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Lee JE, Im DS. Oleoylethanolamide ameliorates collagen-induced rheumatoid arthritis via activation of GPR119. Int Immunopharmacol 2025; 155:114660. [PMID: 40222272 DOI: 10.1016/j.intimp.2025.114660] [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: 02/12/2025] [Revised: 04/08/2025] [Accepted: 04/08/2025] [Indexed: 04/15/2025]
Abstract
Lower levels of oleoylethanolamide (OEA) have been observed in the synovial fluids of patients with rheumatoid arthritis and osteoarthritis compared to healthy controls. OEA is known as an anti-inflammatory lipid and acts as an endogenous ligand for GPR119. This study investigated the functional roles of GPR119 using a murine collagen-induced arthritis (CIA) model. The effects of OEA and AR231453, a selective synthetic GPR119 agonist, were tested on the CIA model in Gpr119 wild-type (WT) and deficient DBA-1 J mice. In the CIA model, administration of OEA or AR231453 reduced arthritis scores, foot thickness, loss of proteoglycan, and bone erosion in Gpr119 WT mice, but not in Gpr119-deficient mice. Treatment with OEA or AR231453 significantly suppressed the CIA-induced increase in pro-inflammatory cytokine expression in the feet and IgG levels in the serum, and rebalanced Th1/Th17 and Treg cells in the spleens of Gpr119 WT mice, but not in Gpr119-deficient mice. Additionally, OEA and AR231453 suppressed mRNA expression levels of inflammatory cytokines in human SW982 synovial cells. Both compounds also suppressed Th1/17 cell differentiation and enhanced Treg differentiation in splenocytes from Gpr119 WT mice, but not in Gpr119 knockout mice. These findings suggest that GPR119 activation may serve as a therapeutic strategy for rheumatoid arthritis by regulating Th1/Th17/Treg cell differentiation and rebalancing Th1/Th17 and Treg cells.
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MESH Headings
- Animals
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/agonists
- Receptors, G-Protein-Coupled/metabolism
- Oleic Acids/therapeutic use
- Oleic Acids/pharmacology
- Arthritis, Experimental/drug therapy
- Arthritis, Experimental/immunology
- Arthritis, Experimental/pathology
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/immunology
- Endocannabinoids/therapeutic use
- Endocannabinoids/pharmacology
- Mice, Inbred DBA
- Mice
- Mice, Knockout
- Humans
- Male
- Cytokines/metabolism
- Cytokines/genetics
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/drug effects
- Anti-Inflammatory Agents/therapeutic use
- Anti-Inflammatory Agents/pharmacology
- Th17 Cells/immunology
- Th17 Cells/drug effects
- Biphenyl Compounds
- Phenylpropionates
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Affiliation(s)
- Jung-Eun Lee
- Department of Biomedical & Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea
| | - Dong-Soon Im
- Department of Biomedical & Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea; Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea.
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2
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Xie A, Shen X, Hong R, Xie Y, Zhang Y, Chen J, Li Z, Li M, Yue X, Quek SY. Unlocking the potential of donkey Milk: Nutritional composition, bioactive properties and future prospects. Food Res Int 2025; 209:116307. [PMID: 40253152 DOI: 10.1016/j.foodres.2025.116307] [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: 10/04/2024] [Revised: 02/27/2025] [Accepted: 03/15/2025] [Indexed: 04/21/2025]
Abstract
Donkey milk has garnered increasing attention due to its remarkable similarity to human milk and its diverse bioactive properties. Analysis of its composition shows that donkey milk is characterized by high lactose content, low protein, low fat, a balanced calcium-to‑phosphorus ratio, and abundant in vitamins C and D, making it a promising human milk alternative. Additionally, donkey milk contains a unique composition of whey proteins and polyunsaturated fatty acids, contributing to its beneficial health effects such as antimicrobial, anti-inflammatory, antioxidant, and hypoallergenic properties. This review provides a comprehensive analysis of the nutritional profile of donkey milk in comparison to other mammalian milk sources. Furthermore, it highlights its bioactive potential and discusses the current challenges and future opportunities for expanding its applications in the dairy and health industries. Despite its valuable properties, the development of donkey milk products remains limited due to low milk yield and high production costs. Further research and technological advancements are necessary to optimize its utilization and commercial potential.
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Affiliation(s)
- Aijun Xie
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 119077, Singapore
| | - Xinyu Shen
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China
| | - Ruiyao Hong
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China
| | - Yuanfang Xie
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China
| | - Yumeng Zhang
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China
| | - Jiali Chen
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China
| | - Zhiwei Li
- Jiangsu Key Laboratory of Oil & Gas Storage and Transportation Technology, Changzhou University, Jiangsu 213164, China
| | - Mohan Li
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China.
| | - Xiqing Yue
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China.
| | - Siew Young Quek
- Food Science, School of Chemical Sciences, The University of Auckland, Auckland, 1010, New Zealand; Riddet Institute, Centre for Research Excellence in Food Research, Palmerston North 4474, New Zealand.
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Ivashkevich D, Ponomarenko A, Manzhulo I, Egoraeva A, Dyuizen I. Hepatoprotective and Antiatherosclerotic Effects of Oleoylethanolamide-Based Dietary Supplement in Dietary-Induced Obesity in Mice. PATHOPHYSIOLOGY 2025; 32:16. [PMID: 40265441 PMCID: PMC12015875 DOI: 10.3390/pathophysiology32020016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/15/2025] [Accepted: 04/17/2025] [Indexed: 04/24/2025] Open
Abstract
Background: Metabolic effects of oleoylethanolamide-based dietary supplement (OEA-DS) were studied in a model of dietary-induced obesity in mice. Obesity was induced by a 2-month high-fat, high-cholesterol diet, resulting in significant morphological changes in liver tissues and elevated cholesterol levels in the animals' blood serum. Elevated levels of proinflammatory cytokines, oxidative stress, and hepatocyte apoptosis were also observed in the liver tissue. The aim of this study was to examine the mechanisms through which an OEA-based dietary supplement (OEA-DS) exerts a comprehensive influence on multiple aspects of the pathogenesis of MASLD, thereby demonstrating a robust hepatoprotective effect. Methods: mice were fed a high-fat, high-cholesterol diet with or without OEA-DS supplementation. Liver tissues and blood serum were analyzed for cholesterol levels, inflammatory markers (CD68, Iba-1, CD163, IL-1β, IL-6, TNFα), apoptotic markers (Bad, Bax, Bcl-2), nuclear receptors (PPAR-α, PPAR-γ, AdipoR1), and enzymes involved in lipolysis (Acox1, Cpt1a) and cholesterol metabolism (Ldlr, Furin, Pcsk9). Immunohistochemistry, Western blotting, and RT-PCR were used to assess protein expression and gene transcription. Results: administration of OEA-DS normalized cholesterol levels, decreased expression of inflammatory markers (CD68 and Iba-1), pro-apoptotic markers (Bad, Bax) and levels of pro-inflammatory cytokines (IL-1β, IL-6, TNFα). In parallel, the expression of nuclear receptors PPAR-α and PPAR-γ, adiponectin receptor 1 (AdipoR1), and anti-inflammatory (CD163) and anti-apoptotic (Bcl-2) markers have risen. OEA-DS administration induced the expression of liver lipolysis enzymes (Acox1, Cpt1a) and cholesterol metabolism factors (Ldlr, Furin), while simultaneously reducing the transcription of the proatherogenic factor Pcsk9. Conclusions: The results of this study suggest a complex action of OEA-DS in obesity-associated liver damage, which includes reduction of systemic inflammation.
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Affiliation(s)
| | | | - Igor Manzhulo
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str., 17, 690041 Vladivostok, Russia; (D.I.); (A.P.); (A.E.); (I.D.)
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4
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Wang Y, Fang F, Liu X. Targeting histamine in metabolic syndrome: Insights and therapeutic potential. Life Sci 2024; 358:123172. [PMID: 39461668 DOI: 10.1016/j.lfs.2024.123172] [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: 07/29/2024] [Revised: 10/04/2024] [Accepted: 10/21/2024] [Indexed: 10/29/2024]
Abstract
Metabolic syndrome is a complex disorder defined by a cluster of interconnected factors including obesity, insulin resistance, hypertension, hyperlipidemia and hyperglycemia which increase the risk of cardiovascular disease, non-alcoholic fatty liver disease, type 2 diabetes mellitus and other related diseases. Histamine, as a biogenic amine, participates in various physiological processes. Increasing evidence suggests histamine plays critical roles in Metabolic syndrome as well as its associated diseases by interacting with four histamine receptors. In this review, we summarize the functions and mechanisms of histamine in Metabolic syndrome, indicating histamine as a possible target in treating Metabolic syndrome and its associated diseases.
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Affiliation(s)
- Yiting Wang
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Fude Fang
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Xiaojun Liu
- Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
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Di Majo D, Ricciardi N, Moncada A, Allegra M, Frinchi M, Di Liberto V, Pitonzo R, Rappa F, Saiano F, Vetrano F, Miceli A, Giglia G, Ferraro G, Sardo P, Gambino G. Golden Tomato Juice Enhances Hepatic PPAR-α Expression, Mitigates Metabolic Dysfunctions and Influences Redox Balance in a High-Fat-Diet Rat Model. Antioxidants (Basel) 2024; 13:1324. [PMID: 39594468 PMCID: PMC11591511 DOI: 10.3390/antiox13111324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/24/2024] [Accepted: 10/28/2024] [Indexed: 11/28/2024] Open
Abstract
Golden tomato (GT), harvested at the veraison stage, has gained attention due to its rich content of bioactive compounds and potential health benefits. Previous studies have highlighted GT's antioxidant properties and its positive effects on metabolic syndrome (MetS), a condition characterized by obesity, dyslipidemia, and oxidative stress. This study investigates for the first time a derivative from GT, i.e., the juice (GTJ), which could be a potential candidate for development as a functional food. We first characterized GT juice, identifying 9-oxo-10(E),12(E)-octadecadienoic (9-oxo-10(E),12(E)-ODA) fatty acid, a known peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, using High-Performance Liquid Chromatography (HPLC)-mass spectrometry. Then, using a high-fat-diet (HFD) rat model, we assessed the impact of daily GT juice supplementation in addressing MetS. We outlined that GTJ improved body weight and leptin-mediated food intake. Moreover, it ameliorated glucose tolerance, lipid profile, systemic redox homeostasis, hepatic oxidative stress, and steatosis in HFD rats. Furthermore, GT juice enhances the hepatic transcription of PPAR-α, thus putatively promoting fatty acid oxidation and lipid metabolism. These findings suggest that GT juice mitigates lipidic accumulation and putatively halters oxidative species at the hepatic level through PPAR-α activation. Our study underscores the protective effects of GT juice against MetS, highlighting its future potential as a nutraceutical for improving dysmetabolism and associated alterations.
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Affiliation(s)
- Danila Di Majo
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy; (N.R.); (M.F.); (V.D.L.); (F.R.); (G.G.); (G.F.); (P.S.); (G.G.)
- Postgraduate School of Nutrition and Food Science, University of Palermo, 90100 Palermo, Italy;
| | - Nicolò Ricciardi
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy; (N.R.); (M.F.); (V.D.L.); (F.R.); (G.G.); (G.F.); (P.S.); (G.G.)
| | - Alessandra Moncada
- Department of Agricultural, Food and Forest Sciences (SAAF), University of Palermo, 90128 Palermo, Italy; (A.M.); (F.S.); (F.V.); (A.M.)
| | - Mario Allegra
- Postgraduate School of Nutrition and Food Science, University of Palermo, 90100 Palermo, Italy;
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy
| | - Monica Frinchi
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy; (N.R.); (M.F.); (V.D.L.); (F.R.); (G.G.); (G.F.); (P.S.); (G.G.)
| | - Valentina Di Liberto
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy; (N.R.); (M.F.); (V.D.L.); (F.R.); (G.G.); (G.F.); (P.S.); (G.G.)
| | - Rosa Pitonzo
- ATeN (Advanced Technologies Network) Center, 90128 Palermo, Italy;
| | - Francesca Rappa
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy; (N.R.); (M.F.); (V.D.L.); (F.R.); (G.G.); (G.F.); (P.S.); (G.G.)
| | - Filippo Saiano
- Department of Agricultural, Food and Forest Sciences (SAAF), University of Palermo, 90128 Palermo, Italy; (A.M.); (F.S.); (F.V.); (A.M.)
| | - Filippo Vetrano
- Department of Agricultural, Food and Forest Sciences (SAAF), University of Palermo, 90128 Palermo, Italy; (A.M.); (F.S.); (F.V.); (A.M.)
| | - Alessandro Miceli
- Department of Agricultural, Food and Forest Sciences (SAAF), University of Palermo, 90128 Palermo, Italy; (A.M.); (F.S.); (F.V.); (A.M.)
| | - Giuseppe Giglia
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy; (N.R.); (M.F.); (V.D.L.); (F.R.); (G.G.); (G.F.); (P.S.); (G.G.)
