However, AOM itself not change plasma cholesterol level. AOM significantly increased liver and spleen weight in male mice, but decreased kidney weight in female mice. On the other hand, mice testis weight decreased when fed canola oil. AOM could induce colorectal carcinogenesis, hypertriglyceridemia and hyperglycemia in Kunming mice at the same time, with subsequent studies required to investigate their genome association.
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Affiliation(s)
- Xiao-Qiong He
- Institute of Nutrition and Food Science, School of Public Health, Kunming Medical College, Yunnan, China E-mail :
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Weidman-Evans E, Metz SM, Evans JD. Cardiovascular risks and benefits with oral drugs for Type 2 diabetes mellitus. Expert Rev Clin Pharmacol 2014; 7:225-33. [PMID: 24490745 DOI: 10.1586/17512433.2014.885836] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Type 2 diabetes mellitus affects approximately 321 million people worldwide. It is estimated that about half of these patients will die from cardiovascular complications. In spite of these statistics, medications for diabetes are approved based not on outcomes, but on surrogate markers such as blood glucose or glycosylated hemoglobin. In recent years, however, the safety of diabetes medications has come under scrutiny, and more studies are being undertaken to determine the effect(s) of the medications on actual outcomes. In this review the authors review available study results for all of the currently approved classes of oral medications for Type 2 diabetes, and discuss the possible mechanisms for the findings. More studies are necessary for many of these classes, however, to make definitive recommendations regarding their cardiovascular effects.
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Affiliation(s)
- Emily Weidman-Evans
- Department of Clinical and Administrative Sciences, University of Louisiana at Monroe College of Pharmacy, Louisiana 71201, LA, USA
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