- Postgraduate School of Nutrition and Food Science, University of Palermo, 90100 Palermo, Italy;
- Euro Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
| | - Giuseppe Ferraro
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy; (N.R.); (M.F.); (V.D.L.); (F.R.); (G.G.); (G.F.); (P.S.); (G.G.)
- Postgraduate School of Nutrition and Food Science, University of Palermo, 90100 Palermo, Italy;
| | - Pierangelo Sardo
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy; (N.R.); (M.F.); (V.D.L.); (F.R.); (G.G.); (G.F.); (P.S.); (G.G.)
- Postgraduate School of Nutrition and Food Science, University of Palermo, 90100 Palermo, Italy;
| | - Giuditta Gambino
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy; (N.R.); (M.F.); (V.D.L.); (F.R.); (G.G.); (G.F.); (P.S.); (G.G.)
- Postgraduate School of Nutrition and Food Science, University of Palermo, 90100 Palermo, Italy;
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Ostadrahimi A, Khajebishak Y, Moradi F, Payahoo L. The effect of Oleoylethanolamide supplementation on lipid profile, fasting blood sugar and dietary habits in obese people: a randomized double-blind placebo-control trial. BMC Endocr Disord 2024; 24:210. [PMID: 39379951 PMCID: PMC11460158 DOI: 10.1186/s12902-024-01738-7] [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: 06/22/2024] [Accepted: 09/18/2024] [Indexed: 10/10/2024] Open
Abstract
BACKGROUND Abnormalities in biochemical parameters and changes in eating habits are considered complications of obesity. Oleoylethanolamide (OEA), an endocannabinoid-like compound, has been shown to have protective effects on many metabolic disorders. Given this evidence, the present study aimed to assess the effects of OEA on lipid profile parameters, fasting blood sugar (FBS), and dietary habits in healthy obese people. METHODS In this randomized, double-blind, placebo-controlled clinical trial, which was carried out in 2016 in Tabriz, Iran, 60 obese people were enrolled in the study based on inclusion criteria. The intervention group consumed 125 mg of OEA capsules, and the placebo group received the same amount of starch twice for 8 weeks. Blood samples (5 mL) were taken at baseline and the end of the study in a fasting state. Serum concentrations of FBS, triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), and total cholesterol (TC) were measured by enzymatic methods using commercial kits. The low-density lipoprotein cholesterol (LDL-C) concentration was obtained using the Friede-Wald formula. To assess dietary habits, a food frequency questionnaire (147 items) was used at baseline and the end of the study. A value less than < 0.05 was considered to indicate statistical significance. RESULTS The TG concentration decreased significantly in the intervention group (mean (SD): 166.29 (70.01) mg/dL to 142.22 (48.05) mg/dL, p = 0.047). Changes in the placebo group were not significant (p > 0.05). After adjusting for baseline values and demographic characteristics, the difference in TG between groups remained significant (p = 0.044). Changes in other biochemical parameters were not significant. There was no significant difference between or within groups in terms of food groups. CONCLUSION OEA, as a complementary agent, plays a protective role in TG regulation. However, future studies with longer durations are needed to explore the impact of OEA on regulating dietary habits and to identify the mechanisms related to metabolic abnormalities in obese people. TRIAL REGISTRATION The study was registered in the Iranian Registry of Clinical Trials (IRCT) center as IRCT201607132017N30 with URL. www.IRCT.IR in date 03/10/2016.
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Affiliation(s)
- Alireza Ostadrahimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yaser Khajebishak
- Nutrition Sciences, Department of Nutrition, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Fardin Moradi
- Student Research Committee, School of Nutritional Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Laleh Payahoo
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
- Nutrition Sciences, Medicinal Plants Research Center, Maragheh University of Medical Sciences, Maragheh, Iran.
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Sahin C, Melanson JR, Le Billan F, Magomedova L, Ferreira TAM, Oliveira AS, Pollock-Tahari E, Saikali MF, Cash SB, Woo M, Romeiro LAS, Cummins CL. A novel fatty acid mimetic with pan-PPAR partial agonist activity inhibits diet-induced obesity and metabolic dysfunction-associated steatotic liver disease. Mol Metab 2024; 85:101958. [PMID: 38763495 PMCID: PMC11170206 DOI: 10.1016/j.molmet.2024.101958] [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: 01/28/2024] [Revised: 05/09/2024] [Accepted: 05/13/2024] [Indexed: 05/21/2024] Open
Abstract
OBJECTIVE The prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it is essential that effective, accessible, low-cost therapeutics are developed. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that tightly regulate glucose homeostasis and lipid metabolism and are important drug targets for the treatment of type 2 diabetes and dyslipidemia. We previously identified LDT409, a fatty acid-like compound derived from cashew nut shell liquid, as a novel pan-active PPARα/γ/δ compound. Herein, we aimed to assess the efficacy of LDT409 in vivo and investigate the molecular mechanisms governing the actions of the fatty acid mimetic LDT409 in diet-induced obese mice. METHODS C57Bl/6 mice (6-11-month-old) were fed a chow or high fat diet (HFD) for 4 weeks; mice thereafter received once daily intraperitoneal injections of vehicle, 10 mg/kg Rosiglitazone, 40 mg/kg WY14643, or 40 mg/kg LDT409 for 18 days while continuing the HFD. During treatments, body weight, food intake, glucose and insulin tolerance, energy expenditure, and intestinal lipid absorption were measured. On day 18 of treatment, tissues and plasma were collected for histological, molecular, and biochemical analysis. RESULTS We found that treatment with LDT409 was effective at reversing HFD-induced obesity and associated metabolic abnormalities in mice. LDT409 lowered food intake and hyperlipidemia, while improving insulin tolerance. Despite being a substrate of both PPARα and PPARγ, LDT409 was crucial for promoting hepatic fatty acid oxidation and reducing hepatic steatosis in HFD-fed mice. We also highlighted a role for LDT409 in white and brown adipocytes in vitro and in vivo where it decreased fat accumulation, increased lipolysis, induced browning of WAT, and upregulated thermogenic gene Ucp1. Remarkably, LDT409 reversed HFD-induced weight gain back to chow-fed control levels. We determined that the LDT409-induced weight-loss was associated with a combination of increased energy expenditure (detectable before weight loss was apparent), decreased food intake, increased systemic fat utilization, and increased fecal lipid excretion in HFD-fed mice. CONCLUSIONS Collectively, LDT409 represents a fatty acid mimetic that generates a uniquely favorable metabolic response for the treatment of multiple abnormalities including obesity, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and diabetes. LDT409 is derived from a highly abundant natural product-based starting material and its development could be pursued as a therapeutic solution to the global metabolic health crisis.
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Affiliation(s)
- Cigdem Sahin
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada
| | - Jenna-Rose Melanson
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada
| | - Florian Le Billan
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada
| | - Lilia Magomedova
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada
| | - Thais A M Ferreira
- Department of Pharmacy, Faculty of Health Sciences, University of Brasilia, Brasilia, DF 71910-900, Brazil
| | - Andressa S Oliveira
- Department of Pharmacy, Faculty of Health Sciences, University of Brasilia, Brasilia, DF 71910-900, Brazil
| | - Evan Pollock-Tahari
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada
| | - Michael F Saikali
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada
| | - Sarah B Cash
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada
| | - Minna Woo
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada; Banting and Best Diabetes Centre, Toronto, ON, M5G 2C4, Canada
| | - Luiz A S Romeiro
- Department of Pharmacy, Faculty of Health Sciences, University of Brasilia, Brasilia, DF 71910-900, Brazil
| | - Carolyn L Cummins
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada; Banting and Best Diabetes Centre, Toronto, ON, M5G 2C4, Canada.
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8
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Shivyari FT, Pakniat H, Nooshabadi MR, Rostami S, Haghighian HK, Shiri-Shahsavari MR. Examining the oleoylethanolamide supplement effects on glycemic status, oxidative stress, inflammation, and anti-mullerian hormone in polycystic ovary syndrome. J Ovarian Res 2024; 17:111. [PMID: 38778429 PMCID: PMC11110282 DOI: 10.1186/s13048-024-01432-1] [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: 10/21/2023] [Accepted: 05/04/2024] [Indexed: 05/25/2024] Open
Abstract
OBJECTIVE This clinical trial was designed and conducted due to the anti-inflammatory potential of Oleoylethanolamide (OEA) to examine the effect of OEA supplement on glycemic status, oxidative stress, inflammatory factors, and anti-Mullerian hormone (AMH) in women with polycystic ovary syndrome (PCOS). METHOD This study was a randomized clinical trial, double-blinded, placebo-controlled that was carried out on 90 women with PCOS. Patients were divided into two groups: receiving an OEA supplement (n = 45) or a placebo (n = 45). The intervention group received 125 mg/day OEA and the placebo group received the wheat flour for 8 weeks. Demographic data were collected through questionnaires. Fasting blood sugar (FBS), insulin resistance (IR), total antioxidant capacity (TAC), malondialdehyde (MDA), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and AMH were measured before and after the study. RESULTS Data analysis of food recall and physical activity questionnaires, showed no significant differences between the two groups (p > 0.05). Biochemical factors including glycemic status, MDA, inflammatory factors, and AMH decreased significantly (p < 0.05). TAC increased remarkably (p < 0.05) in comparison between the two groups, after the intervention. CONCLUSION OEA supplement with anti-inflammatory characteristics could be efficient independent of diet changes and physical activity in improving disrupted biochemical factors, so both supplementation or food resources of this fatty acid could be considered as a compensatory remedy in patients with PCOS. TRIAL REGISTRATION This study was retrospectively (09-01-2022) registered in the Iranian website ( www.irct.ir ) for registration of clinical trials (IRCT20141025019669N20).
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Affiliation(s)
| | - Hamideh Pakniat
- Clinical Research Development Unit, Kowsar Hospital, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | - Shaghayegh Rostami
- Clinical Research Development Unit, Kowsar Hospital, Qazvin University of Medical Sciences, Qazvin, Iran
- Metabolic Diseases Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Hossein Khadem Haghighian
- Metabolic Diseases Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran.
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Takenoya F, Shibato J, Yamashita M, Kimura A, Hirako S, Chiba Y, Nonaka N, Shioda S, Rakwal R. Transcriptomic (DNA Microarray) and Metabolome (LC-TOF-MS) Analyses of the Liver in High-Fat Diet Mice after Intranasal Administration of GALP (Galanin-like Peptide). Int J Mol Sci 2023; 24:15825. [PMID: 37958806 PMCID: PMC10648535 DOI: 10.3390/ijms242115825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/20/2023] [Accepted: 10/28/2023] [Indexed: 11/15/2023] Open
Abstract
The aim of this research was to test the efficacy and potential clinical application of intranasal administration of galanin-like peptide (GALP) as an anti-obesity treatment under the hypothesis that GALP prevents obesity in mice fed a high-fat diet (HFD). Focusing on the mechanism of regulation of lipid metabolism in peripheral tissues via the autonomic nervous system, we confirmed that, compared with a control (saline), intranasally administered GALP prevented further body weight gain in diet-induced obesity (DIO) mice with continued access to an HFD. Using an omics-based approach, we identified several genes and metabolites in the liver tissue of DIO mice that were altered by the administration of intranasal GALP. We used whole-genome DNA microarray and metabolomics analyses to determine the anti-obesity effects of intranasal GALP in DIO mice fed an HFD. Transcriptomic profiling revealed the upregulation of flavin-containing dimethylaniline monooxygenase 3 (Fmo3), metallothionein 1 and 2 (Mt1 and Mt2, respectively), and the Aldh1a3, Defa3, and Defa20 genes. Analysis using the DAVID tool showed that intranasal GALP enhanced gene expression related to fatty acid elongation and unsaturated fatty acid synthesis and downregulated gene expression related to lipid and cholesterol synthesis, fat absorption, bile uptake, and excretion. Metabolite analysis revealed increased levels of coenzyme Q10 and oleoylethanolamide in the liver tissue, increased levels of deoxycholic acid (DCA) and taurocholic acid (TCA) in the bile acids, increased levels of taurochenodeoxycholic acid (TCDCA), and decreased levels of ursodeoxycholic acid (UDCA). In conclusion, intranasal GALP administration alleviated weight gain in obese mice fed an HFD via mechanisms involving antioxidant, anti-inflammatory, and fatty acid metabolism effects and genetic alterations. The gene expression data are publicly available at NCBI GSE243376.
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Affiliation(s)
- Fumiko Takenoya
- Department of Sport Sciences, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan; (F.T.); (M.Y.); (A.K.)
| | - Junko Shibato
- Department of Functional Morphology, Shonan University of Medical Sciences, Kanagawa 244-0806, Japan; (J.S.); (S.S.)
| | - Michio Yamashita
- Department of Sport Sciences, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan; (F.T.); (M.Y.); (A.K.)
| | - Ai Kimura
- Department of Sport Sciences, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan; (F.T.); (M.Y.); (A.K.)
| | - Satoshi Hirako
- Department of Health and Nutrition, University of Human Arts and Sciences, Saitama 339-8539, Japan;
| | - Yoshihiko Chiba
- Laboratory of Molecular Biology and Physiology, School of Pharmacy, Hoshi University, Tokyo 142-8501, Japan;
| | - Naoko Nonaka
- Department of Oral Anatomy and Developmental Biology, Showa University School of Dentistry, Tokyo 142-8555, Japan;
| | - Seiji Shioda
- Department of Functional Morphology, Shonan University of Medical Sciences, Kanagawa 244-0806, Japan; (J.S.); (S.S.)
| | - Randeep Rakwal
- Institute of Health and Sport Sciences, University of Tsukuba, Tsukuba 305-8574, Japan
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10
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Liu X, Li C, Hou C, Jiang Y, Chen F, Zhu Y, Zou L. Dissecting the effects of paraquat-induced pulmonary injury in rats using UPLC-Q-TOF-MS/MS-based metabonomics. Toxicol Res (Camb) 2023; 12:527-538. [PMID: 37397915 PMCID: PMC10311158 DOI: 10.1093/toxres/tfad040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 02/22/2023] [Accepted: 05/14/2023] [Indexed: 07/04/2023] Open
Abstract
Objective Paraquat (PQ) is a toxic compound that selectively accumulates in the lungs, inducing severe pulmonary inflammation and fibrosis. However, data on the metabolomic changes induced by the PQ remain scant. This study aimed to determine the metabolic changes in Sprague-Dawley rats subjected to PQ using UPLC-Q-TOF-MS/MS. Methods We established groups of PQ-induced pulmonary injury rats for 14 or 28 days. Results Our data showed that PQ decreased the survival of the rats and induced pulmonary inflammation at day 14 or pulmonary fibrosis at day 28. There was upregulation of IL-1β expression in the inflammation group as well as upregulation of fibronectin, collagen and α-SMA in the pulmonary fibrosis group. OPLS-DA revealed differential expression of 26 metabotites between the normal and the inflammation groups; 31 plasma metabotites were also differently expressed between the normal and the fibrosis groups. There was high expression of lysoPc160-, hydroxybutyrylcarnitine, stearic acid, and imidazolelactic acid in the pulmonary injury group compared to the normal group. Conclusion Metabolomics analysis confirmed that the PQ-induced lung injury was not only related to the aggravation of inflammation and apoptosis but also to mediated histidine, serine, glycerophospholipid, and lipid metabolism. This study gives insights into the mechanisms of PQ-induced lung injury and highlights the potential therapeutic targets. Nonstructured abstract The effect of PQ on lung injury in rats was detected by metabonomics, and the possible metabolic mechanism was investigated by KEGG analysis. OPLS-DA revealed the differential expression of 26 metabotites and 31 plasma metabotites between the normal and the pulmonary injury groups. Metabolomics analysis confirmed that the PQ-induced lung injury was not only related to the aggravation of inflammation and apoptosis but also to mediated histidine, serine, glycerophospholipid, and lipid metabolism. Oleoylethanolamine, stearic acid, and imidazolelactic acid are potential molecular markers in PQ-induced pulmonary injury.
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Affiliation(s)
- Xiehong Liu
- Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics,61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provinicial Institute of Emergency Medicine, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
| | - Chi Li
- Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics,61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provinicial Institute of Emergency Medicine, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
| | - Changmiao Hou
- Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics,61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provinicial Institute of Emergency Medicine, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- School of Clinical Medicine, Hunan University of Chinese Medicine, 113 Shaoshan Middle Road, Changsha, Hunan, PC 410000, China
| | - Yu Jiang
- Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics,61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provinicial Institute of Emergency Medicine, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
| | - Fang Chen
- Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics,61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provinicial Institute of Emergency Medicine, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
| | - Yimin Zhu
- Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics,61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provinicial Institute of Emergency Medicine, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
| | - Lianhong Zou
- Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics,61 Jiefang West Road, Changsha, Hunan, PC 410005, China
- Hunan Provinicial Institute of Emergency Medicine, 61 Jiefang West Road, Changsha, Hunan, PC 410005, China
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11
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De Filippo C, Costa A, Becagli MV, Monroy MM, Provensi G, Passani MB. Gut microbiota and oleoylethanolamide in the regulation of intestinal homeostasis. Front Endocrinol (Lausanne) 2023; 14:1135157. [PMID: 37091842 PMCID: PMC10113643 DOI: 10.3389/fendo.2023.1135157] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 03/22/2023] [Indexed: 04/08/2023] Open
Abstract
A vast literature strongly suggests that the endocannabinoid (eCB) system and related bioactive lipids (the paracannabinoid system) contribute to numerous physiological processes and are involved in pathological conditions such as obesity, type 2 diabetes, and intestinal inflammation. The gut paracannabinoid system exerts a prominent role in gut physiology as it affects motility, permeability, and inflammatory responses. Another important player in the regulation of host metabolism is the intestinal microbiota, as microorganisms are indispensable to protect the intestine against exogenous pathogens and potentially harmful resident microorganisms. In turn, the composition of the microbiota is regulated by intestinal immune responses. The intestinal microbial community plays a fundamental role in the development of the innate immune system and is essential in shaping adaptive immunity. The active interplay between microbiota and paracannabinoids is beginning to appear as potent regulatory system of the gastrointestinal homeostasis. In this context, oleoylethanolamide (OEA), a key component of the physiological systems involved in the regulation of dietary fat consumption, energy homeostasis, intestinal motility, and a key factor in modulating eating behavior, is a less studied lipid mediator. In the small intestine namely duodenum and jejunum, levels of OEA change according to the nutrient status as they decrease during food deprivation and increase upon refeeding. Recently, we and others showed that OEA treatment in rodents protects against inflammatory events and changes the intestinal microbiota composition. In this review, we briefly define the role of OEA and of the gut microbiota in intestinal homeostasis and recapitulate recent findings suggesting an interplay between OEA and the intestinal microorganisms.
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Affiliation(s)
- Carlotta De Filippo
- Istituto di Biologia e Biotecnologia Agraria, Consiglio Nazionale delle Ricerche, Pisa, Italy
| | - Alessia Costa
- Dipartimento di Scienze della Salute, Università di Firenze, Firenze, Italy
| | | | - Mariela Mejia Monroy
- Istituto di Biologia e Biotecnologia Agraria, Consiglio Nazionale delle Ricerche, Pisa, Italy
| | - Gustavo Provensi
- Dipartimento di Neurofarba, Università di Firenze, Firenze, Italy
- *Correspondence: Maria Beatrice Passani, ; Gustavo Provensi,
| | - Maria Beatrice Passani
- Dipartimento di Scienze della Salute, Università di Firenze, Firenze, Italy
- *Correspondence: Maria Beatrice Passani, ; Gustavo Provensi,
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12
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Down-regulation of hepatic CLOCK by PPARα is involved in inhibition of NAFLD. J Mol Med (Berl) 2023; 101:139-149. [PMID: 36527474 DOI: 10.1007/s00109-022-02279-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 11/24/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022]
Abstract
This work aimed to investigate the role of nuclear factor peroxisome proliferator-activated receptor α (PPARα) in modification of circadian clock and their relevance to development of nonalcoholic fatty liver disease (NAFLD). Both male wild-type (WT) and Pparα-null (KO) mice treated with high-fat diet (HFD) were used to explore the effect of PPARα and lipid diet on the circadian rhythm. WT, KO, and PPARα-humanized (hPPARα) mice were treated with PPARα agonist fenofibrate to reveal the hPPARα dependence of circadian locomotor output cycles kaput (CLOCK) down-regulation. The mouse model and hepatocyte experiments were designed to verify the action of PPARα in down-regulating CLOCK and lipid accumulation in vivo and in vitro. Strongest NAFLD developed in mice fed 45%HFD, and it was inhibited in WT mice. The activity rhythm of WT mice was found to be different from that of the KO mice on normal diet and HFD. The core circadian factor CLOCK was down-regulated by HFD in both WT and KO mice in the liver, not in the hypothalamus. More interestingly, hepatic CLOCK was down-regulated by basal PPARα and activated PPARα in dose dependence of fenofibrate. Accordingly, CLOCK down-regulation dependent of PPARα activity was involved in inhibition of lipid metabolism in hepatocytes. Down-regulation of hepatic CLOCK by basal PPARα contributes to tolerance against development of NAFLD. Inhibition of CLOCK by activated PPARα is involved in inhibition of NAFLD by PPARα agonists. KEY MESSAGES: • PPARα inhibited NAFLD development induced by HFD. • PPARα mediated modifications of circadian rhythm and the hepatic circadian factor CLOCK in NAFLD models. • Down-regulation of hepatic CLOCK by basal PPARα contributed to tolerance against development of NAFLD. • Inhibition of CLOCK by activated PPARα was involved in therapeutic actions against fatty liver diseases by PPARα agonists.
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13
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Tutunchi H, Zolrahim F, Nikbaf-Shandiz M, Naeini F, Ostadrahimi A, Naghshi S, Salek R, Najafipour F. Effects of oleoylethanolamide supplementation on inflammatory biomarkers, oxidative stress and antioxidant parameters of obese patients with NAFLD on a calorie-restricted diet: A randomized controlled trial. Front Pharmacol 2023; 14:1144550. [PMID: 37089938 PMCID: PMC10119414 DOI: 10.3389/fphar.2023.1144550] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 03/28/2023] [Indexed: 04/25/2023] Open
Abstract
Background: Oxidative stress is considered a major factor in the pathophysiology of non-alcoholic liver disease (NAFLD). A growing body of evidence indicates that oleoylethanolamide (OEA), a bioactive lipid mediator, has anti-inflammatory and antioxidant properties. This trial investigated the effects of OEA administration on inflammatory markers, oxidative stress and antioxidant parameters of patients with NAFLD. Methods: The present randomized controlled trial was conducted on 60 obese patients with NAFLD. The patients were treated with OEA (250 mg/day) or placebo along with a low-calorie diet for 12 weeks. Inflammatory markers and oxidative stress and antioxidant parameters were evaluated pre-and post-intervention. Results: At the end of the study, neither the between-group changes, nor the within-group differences were significant for serum levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-1 beta (IL-1β), IL-6, IL-10, and tumor necrosis-factor α (TNF-α). Serum levels of total antioxidant capacity (TAC) and superoxide dismutase (SOD) significantly increased and serum concentrations of malondialdehyde (MDA) and oxidized-low density lipoprotein (ox-LDL) significantly decreased in the OEA group compared to placebo at study endpoint (p = 0.039, 0.018, 0.003 and 0.001, respectively). Although, no significant between-group alterations were found in glutathione peroxidase and catalase. There were significant correlations between percent of changes in serum oxidative stress and antioxidant parameters with percent of changes in some anthropometric indices in the intervention group. Conclusion: OEA supplementation could improve some oxidative stress/antioxidant biomarkers without any significant effect on inflammation in NAFLD patients. Further clinical trials with longer follow-up periods are demanded to verify profitable effects of OEA in these patients. Clinical Trial Registration: www.irct.ir, Iranian Registry of Clinical Trials IRCT20090609002017N32.
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Affiliation(s)
- Helda Tutunchi
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farideh Zolrahim
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Fatemeh Naeini
- Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Ostadrahimi
- Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sina Naghshi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Salek
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farzad Najafipour
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- *Correspondence: Farzad Najafipour,
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14
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Pu J. Targeting the lysosome: Mechanisms and treatments for nonalcoholic fatty liver disease. J Cell Biochem 2022; 123:1624-1633. [PMID: 35605052 PMCID: PMC9617749 DOI: 10.1002/jcb.30274] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/24/2022] [Accepted: 05/02/2022] [Indexed: 11/11/2022]
Abstract
The multiple functions of the lysosome, including degradation, nutrient sensing, signaling, and gene regulation, enable the lysosome to regulate lipid metabolism at different levels. In this review, I summarize the recent studies on lysosomal regulation of lipid metabolism and the alterations of the lysosome functions in the livers affected by nonalcoholic fatty liver disease (NAFLD). NAFLD is a highly prevalent lipid metabolic disorder. The progression of NAFLD leads to nonalcoholic steatohepatitis (NASH) and other severe liver diseases, and thus the prevention and treatments of NAFLD progression are critically needed. Targeting the lysosome is a promising strategy. I also discuss the current manipulations of the lysosome functions in the preclinical studies of NAFLD and propose my perspectives on potential future directions.
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Affiliation(s)
- Jing Pu
- Department of Molecular Genetics and Microbiology, Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence, University of New Mexico, Albuquerque, New Mexico, USA
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15
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The Effect of Oleoylethanolamide (OEA) Add-On Treatment on Inflammatory, Oxidative Stress, Lipid, and Biochemical Parameters in the Acute Ischemic Stroke Patients: Randomized Double-Blind Placebo-Controlled Study. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5721167. [PMID: 36120593 PMCID: PMC9477639 DOI: 10.1155/2022/5721167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 04/01/2022] [Accepted: 06/05/2022] [Indexed: 11/18/2022]
Abstract
Methods Sixty patients with a mean age of 68.60 ± 2.10 comprising 29 females (48.33%), who were admitted to an academic tertiary care facility within the first 12 hours poststroke symptoms onset or last known well (LKW), in case symptom onset time is not clear, were included in this study. AIS was confirmed based on a noncontrast head CT scan and also neurological symptoms. Patients were randomly and blindly assigned to OEA of 300 mg/day (n = 20) or 600 mg/day (n = 20) or placebo (n = 20) in addition to the standard AIS treatment for three days. A blood sample was drawn at 12 hours from symptoms onset or LKW as the baseline followed by the second blood sample at 72 hours post symptoms onset or LKW. Blood samples were assessed for inflammatory and biochemical parameters, oxidative stress (OS) biomarkers, and lipid profile. Results Compared to the baseline, there is a significant reduction in the urea, creatinine, triglyceride, high-density lipoprotein, cholesterol, alanine transaminase, total antioxidant capacity, malondialdehyde (MDA), total thiol groups (TTG), interleukin-6 (IL-6), and C-reactive protein levels on the follow-up blood testing in the OEA (300 mg/day) group. In patients receiving OEA (600 mg/day) treatment, there was only a significant reduction in the MDA level comparing baseline with follow-up blood testing. Also, the between-group analysis revealed a statistically significant difference between patients receiving OEA (300 mg/day) and placebo in terms of IL-6 and TTG level reduction when comparing them between baseline and follow-up blood testing. Conclusion OEA in moderate dosage, 300 mg/day, add-on to the standard stroke treatment improves short-term inflammatory, OS, lipid, and biochemical parameters in patients with AIS. This effect might lead to a better long-term neurological prognosis.
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16
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Yu H, Yi X, Gao X, Ji J, Liu Z, Xia G, Li C, Zhang X, Shen X. Tilapia-Head Chondroitin Sulfate Protects against Nonalcoholic Fatty Liver Disease via Modulating the Gut-Liver Axis in High-Fat-Diet-Fed C57BL/6 Mice. Foods 2022; 11:foods11070922. [PMID: 35407014 PMCID: PMC8997817 DOI: 10.3390/foods11070922] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/15/2022] [Accepted: 03/18/2022] [Indexed: 12/12/2022] Open
Abstract
We isolated and characterized tilapia-head chondroitin sulfate (TH-CS) and explored its biological activity and mechanisms of action as an oral supplement for nonalcoholic fatty liver disease (NAFLD) induced by a high-fat diet (HFD) in mice. The results showed that treatment with TH-CS for 8 weeks alleviated the development of NAFLD, as evidenced by the notable improvement in liver damage, blood lipid accumulation and insulin resistance (IR). Meanwhile, TH-CS treatment reduced the expression of proinflammatory cytokines and normalized oxidative stress. Additionally, the analysis of 16S rDNA sequencing revealed that TH-CS could restore gut microbiota balance and increase the relative abundance of short-chain fatty acid (SCFA)-producing bacteria. Furthermore, SCFAs produced by related bacteria can further improve lipid metabolism and IR by regulating lipid synthesis signals. In conclusion, TH-CS is an effective dietary supplement for the prevention of NAFLD, and may serve as a potential supplementary treatment for lipid-related metabolic syndrome.
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Affiliation(s)
- Hui Yu
- Hainan Engineering Research Center of Aquatic Resources Efficient Utilization in South China Sea, Hainan University, Haikou 570228, China; (H.Y.); (X.Y.); (X.G.); (J.J.); (Z.L.); (G.X.); (C.L.); (X.Z.)
- College of Food Science and Technology, Hainan University, Haikou 570228, China
| | - Xiangzhou Yi
- Hainan Engineering Research Center of Aquatic Resources Efficient Utilization in South China Sea, Hainan University, Haikou 570228, China; (H.Y.); (X.Y.); (X.G.); (J.J.); (Z.L.); (G.X.); (C.L.); (X.Z.)
- College of Food Science and Technology, Hainan University, Haikou 570228, China
| | - Xia Gao
- Hainan Engineering Research Center of Aquatic Resources Efficient Utilization in South China Sea, Hainan University, Haikou 570228, China; (H.Y.); (X.Y.); (X.G.); (J.J.); (Z.L.); (G.X.); (C.L.); (X.Z.)
- College of Food Science and Technology, Hainan University, Haikou 570228, China
| | - Jun Ji
- Hainan Engineering Research Center of Aquatic Resources Efficient Utilization in South China Sea, Hainan University, Haikou 570228, China; (H.Y.); (X.Y.); (X.G.); (J.J.); (Z.L.); (G.X.); (C.L.); (X.Z.)
- College of Food Science and Technology, Hainan University, Haikou 570228, China
| | - Zhongyuan Liu
- Hainan Engineering Research Center of Aquatic Resources Efficient Utilization in South China Sea, Hainan University, Haikou 570228, China; (H.Y.); (X.Y.); (X.G.); (J.J.); (Z.L.); (G.X.); (C.L.); (X.Z.)
- College of Food Science and Technology, Hainan University, Haikou 570228, China
- Collaborative Innovation Center of Marine Food Deep Processing, Dalian Polytechnic University, Dalian 116000, China
| | - Guanghua Xia
- Hainan Engineering Research Center of Aquatic Resources Efficient Utilization in South China Sea, Hainan University, Haikou 570228, China; (H.Y.); (X.Y.); (X.G.); (J.J.); (Z.L.); (G.X.); (C.L.); (X.Z.)
- College of Food Science and Technology, Hainan University, Haikou 570228, China
- Collaborative Innovation Center of Marine Food Deep Processing, Dalian Polytechnic University, Dalian 116000, China
| | - Chuan Li
- Hainan Engineering Research Center of Aquatic Resources Efficient Utilization in South China Sea, Hainan University, Haikou 570228, China; (H.Y.); (X.Y.); (X.G.); (J.J.); (Z.L.); (G.X.); (C.L.); (X.Z.)
- College of Food Science and Technology, Hainan University, Haikou 570228, China
- Collaborative Innovation Center of Marine Food Deep Processing, Dalian Polytechnic University, Dalian 116000, China
| | - Xueying Zhang
- Hainan Engineering Research Center of Aquatic Resources Efficient Utilization in South China Sea, Hainan University, Haikou 570228, China; (H.Y.); (X.Y.); (X.G.); (J.J.); (Z.L.); (G.X.); (C.L.); (X.Z.)
- College of Food Science and Technology, Hainan University, Haikou 570228, China
- Collaborative Innovation Center of Marine Food Deep Processing, Dalian Polytechnic University, Dalian 116000, China
| | - Xuanri Shen
- Hainan Engineering Research Center of Aquatic Resources Efficient Utilization in South China Sea, Hainan University, Haikou 570228, China; (H.Y.); (X.Y.); (X.G.); (J.J.); (Z.L.); (G.X.); (C.L.); (X.Z.)
- College of Food Science and Technology, Hainan University, Haikou 570228, China
- Collaborative Innovation Center of Marine Food Deep Processing, Dalian Polytechnic University, Dalian 116000, China
- Correspondence: ; Tel./Fax: +86-0898-6619-3581
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Gu H, An HJ, Gwon MG, Bae S, Leem J, Lee SJ, Han SM, Zouboulis CC, Park KK. Bee Venom and Its Major Component Melittin Attenuated Cutibacterium acnes- and IGF-1-Induced Acne Vulgaris via Inactivation of Akt/mTOR/SREBP Signaling Pathway. Int J Mol Sci 2022; 23:3152. [PMID: 35328573 PMCID: PMC8953527 DOI: 10.3390/ijms23063152] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/07/2022] [Accepted: 03/09/2022] [Indexed: 01/27/2023] Open
Abstract
Acne vulgaris is the most common disease of the pilosebaceous unit. The pathogenesis of this disease is complex, involving increased sebum production and perifollicular inflammation. Understanding the factors that regulate sebum production is important in identifying novel therapeutic targets for the treatment of acne. Bee Venom (BV) and melittin have multiple effects including antibacterial, antiviral, and anti-inflammatory activities in various cell types. However, the anti-lipogenic mechanisms of BV and melittin have not been elucidated. We investigated the effects of BV and melittin in models of Insulin-like growth factor-1 (IGF-1) or Cutibacterium acnes (C. acnes)-induced lipogenic skin disease. C. acnes or IGF-1 increased the expression of sterol regulatory element-binding protein-1 (SREBP-1) and proliferator-activated receptor gamma (PPAR-γ), transcription factors that regulate numerous genes involved in lipid biosynthesis through the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/SREBP signaling pathway. In this study using a C. acnes or IGF-1 stimulated lipogenic disease model, BV and melittin inhibited the increased expression of lipogenic and pro-inflammatory factor through the blockade of the Akt/mTOR/SREBP signaling pathway. This study suggests for the first time that BV and melittin could be developed as potential natural anti-acne agents with anti-lipogenesis, anti-inflammatory, and anti-C. acnes activity.
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Affiliation(s)
- Hyemin Gu
- Department of Pathology, School of Medicine, Catholic University of Daegu, Gyeongsan 42472, Korea; (H.G.); (H.-J.A.); (M.-G.G.); (S.B.); (S.-J.L.)
| | - Hyun-Jin An
- Department of Pathology, School of Medicine, Catholic University of Daegu, Gyeongsan 42472, Korea; (H.G.); (H.-J.A.); (M.-G.G.); (S.B.); (S.-J.L.)
| | - Mi-Gyeong Gwon
- Department of Pathology, School of Medicine, Catholic University of Daegu, Gyeongsan 42472, Korea; (H.G.); (H.-J.A.); (M.-G.G.); (S.B.); (S.-J.L.)
| | - Seongjae Bae
- Department of Pathology, School of Medicine, Catholic University of Daegu, Gyeongsan 42472, Korea; (H.G.); (H.-J.A.); (M.-G.G.); (S.B.); (S.-J.L.)
| | - Jaechan Leem
- Department of Immunology, School of Medicine, Catholic University of Daegu, Gyeongsan 42472, Korea;
| | - Sun-Jae Lee
- Department of Pathology, School of Medicine, Catholic University of Daegu, Gyeongsan 42472, Korea; (H.G.); (H.-J.A.); (M.-G.G.); (S.B.); (S.-J.L.)
| | - Sang-Mi Han
- Department of Agricultural Biology, National Academy of Agricultural Science, RDA, Wanju 54875, Korea;
| | - Christos C. Zouboulis
- Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, Faculty of Health Sciences Brandenburg, Auenweg 38, 06847 Dessau, Germany;
| | - Kwan-Kyu Park
- Department of Pathology, School of Medicine, Catholic University of Daegu, Gyeongsan 42472, Korea; (H.G.); (H.-J.A.); (M.-G.G.); (S.B.); (S.-J.L.)
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18
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He LF, Wang C, Zhang YF, Guo CC, Wan Y, Li YX. Effect of Emodin on Hyperlipidemia and Hepatic Lipid Metabolism in Zebrafish Larvae Fed a High-Cholesterol Diet. Chem Biodivers 2021; 19:e202100675. [PMID: 34866324 DOI: 10.1002/cbdv.202100675] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 12/03/2021] [Indexed: 12/15/2022]
Abstract
Hyperlipidemia (HLP) is a complex pathological condition results from lipid metabolism disorder, which is closely related to obesity, atherosclerosis and steatohepatitis. Emodin (EM), a natural anthraquinone, exhibits prominent hypolipidemic effects. However, its exact mechanism is still unclear. In this study, we successfully established hyperlipidemic zebrafish model induced by 4 % high-cholesterol diet (HCD) for 10 days and explored the anti-hyperlipidemic roles and underlying mechanisms of EM. The results indicated that EM attenuated the mortality and body mass index (BMI) of zebrafish with HLP, and ameliorated abnormal lipid levels involved in TC, TG, LDL-C and HDL-C levels. Besides, EM effectively reduced lipid accumulation in blood vessels and liver, alleviated hepatic histological damage, and inhibited vascular neutrophil inflammation. Finally, the mRNA expression of molecules related to lipid metabolism were studied by using real-time quantitative polymerase chain reaction (RT-qPCR) to investigated the underlying mechanism. Further results found that treatment with EM up-regulated AMPKα, LDLR, ABCA1 and ABCG1, and down-regulated SREBP-2, PCSK9 and HMGCR expression. In conclusion, EM showed a prominent mitigative effect on lipid metabolism disorder in zebrafish larvae with HCD-stimulated HLP, which was associated with the enhancement of LDL-C uptake and reverse cholesterol transport, and inhibition of cholesterol synthesis.
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Affiliation(s)
- Lin-Feng He
- National Key Laboratory of Southwestern Chinese Medicine Resources & Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education & School of Pharmacy, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Cheng Wang
- National Key Laboratory of Southwestern Chinese Medicine Resources & Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education & School of Pharmacy, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Ya-Fang Zhang
- National Key Laboratory of Southwestern Chinese Medicine Resources & Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education & School of Pharmacy, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Chao-Cheng Guo
- National Key Laboratory of Southwestern Chinese Medicine Resources & Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education & School of Pharmacy, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Yan Wan
- National Key Laboratory of Southwestern Chinese Medicine Resources & Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education & School of Pharmacy, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Yun-Xia Li
- National Key Laboratory of Southwestern Chinese Medicine Resources & Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education & School of Pharmacy, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
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Hu J, Ying H, Yao J, Yang L, Jin W, Ma H, Li L, Zhao Y. Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy. Front Pharmacol 2021; 12:744483. [PMID: 34712137 PMCID: PMC8546106 DOI: 10.3389/fphar.2021.744483] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 09/08/2021] [Indexed: 01/14/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) has become one of the serious causes of chronic liver diseases, characterized by hepatic steatosis, hepatocellular injury, inflammation and fibrosis, and lack of efficient therapeutic agents. Palmitoylethanolamide (PEA) is an endogenous bioactive lipid with various pharmacological activities, including anti-inflammatory, analgesic, and neuroprotective effects. However, the effect of PEA on nonalcoholic steatohepatitis is still unknown. Our study aims to explore the potential protective role of PEA on NASH and to reveal the underlying mechanism. In this study, the C57BL/6 mice were used to establish the NASH model through methionine- and choline-deficient (MCD) diet feeding. Here, we found that PEA treatment significantly improved liver function, alleviated hepatic pathological changes, and attenuated the lipid accumulation and hepatic fibrosis in NASH mice induced by MCD diet feeding. Mechanistically, the anti-steatosis effect of PEA may be due to the suppressed expression of ACC1 and CD36, elevated expression of PPAR-α, and the phosphorylation levels of AMPK. In addition, hepatic oxidative stress was greatly inhibited in MCD-fed mice treated with PEA via enhancing the expression and activities of antioxidant enzymes, including GSH-px and SOD. Moreover, PEA exerted a clear anti-inflammatory effect though ameliorating the expression of inflammatory mediators and suppressing the NLRP3 inflammasome pathway activation. Furthermore, the impaired autophagy in MCD-induced mice was reactivated with PEA treatment. Taken together, our research suggested that PEA protects against NASH through the inhibition of inflammation and restoration of autophagy. Thus, PEA may represent an efficient therapeutic agent to treat NASH.
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Affiliation(s)
- Jiaji Hu
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Hanglu Ying
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Jie Yao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Longhe Yang
- Technology Innovation Center for Exploitation of Marine Biological Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen, China
| | - Wenhui Jin
- Technology Innovation Center for Exploitation of Marine Biological Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen, China
| | - Huabin Ma
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Long Li
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Yufen Zhao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
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20
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Oleoylethanolamide Reduces Hepatic Oxidative Stress and Endoplasmic Reticulum Stress in High-Fat Diet-Fed Rats. Antioxidants (Basel) 2021; 10:antiox10081289. [PMID: 34439537 PMCID: PMC8389293 DOI: 10.3390/antiox10081289] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 08/03/2021] [Accepted: 08/11/2021] [Indexed: 12/30/2022] Open
Abstract
Long-term high-fat diet (HFD) consumption can cause weight gain and obesity, two conditions often associated with hepatic non-alcoholic fatty liver and oxidative stress. Oleoylethanolamide (OEA), a lipid compound produced by the intestine from oleic acid, has been associated with different beneficial effects in diet-induced obesity and hepatic steatosis. However, the role of OEA on hepatic oxidative stress has not been fully elucidated. In this study, we used a model of diet-induced obesity to study the possible antioxidant effect of OEA in the liver. In this model rats with free access to an HFD for 77 days developed obesity, steatosis, and hepatic oxidative stress, as compared to rats consuming a low-fat diet for the same period. Several parameters associated with oxidative stress were then measured after two weeks of OEA administration to diet-induced obese rats. We showed that OEA reduced, compared to HFD-fed rats, obesity, steatosis, and the plasma level of triacylglycerols and transaminases. Moreover, OEA decreased the amount of malondialdehyde and carbonylated proteins and restored the activity of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, which decreased in the liver of HFD-fed rats. OEA had also an improving effect on parameters linked to endoplasmic reticulum stress, thus demonstrating a role in the homeostatic control of protein folding. Finally, we reported that OEA differently regulated the expression of two transcription factors involved in the control of lipid metabolism and antioxidant genes, namely nuclear factor erythroid-derived 2-related factor 1 (Nrf1) and Nrf2, thus suggesting, for the first time, new targets of the protective effect of OEA in the liver.
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21
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Martini M, Altomonte I, Tricò D, Lapenta R, Salari F. Current Knowledge on Functionality and Potential Therapeutic Uses of Donkey Milk. Animals (Basel) 2021; 11:ani11051382. [PMID: 34067986 PMCID: PMC8152225 DOI: 10.3390/ani11051382] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/05/2021] [Accepted: 05/06/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary This paper examines scientific evidence on the positive effects of donkey milk consumption on human health and its possible therapeutic applications. The most investigated clinical use of donkey milk is in feeding infants with food allergies, in whom donkey milk is well tolerated in the 82.6–98.5% of cases. Donkey milk has shown several beneficial properties, including immunomodulatory activity, antioxidant and detoxifying effects, modulation of the intestinal microbiota, and lowering of blood sugar and triglycerides, which have been tested almost exclusively in experimental animals. Inhibitory actions on microorganisms have been also observed in vitro studies. This literature review highlights the need for new clinical trials to collect stronger evidence about the positive effects observed in experimental models which could lead to new therapeutic applications of donkey milk in humans. Abstract The increase of knowledge on the composition of donkey milk has revealed marked similarities to human milk, which led to a growing number of investigations focused on testing the potential effects of donkey milk in vitro and in vivo. This paper examines the scientific evidence regarding the beneficial effects of donkey milk on human health. Most clinical studies report a tolerability of donkey milk in 82.6–98.5% of infants with cow milk protein allergies. The average protein content of donkey milk is about 18 g/L. Caseins, which are main allergenic components of milk, are less represented compared to cow milk (56% of the total protein in donkey vs. 80% in cow milk). Donkey milk is well accepted by children due to its high concentration of lactose (about 60 g/L). Immunomodulatory properties have been reported in one study in humans and in several animal models. Donkey milk also seems to modulate the intestinal microbiota, enhance antioxidant defense mechanisms and detoxifying enzymes activities, reduce hyperglycemia and normalize dyslipidemia. Donkey milk has lower calorie and fat content compared with other milks used in human nutrition (fat ranges from 0.20% to 1.7%) and a more favourable fatty acid profile, being low in saturated fatty acids (3.02 g/L) and high in alpha-linolenic acid (about 7.25 g/100 g of fat). Until now, the beneficial properties of donkey milk have been mostly related to whey proteins, among which β-lactoglobulin is the most represented (6.06 g/L), followed by α-lactalbumin (about 2 g/L) and lysozyme (1.07 g/L). So far, the health functionality of donkey milk has been tested almost exclusively on animal models. Furthermore, in vitro studies have described inhibitory action against bacteria, viruses, and fungi. From the literature review emerges the need for new randomized clinical trials on humans to provide stronger evidence of the potential beneficial health effects of donkey milk, which could lead to new applications as an adjuvant in the treatment of cardiometabolic diseases, malnutrition, and aging.
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Affiliation(s)
- Mina Martini
- Department of Veterinary Science, University of Pisa, 56124 Pisa, Italy; (M.M.); (R.L.); (F.S.)
- Interdepartmental Center for Agricultural and Environmental Research “E. Avanzi,”, University of Pisa, San Piero a Gardo (PI), 56122 Pisa, Italy
| | - Iolanda Altomonte
- Interdepartmental Center for Agricultural and Environmental Research “E. Avanzi,”, University of Pisa, San Piero a Gardo (PI), 56122 Pisa, Italy
- Correspondence:
| | - Domenico Tricò
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, 56100 Pisa, Italy;
| | - Riccardo Lapenta
- Department of Veterinary Science, University of Pisa, 56124 Pisa, Italy; (M.M.); (R.L.); (F.S.)
| | - Federica Salari
- Department of Veterinary Science, University of Pisa, 56124 Pisa, Italy; (M.M.); (R.L.); (F.S.)
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Yamagata K, Uzu E, Yoshigai Y, Kato C, Tagami M. Oleic acid and oleoylethanolamide decrease interferon-γ-induced expression of PD-L1 and induce apoptosis in human lung carcinoma cells. Eur J Pharmacol 2021; 903:174116. [PMID: 33957086 DOI: 10.1016/j.ejphar.2021.174116] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 04/16/2021] [Accepted: 04/20/2021] [Indexed: 01/10/2023]
Abstract
Inhibition of programmed death-ligand 1 (PD-L1) in cancer cells provides a reasonable avenue to prevent cancer progression. Although oleate is known to exert anti-cancer effects, its PD-L1 inhibitory effects have not been proven. This study investigated the effects of oleic acid and an oleic acid metabolite, oleoylethanolamide (OEA), on PD-L1 expression and biomarkers of tumorigenesis in several cancer cell lines, namely A549, HuH-7, MCF-7, DLD-1, and LoVo cells. Specifically, we analyzed the expression of PD-L1 and several apoptosis-related genes using RT-PCR. Interferon-gamma (IFN-γ)-induced modulation of PD-L1 protein expression was investigated using western blotting. Results indicate that IFN-γ stimulation increased the expression of PD-L1 in the chosen cancer cell lines. The IFN-γ-induced expression of PD-L1 was greater in A549 cells, than in other cancerous cell lines. In A549 cells, oleic acid and OEA decreased IFN-γ-induced expression of PD-L1, Bax, Bcl-2, and caspase 3. Oleic acid and OEA decreased IFN-γ-induced phosphorylation of STAT. These results indicate that oleic acid and OEA inhibit PD-1 expression, and induce apoptosis via STAT phosphorylation. Therefore, oleic acid and OEA may prevent cancer formation through STAT phosphorylation with IFN-γ. These findings provide novel insights into the anti-cancer effects of oleic acid-rich oil, such as olive oil.
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Affiliation(s)
- Kazuo Yamagata
- Department of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University (NUBS), Fujisawa, Japan.
| | - Erika Uzu
- Department of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University (NUBS), Fujisawa, Japan
| | - Yuri Yoshigai
- Department of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University (NUBS), Fujisawa, Japan
| | - Chihiro Kato
- Department of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University (NUBS), Fujisawa, Japan
| | - Motoki Tagami
- Department of Internal Medicine, Sanraku Hospital, Chiyoda-Ku, Tokyo, Japan
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Romano A, Friuli M, Del Coco L, Longo S, Vergara D, Del Boccio P, Valentinuzzi S, Cicalini I, Fanizzi FP, Gaetani S, Giudetti AM. Chronic Oleoylethanolamide Treatment Decreases Hepatic Triacylglycerol Level in Rat Liver by a PPARγ/SREBP-Mediated Suppression of Fatty Acid and Triacylglycerol Synthesis. Nutrients 2021; 13:394. [PMID: 33513874 PMCID: PMC7910994 DOI: 10.3390/nu13020394] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/18/2021] [Accepted: 01/23/2021] [Indexed: 12/14/2022] Open
Abstract
Oleoylethanolamide (OEA) is a naturally occurring bioactive lipid belonging to the family of N-acylethanolamides. A variety of beneficial effects have been attributed to OEA, although the greater interest is due to its potential role in the treatment of obesity, fatty liver, and eating-related disorders. To better clarify the mechanism of the antiadipogenic effect of OEA in the liver, using a lipidomic study performed by 1H-NMR, LC-MS/MS and thin-layer chromatography analyses we evaluated the whole lipid composition of rat liver, following a two-week daily treatment of OEA (10 mg kg-1 i.p.). We found that OEA induced a significant reduction in hepatic triacylglycerol (TAG) content and significant changes in sphingolipid composition and ceramidase activity. We associated the antiadipogenic effect of OEA to decreased activity and expression of key enzymes involved in fatty acid and TAG syntheses, such as acetyl-CoA carboxylase, fatty acid synthase, diacylglycerol acyltransferase, and stearoyl-CoA desaturase 1. Moreover, we found that both SREBP-1 and PPARγ protein expression were significantly reduced in the liver of OEA-treated rats. Our findings add significant and important insights into the molecular mechanism of OEA on hepatic adipogenesis, and suggest a possible link between the OEA-induced changes in sphingolipid metabolism and suppression of hepatic TAG level.
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Affiliation(s)
- Adele Romano
- Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy; (A.R.); (M.F.); (S.G.)
| | - Marzia Friuli
- Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy; (A.R.); (M.F.); (S.G.)
| | - Laura Del Coco
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy; (L.D.C.); (S.L.); (D.V.)
| | - Serena Longo
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy; (L.D.C.); (S.L.); (D.V.)
| | - Daniele Vergara
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy; (L.D.C.); (S.L.); (D.V.)
| | - Piero Del Boccio
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (P.D.B.); (S.V.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy;
| | - Silvia Valentinuzzi
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (P.D.B.); (S.V.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy;
| | - Ilaria Cicalini
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy;
- Department of Medicine and Aging Science, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Francesco P. Fanizzi
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy; (L.D.C.); (S.L.); (D.V.)
| | - Silvana Gaetani
- Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy; (A.R.); (M.F.); (S.G.)
| | - Anna M. Giudetti
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy; (L.D.C.); (S.L.); (D.V.)
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Hu J, Zhu Z, Ying H, Yao J, Ma H, Li L, Zhao Y. Oleoylethanolamide Protects Against Acute Liver Injury by Regulating Nrf-2/HO-1 and NLRP3 Pathways in Mice. Front Pharmacol 2021; 11:605065. [PMID: 33536915 PMCID: PMC7848133 DOI: 10.3389/fphar.2020.605065] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/14/2020] [Indexed: 12/14/2022] Open
Abstract
Acute liver injury is a rapidly deteriorating clinical condition with markedly high morbidity and mortality. Oleoylethanolamide (OEA) is an endogenous lipid messenger with multiple bioactivities, and has therapeutic effects on various liver diseases. However, effects of OEA on acute liver injury remains unknown. In this study, effects and mechanisms of OEA in lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced acute liver injury in mice were investigated. We found that OEA treatment significantly attenuated LPS/D-Gal-induced hepatocytes damage, reduced liver index (liver weight/body weight), decreased plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels. Moreover, mechanism study suggested that OEA pretreatment significantly reduced hepatic MDA levels, increased Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-PX) activities via up-regulate Nrf-2 and HO-1 expression to exert anti-oxidation activity. Additionally, OEA markedly reduced the expression levels of Bax, Bcl-2 and cleaved caspase-3 to suppress hepatocyte apoptosis. Meanwhile, OEA remarkedly reduced the number of activated intrahepatic macrophages, and alleviated the mRNA expression of pro-inflammatory factors, including TNF-α, IL-6, MCP1 and RANTES. Furthermore, OEA obviously reduced the expression of IL-1β in liver and plasma through inhibit protein levels of NLRP3 and caspase-1, which indicated that OEA could suppress NLRP3 inflammasome pathway. We further determined the protein expression of PPAR-α in liver and found that OEA significantly increase hepatic PPAR-α expression. In addition, HO-1 inhibitor ZnPP blocked the therapeutic effects of OEA on LPS/D-Gal-induced liver damage and oxidative stress, suggesting crucial role of Nrf-2/HO-1 pathway in the protective effects of OEA in acute liver injury. Together, these findings demonstrated that OEA protect against the LPS/D-Gal-induced acute liver injury in mice through the inhibition of apoptosis, oxidative stress and inflammation, and its mechanisms might be associated with the Nrf-2/HO-1 and NLRP3 inflammasome signaling pathways.
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Affiliation(s)
- Jiaji Hu
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Zhoujie Zhu
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Hanglu Ying
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Jie Yao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Huabin Ma
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Long Li
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Yufen Zhao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
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Tutunchi H, Naeini F, Saghafi-Asl M, Farrin N, Monshikarimi A, Ostadrahimi A. Effects of oleoylethanolamide supplementation on atherogenic indices and hematological parameters in patients with nonalcoholic fatty liver disease: A clinical trial. Health Promot Perspect 2020; 10:373-382. [PMID: 33312933 PMCID: PMC7722997 DOI: 10.34172/hpp.2020.56] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 10/10/2020] [Indexed: 12/13/2022] Open
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease in the world. The current interventional trial aimed to evaluate the effects of supplementation with oleoylethanolamide (OEA) in combination with weight loss intervention on some atherogenic indices as well as hematological parameters in patients newly diagnosed with NAFLD. Methods: In this triple-blinded, randomized, placebo-controlled clinical trial, 76 obese patients with NAFLD confirmed by ultra-sonographic findings were randomly assigned to receive a weight reduction diet plus either 250 mg OEA (n=38) or placebo (n=38) for 12 weeks. Atherogenic factors including total cholesterol/high-density lipoprotein cholesterol (HDL-C),low-density lipoprotein cholesterol (LDL-C)/HDL-C, triglyceride (TG)/HDL-C, non-HDL-C/HDL-C ratios and non-HDL-C level, as well as hematological parameters were assessed before and after intervention. Results : After adjustment for potential confounding factors, between group analyses demonstrated a significantly lower LDL-C/HDL-C, TG/HDL-C, and non-HDL-C/HDL-C ratios in the OEA group compared to the placebo, post-intervention (95% confidence interval [CI]:0.06 to 0.85, P = 0.024; 95% CI: -2.06 to -0.05, P = 0.039; 95% CI: -1.05 to -0.02, P = 0.042,respectively). Additionally, OEA supplementation could significantly decrease the levels of red blood cell distribution width (RDW) compared to the placebo at the endpoint after considering potential confounding variables (95% CI: -0.56 to -0.003, P = 0.041). No significant differences were found between the two study groups in terms of other hematological parameters. Conclusion: The results of the current study indicated that OEA supplementation had beneficial effects on LDL-C/HDL-C, TG/HDL-C, and non-HDL-C/HDL-C ratios as well as RDW in obese patients with NAFLD. Trial Registration: IRCT20110530006652N2; https://www.irct.ir/trial/37228.
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Affiliation(s)
- Helda Tutunchi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Naeini
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Saghafi-Asl
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazila Farrin
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Monshikarimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Ostadrahimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Azar S, Udi S, Drori A, Hadar R, Nemirovski A, Vemuri KV, Miller M, Sherill-Rofe D, Arad Y, Gur-Wahnon D, Li X, Makriyannis A, Ben-Zvi D, Tabach Y, Ben-Dov IZ, Tam J. Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent. Mol Metab 2020; 42:101087. [PMID: 32987186 PMCID: PMC7563015 DOI: 10.1016/j.molmet.2020.101087] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 09/03/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE The endocannabinoid (eCB) system is increasingly recognized as being crucially important in obesity-related hepatic steatosis. By activating the hepatic cannabinoid-1 receptor (CB1R), eCBs modulate lipogenesis and fatty acid oxidation. However, the underlying molecular mechanisms are largely unknown. METHODS We combined unbiased bioinformatics techniques, mouse genetic manipulations, multiple pharmacological, molecular, and cellular biology approaches, and genomic sequencing to systematically decipher the role of the hepatic CB1R in modulating fat utilization in the liver and explored the downstream molecular mechanisms. RESULTS Using an unbiased normalized phylogenetic profiling analysis, we found that the CB1R evolutionarily coevolves with peroxisome proliferator-activated receptor-alpha (PPARα), a key regulator of hepatic lipid metabolism. In diet-induced obese (DIO) mice, peripheral CB1R blockade (using AM6545) induced the reversal of hepatic steatosis and improved liver injury in WT, but not in PPARα-/- mice. The antisteatotic effect mediated by AM6545 in WT DIO mice was accompanied by increased hepatic expression and activity of PPARα as well as elevated hepatic levels of the PPARα-activating eCB-like molecules oleoylethanolamide and palmitoylethanolamide. Moreover, AM6545 was unable to rescue hepatic steatosis in DIO mice lacking liver sirtuin 1 (SIRT1), an upstream regulator of PPARα. Both of these signaling molecules were modulated by the CB1R as measured in hepatocytes exposed to lipotoxic conditions or treated with CB1R agonists in the absence/presence of AM6545. Furthermore, using microRNA transcriptomic profiling, we found that the CB1R regulated the hepatic expression, acetylation, and transcriptional activity of p53, resulting in the enhanced expression of miR-22, which was found to specifically target SIRT1 and PPARα. CONCLUSIONS We provide strong evidence for a functional role of the p53/miR-22/SIRT1/PPARα signaling pathway in potentially mediating the antisteatotic effect of peripherally restricted CB1R blockade.
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Affiliation(s)
- Shahar Azar
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Shiran Udi
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Adi Drori
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Rivka Hadar
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Alina Nemirovski
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Kiran V Vemuri
- Center for Drug Discovery, Northeastern University, Boston, MA, USA
| | - Maya Miller
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Dana Sherill-Rofe
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yhara Arad
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Devorah Gur-Wahnon
- Laboratory of Medical Transcriptomics, Department of Nephrology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Xiaoling Li
- Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | | | - Danny Ben-Zvi
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yuval Tabach
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Iddo Z Ben-Dov
- Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | - Joseph Tam
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
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Otagiri S, Ohnishi S, Ohara M, Fu Q, Yamamoto K, Yamamoto K, Katsurada T, Sakamoto N. Oleoylethanolamide Ameliorates Dextran Sulfate Sodium-Induced Colitis in Rats. Front Pharmacol 2020; 11:1277. [PMID: 32922296 PMCID: PMC7457075 DOI: 10.3389/fphar.2020.01277] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 08/03/2020] [Indexed: 12/13/2022] Open
Abstract
Oleoylethanolamide (OEA) is an endogenous fatty acid ethanolamide known for its anti-inflammatory effects and its influence on gut microbiota composition; however, the effects of OEA in inflammatory bowel disease (IBD) remain unknown. During in vitro experiments, OEA downregulated the expression of tumor necrosis factor (TNF)-α and reduced phosphorylation of inhibitor of kappa (Iκ) Bα induced by lipopolysaccharide in human embryonic kidney cells. Moreover, OEA downregulated the expression of interleukin (IL)-8 and IL-1β and inhibited the phosphorylation of IκBα and p65 induced by TNF-α in human enterocytes (Caco-2). The effect of OEA in reducing the expression of IL-8 was blocked by the peroxisome proliferator-activated receptor (PPAR)-α antagonist. During in vivo experiments on rats, colitis was induced by the oral administration of 8% dextran sulfate sodium from day 0 through day 5, and OEA (20 mg/kg) was intraperitoneally injected once a day from day 0 for 6 days. OEA administration significantly ameliorated the reduction in body weight, the increase in disease activity index score, and the shortening of colon length. In rectums, OEA administration reduced the infiltration of macrophages and neutrophils and tended to reduce the histological score and the expression of inflammatory cytokines. Administration of OEA produced significant improvement in a colitis model, possibly by inhibiting the nuclear factor kappa B signaling pathway through PPAR-α receptors. OEA could be a potential new treatment for IBD.
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Affiliation(s)
- Shinsuke Otagiri
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shunsuke Ohnishi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Qingjie Fu
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Koji Yamamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Keiko Yamamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Takehiko Katsurada
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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28
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Wang C, Hu NH, Yu LY, Gong LH, Dai XY, Peng C, Li YX. 2,3,5,4'-tetrahydroxystilbence-2-O-β-D-glucoside attenuates hepatic steatosis via IKKβ/NF-κB and Keap1-Nrf2 pathways in larval zebrafish. Biomed Pharmacother 2020; 127:110138. [DOI: 10.1016/j.biopha.2020.110138] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 03/30/2020] [Accepted: 03/31/2020] [Indexed: 12/13/2022] Open
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29
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Tutunchi H, Ostadrahimi A, Saghafi-Asl M, Roshanravan N, Shakeri-Bavil A, Asghari-Jafarabadi M, Farrin N, Mobasseri M. Expression of NF-κB, IL-6, and IL-10 genes, body composition, and hepatic fibrosis in obese patients with NAFLD-Combined effects of oleoylethanolamide supplementation and calorie restriction: A triple-blind randomized controlled clinical trial. J Cell Physiol 2020; 236:417-426. [PMID: 32572955 DOI: 10.1002/jcp.29870] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 05/27/2020] [Accepted: 05/31/2020] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common noncommunicable diseases worldwide. The present study aimed to investigate the effects of oleoylethanolamide (OEA) supplementation combined with calorie restriction on inflammation, body composition, and hepatic fibrosis among obese patients with NAFLD. In this 12-week randomized clinical trial, 76 obese patients newly diagnosed with NAFLD were randomly allocated into either OEA or placebo group. The weight-loss diet was also designed for both groups. Pre- and postintervention messenger RNA expression levels of the transcription factor nuclear factor-κB (NF-κB), interleukin-6 (IL-6) and IL-10, body composition, and NAFLD fibrosis score were assessed. At the end of the study, the OEA group showed lower NF-κB and IL-6 expression levels compared to the placebo (p < .01). However, IL-10 expression level was approximately twofold higher in the OEA group compared to the placebo group (p = .008). A significant reduction was observed in the fat mass of the OEA group compared to the placebo (p = .044) postintervention. In addition, OEA supplementation led to a significant increase in fat-free mass in the OEA group compared to the placebo (p = .032). A remarkable increase was observed in resting metabolic rate (RMR) in the OEA group (p = .009); however, it was not found in the placebo group. There were no significant between-group differences in RMR postintervention. In addition, no significant within-and between-group differences were observed in the NAFLD fibrosis score at the end of the trial. Treatment with OEA along with weight-loss intervention could significantly improve inflammation and body composition in patients with NAFLD.
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Affiliation(s)
- Helda Tutunchi
- Student Research Committee, Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Nutrition, Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Ostadrahimi
- Department of Clinical Nutrition, Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Saghafi-Asl
- Department of Clinical Nutrition, Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Roshanravan
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abolhassan Shakeri-Bavil
- Department of Radiology, Imam Reza Teaching Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Nazila Farrin
- Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Mobasseri
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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30
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Li Y, Yu X, Xu YJ, Li J, Du L, Su Q, Cao P, Liu Y. Effects of polar compounds in fried palm oil on liver lipid metabolism in C57 mice. J Food Sci 2020; 85:1915-1923. [PMID: 32460375 DOI: 10.1111/1750-3841.15152] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 04/01/2020] [Accepted: 04/03/2020] [Indexed: 12/30/2022]
Abstract
Polar components (PCs) are produced during the frying of oil, affecting the quality of edible oil and posing a hazard to human health. In this study, C57 mice were fed a high-fat (HF) diet containing purified PCs for nine weeks. Their effects on lipid metabolism and liver function in animals were analyzed. Our results indicated that the contents of total PCs and saturated fatty acid increased from 6.07 ± 0.6% and 58.27 ± 0.35% to 19.17 ± 1.8% and 69.91 ± 0.51%, respectively (P < 0.01). PC intake resulted an 18.56% higher liver index in mice than that in the HF group. The PC group had the highest malondialdehyde (MDA) content (1.94 ± 0.11 nmol/mg protein) and the liver nonalcoholic fatty liver disease (NAFLD) activity score (NAS) was 4, which already showed NAFLD characteristics. In addition, the expression levels of lipid metabolism-related genes, including sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthetase (FAS), peroxisome proliferator-activated receptor-alpha, and peroxisome acyl-CoA oxidase 1, indicated that PC increased hepatic lipid accumulation by upregulating the transcriptional level of fat synthesis genes and further leads to liver damage by affecting mitochondrial function. Our results provided important information about the effects of PCs produced in the frying process of PO on animal health, which is critical for assessing the biosafety of fried products. PRACTICAL APPLICATION: The research will help promote the industrial upgrading of fried foods and help consumers build healthy lifestyles.
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Affiliation(s)
- Youdong Li
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, PR China
| | - Xiaoyan Yu
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, PR China
| | - Yong-Jiang Xu
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, PR China.,State Key Laboratory of Food Science and Technology, National Engineering Laboratory for Cereal Fermentation Technology, National Engineering Research Center for Functional Food, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, PR China
| | - Jinwei Li
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, PR China.,State Key Laboratory of Food Science and Technology, National Engineering Laboratory for Cereal Fermentation Technology, National Engineering Research Center for Functional Food, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, PR China
| | - Liyang Du
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, PR China
| | - Qingfeng Su
- Red Dragonfly Oil Co., Ltd, eastern section of the Huangshan Road, Yubei District, Chongqing, 401121, PR China
| | - Peirang Cao
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, PR China.,State Key Laboratory of Food Science and Technology, National Engineering Laboratory for Cereal Fermentation Technology, National Engineering Research Center for Functional Food, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, PR China
| | - Yuanfa Liu
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, PR China.,State Key Laboratory of Food Science and Technology, National Engineering Laboratory for Cereal Fermentation Technology, National Engineering Research Center for Functional Food, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, PR China
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31
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Tutunchi H, Ostadrahimi A, Saghafi-Asl M, Hosseinzadeh-Attar MJ, Shakeri A, Asghari-Jafarabadi M, Roshanravan N, Farrin N, Naemi M, Hasankhani M. Oleoylethanolamide supplementation in obese patients newly diagnosed with non-alcoholic fatty liver disease: Effects on metabolic parameters, anthropometric indices, and expression of PPAR-α, UCP1, and UCP2 genes. Pharmacol Res 2020; 156:104770. [PMID: 32217148 DOI: 10.1016/j.phrs.2020.104770] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/18/2020] [Accepted: 03/19/2020] [Indexed: 12/18/2022]
Abstract
The effects of oleoylethanolamide (OEA) on NAFLD are yet to be examined in human. The objective of the present study was to examine the effects of OEA supplementation along with weight loss intervention on the expression of PPAR-α, uncoupling proteins 1and 2 (UCP1 and UCP2) genes in the peripheral blood mononuclear cells (PBMCs), metabolic parameters, and anthropometric indices among obese patients with NAFLD. In this triple-blind placebo-controlled randomized clinical trial, 76 obese patients newly diagnosed with NAFLD were randomly allocated into either OEA or placebo group along with calorie-restricted diets for 12 weeks. At pre-and post-intervention phase, mRNA expression levels of PPAR-α, UCP1, and UCP2 genes in the PBMCs, serum levels of metabolic parameters as well as diet and appetite sensations were assessed. There was a significant increase in the expression levels of PPAR-α, UCP1, and UCP2 genes in the PBMCs, compared to the placebo at the endpoint. A significant decrease in the anthropometric indices, energy and carbohydrate intakes, glycemic parameters, except for hemoglobin A1c concentration was also observed in the OEA group, compared to the placebo group. OEA treatment significantly resulted in decreased serum levels of triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST, increased serum levels of high-density lipoprotein cholesterol (HDL-C), and improved appetite sensations. Importantly, a significant improvement in TG, ALT, AST, ALT/AST, HDL-C levels as well as appetite sensations by OEA were under the influence of body mass index (BMI). Although liver steatosis severity was significantly reduced in both groups, the between-group differences did not reach statistical significance (P = 0.061). In conclusion, the present study, for the first time, revealed that OEA supplementation significantly improved anthropometric and metabolic risk factors related to NAFLD.
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Affiliation(s)
- Helda Tutunchi
- Student Research Committee, Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Alireza Ostadrahimi
- Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Maryam Saghafi-Asl
- Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad-Javad Hosseinzadeh-Attar
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
| | - Abolhasan Shakeri
- Department of Radiology, Imam Reza Teaching Hospital, Clinical Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | - Neda Roshanravan
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Nazila Farrin
- Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad Naemi
- Student Research Committee, Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Milad Hasankhani
- Student Research Committee, Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Veilleux A, Di Marzo V, Silvestri C. The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus. Curr Diab Rep 2019; 19:117. [PMID: 31686231 DOI: 10.1007/s11892-019-1248-9] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW The endocannabinoid (eCB) system, i.e. the receptors that respond to the psychoactive component of cannabis, their endogenous ligands and the ligand metabolic enzymes, is part of a larger family of lipid signals termed the endocannabinoidome (eCBome). We summarize recent discoveries of the roles that the eCBome plays within peripheral tissues in diabetes, and how it is being targeted, in an effort to develop novel therapeutics for the treatment of this increasingly prevalent disease. RECENT FINDINGS As with the eCB system, many eCBome members regulate several physiological processes, including energy intake and storage, glucose and lipid metabolism and pancreatic health, which contribute to the development of type 2 diabetes (T2D). Preclinical studies increasingly support the notion that targeting the eCBome may beneficially affect T2D. The eCBome is implicated in T2D at several levels and in a variety of tissues, making this complex lipid signaling system a potential source of many potential therapeutics for the treatments for T2D.
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Affiliation(s)
- Alain Veilleux
- École de nutrition, Université Laval, Québec, QC, Canada
- Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, QC, Canada
- Canadian Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Québec, Canada
| | - Vincenzo Di Marzo
- École de nutrition, Université Laval, Québec, QC, Canada
- Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, QC, Canada
- Canadian Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Québec, Canada
- Institut de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, Canada
- Department de médecine, Université Laval, Québec, QC, Canada
| | - Cristoforo Silvestri
- Canadian Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Québec, Canada.
- Institut de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, Canada.
- Department de médecine, Université Laval, Québec, QC, Canada.
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33
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Tutunchi H, Ostadrahimi A, Saghafi-Asl M, Maleki V. The effects of oleoylethanolamide, an endogenous PPAR-α agonist, on risk factors for NAFLD: A systematic review. Obes Rev 2019; 20:1057-1069. [PMID: 31111657 DOI: 10.1111/obr.12853] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 03/04/2019] [Accepted: 03/04/2019] [Indexed: 12/15/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. Recently, some novel compounds have been investigated for the prevention and treatment of NAFLD. Oleoylethanolamide (OEA), an endogenous PPAR-α agonist, has exhibited a plethora of pharmacological properties for the treatment of obesity and other obesity-associated metabolic complications. This systematic review was performed with a focus on the effects of OEA on the risk factors for NAFLD. PubMed, Scopus, Embase, ProQuest, and Google Scholar databases were searched up to December 2018 using relevant keywords. All articles written in English evaluating the effects of OEA on the risk factors for NAFLD were eligible for the review. The evidence reviewed in this article illustrates that OEA regulates multiple biological processes associated with NAFLD, including lipid metabolism, inflammation, oxidative stress, and energy homeostasis through different mechanisms. In summary, many beneficial effects of OEA have led to the understanding that OEA may be an effective therapeutic strategy for the management of NAFLD. Although a wide range of studies have demonstrated the most useful effects of OEA on NAFLD and the associated risk factors, further clinical trials, from both in vivo studies and in vitro experiments, are warranted to verify these outcomes.
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Affiliation(s)
- Helda Tutunchi
- Student Research Committee, Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Ostadrahimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Saghafi-Asl
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Maleki
- Student Research Committee, Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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34
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Hajighasem A, Farzanegi P, Mazaheri Z. Effects of combined therapy with resveratrol, continuous and interval exercises on apoptosis, oxidative stress, and inflammatory biomarkers in the liver of old rats with non-alcoholic fatty liver disease. Arch Physiol Biochem 2019; 125:142-149. [PMID: 29463133 DOI: 10.1080/13813455.2018.1441872] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
CONTEXT Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. OBJECTIVE Effects of combined therapy with resveratrol, interval and continuous exercises on oxidative stress, inflammation, and apoptosis in the liver of rats with NAFLD. METHODS NAFLD rats were organised in patient, saline, resveratrol (RSV), continuous exercise, interval exercise, continuous exercise + RSV, and interval exercise + RSV groups. RESULTS Resveratrol supplementation alone or in combination with interval and continuous training significantly decreased malondialdehyde and TNF-α level (p < .05), while the levels of catalase; superoxide dismutase and IL-10 were significantly increased (p < .05). Although RSV alone significantly decreased the percentage of apoptotic cells (17.12%), its combination with interval (10.74%), and continuous (14.85%) exercise training demonstrated higher anti-apoptotic activity (p < .05). CONCLUSIONS Although resveratrol alone has an antioxidant, anti-apoptotic and anti-inflammatory properties, combined therapy with interval, and continuous training can be more effective to mitigate these abnormalities in NAFLD patients.
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Affiliation(s)
- Amir Hajighasem
- a Department of Exercise Physiology, Sari Branch , Islamic Azad University , Sari , Iran
| | - Parvin Farzanegi
- a Department of Exercise Physiology, Sari Branch , Islamic Azad University , Sari , Iran
| | - Zohreh Mazaheri
- b Department of Anatomical Sciences, Faculty of Medical Sciences , Tarbiat Modares University , Tehran , Iran
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35
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Hu SJ, Jiang SS, Zhang J, Luo D, Yu B, Yang LY, Zhong HH, Yang MW, Liu LY, Hong FF, Yang SL. Effects of apoptosis on liver aging. World J Clin Cases 2019; 7:691-704. [PMID: 30968034 PMCID: PMC6448073 DOI: 10.12998/wjcc.v7.i6.691] [Citation(s) in RCA: 14] [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: 11/21/2018] [Revised: 01/10/2019] [Accepted: 01/26/2019] [Indexed: 02/05/2023] Open
Abstract
As an irreversible and perennial process, aging is accompanied by functional and morphological declines in organs. Generally, aging liver exhibits a decline in volume and hepatic blood flow. Even with a preeminent regenerative capacity to restore its functions after liver cell loss, its biosynthesis and metabolism abilities decline, and these are difficult to restore to previous standards. Apoptosis is a programmed death process via intrinsic and extrinsic pathways, in which Bcl-2 family proteins and apoptosis-related genes, such as p21 and p53, are involved. Apoptosis inflicts both favorable and adverse influences on liver aging. Apoptosis eliminates transformed abnormal cells but promotes age-related liver diseases, such as nonalcoholic fatty liver disease, liver fibrosis, cirrhosis, and liver cancer. We summarize the roles of apoptosis in liver aging and age-related liver diseases.
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Affiliation(s)
- Shao-Jie Hu
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Sha-Sha Jiang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jin Zhang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Dan Luo
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Bo Yu
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Liang-Yan Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Hua-Hua Zhong
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Mei-Wen Yang
- Department of Nurse, Nanchang University Hospital, Nanchang 330006, Jiangxi Province, China
| | - Li-Yu Liu
- Department of Nurse, Nanchang University Hospital, Nanchang 330006, Jiangxi Province, China
| | - Fen-Fang Hong
- Experimental Teaching Center, Nanchang University, Nanchang 330031, Jiangxi Province, China
| | - Shu-Long Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, Jiangxi Province, China
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36
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Yao E, Zhang G, Huang J, Yang X, Peng L, Huang X, Luo X, Ren J, Huang R, Yang L, Zhou Y, Zhuo R, Zhao Y, Jin X. Immunomodulatory effect of oleoylethanolamide in dendritic cells via TRPV1/AMPK activation. J Cell Physiol 2019; 234:18392-18407. [PMID: 30895621 DOI: 10.1002/jcp.28474] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 02/15/2019] [Accepted: 02/19/2019] [Indexed: 12/26/2022]
Abstract
Oleoylethanolamide (OEA) is an endogenous lipid mediator involved in the control of feeding, body weight, and energy metabolism. However, whether OEA modulates maturation of dendritic cells (DCs) has never been addressed. Hence, we evaluated the effect of OEA on DCs maturation in bone marrow-derived DCs (BMDCs) in four aspects: (a) Cell surface markers were determined using flow cytometric analysis; (b) cell mobile ability was testified with the transwell assay; (c) stimulation of T cells proliferation was performed in a coculture system; and (d) cytokine production was measured using polymerase chain reaction (PCR). The result showed that, in mature BMDCs induced by lipopolysaccharides (LPS), the OEA treatment decreased expressions of cell surface markers, reduced cell migration, diminished the proliferation of cocultured T cells, and regulated cytokine production of BMDCs, indicating the modulatory effect of OEA on DCs maturation. Furthermore, to explore the underlying mechanism of the immunomodulatory effect of OEA, we used antagonists of transient receptor potential vanilloid-1 (TRPV1) and AMP-activated protein kinase (AMPK), determined the protein expressions of TRPV1/AMPK and Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) using western blot, and measured the intracellular calcium concentration using calcium imaging. The result illustrated that OEA downregulated TLR4/NF-κB, the classical pathway leading to DCs maturation induced by LPS, through the activation of TRPV1 and AMPK. Collectively, the present study suggests that OEA suppresses DCs maturation through the activation of TRPV1/AMPK. These findings increase our understanding of this endogenous lipid OEA.
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Affiliation(s)
- Enhui Yao
- Medical College, Xiamen University, Xiamen, China.,Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Guixiang Zhang
- Medical College, Xiamen University, Xiamen, China.,Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Jinhua Huang
- Medical College, Xiamen University, Xiamen, China.,Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Xiazhen Yang
- Medical College, Xiamen University, Xiamen, China.,Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Lu Peng
- Medical College, Xiamen University, Xiamen, China
| | - Xuefeng Huang
- Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Xiaoxin Luo
- Medical College, Xiamen University, Xiamen, China
| | - Jie Ren
- Medical College, Xiamen University, Xiamen, China
| | - Rui Huang
- Medical College, Xiamen University, Xiamen, China
| | - Lichao Yang
- Medical College, Xiamen University, Xiamen, China
| | - Yu Zhou
- Medical College, Xiamen University, Xiamen, China
| | - Rengong Zhuo
- Medical College, Xiamen University, Xiamen, China
| | - Yun Zhao
- Medical College, Xiamen University, Xiamen, China
| | - Xin Jin
- Medical College, Xiamen University, Xiamen, China
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Ontawong A, Boonphang O, Pasachan T, Duangjai A, Pongchaidecha A, Phatsara M, Jinakote M, Amornlerdpison D, Srimaroeng C. Hepatoprotective effect of coffee pulp aqueous extract combined with simvastatin against hepatic steatosis in high-fat diet-induced obese rats. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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38
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May-Zhang LS, Chen Z, Dosoky NS, Yancey PG, Boyd KL, Hasty AH, Linton MF, Davies SS. Administration of N-Acyl-Phosphatidylethanolamine Expressing Bacteria to Low Density Lipoprotein Receptor -/- Mice Improves Indices of Cardiometabolic Disease. Sci Rep 2019; 9:420. [PMID: 30674978 PMCID: PMC6344515 DOI: 10.1038/s41598-018-37373-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 11/13/2018] [Indexed: 01/19/2023] Open
Abstract
Obesity increases the risk for cardiometabolic diseases. N-acyl phosphatidylethanolamines (NAPEs) are precursors of N-acylethanolamides, which are endogenous lipid satiety factors. Incorporating engineered bacteria expressing NAPEs into the gut microbiota retards development of diet induced obesity in wild-type mice. Because NAPEs can also exert anti-inflammatory effects, we hypothesized that administering NAPE-expressing bacteria to low-density lipoprotein receptor (Ldlr)-/- mice fed a Western diet would improve various indices of cardiometabolic disease manifested by these mice. NAPE-expressing E. coli Nissle 1917 (pNAPE-EcN), control Nissle 1917 (pEcN), or vehicle (veh) were given via drinking water to Ldlr-/- mice for 12 weeks. Compared to pEcN or veh treatment, pNAPE-EcN significantly reduced body weight and adiposity, hepatic triglycerides, fatty acid synthesis genes, and increased expression of fatty acid oxidation genes. pNAPE-EcN also significantly reduced markers for hepatic inflammation and early signs of fibrotic development. Serum cholesterol was reduced with pNAPE-EcN, but atherosclerotic lesion size showed only a non-significant trend for reduction. However, pNAPE-EcN treatment reduced lesion necrosis by 69% indicating an effect on preventing macrophage inflammatory death. Our results suggest that incorporation of NAPE expressing bacteria into the gut microbiota can potentially serve as an adjuvant therapy to retard development of cardiometabolic disease.
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Affiliation(s)
- Linda S May-Zhang
- Division of Clinical Pharmacology, Department of Pharmacology, 2220 Pierce Avenue, Vanderbilt University, 556 Robinson Research Building, Nashville, TN, 37221, USA
| | - Zhongyi Chen
- Division of Clinical Pharmacology, Department of Pharmacology, 2220 Pierce Avenue, Vanderbilt University, 556 Robinson Research Building, Nashville, TN, 37221, USA
| | - Noura S Dosoky
- Division of Clinical Pharmacology, Department of Pharmacology, 2220 Pierce Avenue, Vanderbilt University, 556 Robinson Research Building, Nashville, TN, 37221, USA
| | - Patricia G Yancey
- Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt Medical Center, 2220 Pierce Avenue, 312 Preston Research Building, Nashville, TN, 37232, USA
| | - Kelli L Boyd
- AA-6206 Medical Center North, Department of Pathology, Microbiology, and Immunology, Vanderbilt Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA
| | - Alyssa H Hasty
- Department of Molecular Physiology and Biophysics, Vanderbilt University, 2220 Pierce Avenue, 813 Light Hall, Nashville, TN, 37232, USA
| | - MacRae F Linton
- Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt Medical Center, 2220 Pierce Avenue, 312 Preston Research Building, Nashville, TN, 37232, USA
| | - Sean S Davies
- Division of Clinical Pharmacology, Department of Pharmacology, 2220 Pierce Avenue, Vanderbilt University, 556 Robinson Research Building, Nashville, TN, 37221, USA.
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Misto A, Provensi G, Vozella V, Passani MB, Piomelli D. Mast Cell-Derived Histamine Regulates Liver Ketogenesis via Oleoylethanolamide Signaling. Cell Metab 2019; 29:91-102.e5. [PMID: 30318340 DOI: 10.1016/j.cmet.2018.09.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 06/11/2018] [Accepted: 09/12/2018] [Indexed: 01/30/2023]
Abstract
The conversion of lipolysis-derived fatty acids into ketone bodies (ketogenesis) is a crucial metabolic adaptation to prolonged periods of food scarcity. The process occurs primarily in liver mitochondria and is initiated by fatty-acid-mediated stimulation of the ligand-operated transcription factor, peroxisome proliferator-activated receptor-α (PPAR-α). Here, we present evidence that mast cells contribute to the control of fasting-induced ketogenesis via a paracrine mechanism that involves secretion of histamine into the hepatic portal circulation, stimulation of liver H1 receptors, and local biosynthesis of the high-affinity PPAR-α agonist, oleoylethanolamide (OEA). Genetic or pharmacological interventions that disable any one of these events, including mast cell elimination, deletion of histamine- or OEA-synthesizing enzymes, and H1 blockade, blunt ketogenesis without affecting lipolysis. The results reveal an unexpected role for mast cells in the regulation of systemic fatty-acid homeostasis, and suggest that OEA may act in concert with lipolysis-derived fatty acids to activate liver PPAR-α and promote ketogenesis.
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Affiliation(s)
- Alessandra Misto
- Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Genoa 16163, Italy; School of Advanced Studies Sant'Anna, Pisa 56127, Italy
| | - Gustavo Provensi
- Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence 50139, Italy
| | - Valentina Vozella
- Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Genoa 16163, Italy
| | | | - Daniele Piomelli
- Departments of Anatomy and Neurobiology, Biological Chemistry and Pharmacology, School of Medicine, University of California, Irvine, CA 92697, USA.
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40
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Li M, Ma J, Ahmad O, Cao Y, Wang B, He Q, Li J, Yin H, Zhang Y, He J, Shang J. Lipid-modulate activity of Cichorium glandulosum Boiss. et Huet polysaccharide in nonalcoholic fatty liver disease larval zebrafish model. J Pharmacol Sci 2018; 138:257-262. [DOI: 10.1016/j.jphs.2018.09.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 09/20/2018] [Accepted: 09/25/2018] [Indexed: 01/12/2023] Open
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Forner-Piquer I, Mylonas CC, Calduch-Giner J, Maradonna F, Gioacchini G, Allarà M, Piscitelli F, Di Marzo V, Pérez-Sánchez J, Carnevali O. Endocrine disruptors in the diet of male Sparus aurata: Modulation of the endocannabinoid system at the hepatic and central level by Di-isononyl phthalate and Bisphenol A. ENVIRONMENT INTERNATIONAL 2018; 119:54-65. [PMID: 29933238 DOI: 10.1016/j.envint.2018.06.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/17/2018] [Accepted: 06/08/2018] [Indexed: 06/08/2023]
Abstract
The increasing manufacture of plastics and their mismanagement has turned plastic into a ubiquitous waste in the marine environment. Among all the substances conforming the plastic items, the effects of a dietary Bisphenol A (BPA) and Di-isononyl phthalate (DiNP) have been evaluated in adult male gilthead sea bream, focusing on their effects in the modulation of the Endocannabinoid System (ECS). In zebrafish, the ECS has been recently chosen as a new target for the activity of some Endocrine Disrupting Chemicals (EDC), since it represents a complex lipid signaling network essential for the well-being of the organisms. The results obtained in gilthead seabream showed that BPA and DiNP altered the structure and the biochemical composition of liver, increasing the presence of lipids and triglycerides and decreasing the glycogen and phospholipids. Moreover, the addition of BPA or DiNP in the gilthead sea bream diet altered the levels of endocannabinoids (EC) and EC-like mediators in the liver. These alterations were also associated to changes at the transcriptomic level of genes involved in lipid biosynthesis and ECS metabolism. At the central level, both BPA and DiNP reduced the expression of the endocannabinoid receptor type I (cnr1) and the neuropeptide Y (npy) as well as the levels of the endocannabinoid Anandamide (AEA), suggesting a downregulation of appetite. The results herein reported highlighted the negative effects of chronic dietary exposure to DiNP or BPA on ECS functions and lipid metabolism of male gilthead sea bream liver, showing a similar disruptive activity of these contaminants at metabolic level. Moreover, the novelty of the biomarkers used evidenced possible innovative endpoints for the development of novel OEDCS test guidelines.
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Affiliation(s)
- Isabel Forner-Piquer
- Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
| | - Constantinos C Mylonas
- Institute of Marine Biology, Biotechnology and Aquaculture, Hellenic Center for Marine Research, P.O. Box 2214, Heraklion, Crete 71003, Greece
| | - Josep Calduch-Giner
- Nutrigenomics and Fish Endocrinology Group, Institute of Aquaculture Torre de la Sal (IATS-CSIC), 12595, Ribera de Cabanes, Castellón, Spain
| | - Francesca Maradonna
- Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
| | - Giorgia Gioacchini
- Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
| | - Marco Allarà
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei, 80078 Pozzuoli, Italy
| | - Fabiana Piscitelli
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei, 80078 Pozzuoli, Italy
| | - Vincenzo Di Marzo
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei, 80078 Pozzuoli, Italy
| | - Jaume Pérez-Sánchez
- Nutrigenomics and Fish Endocrinology Group, Institute of Aquaculture Torre de la Sal (IATS-CSIC), 12595, Ribera de Cabanes, Castellón, Spain
| | - Oliana Carnevali
- Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy.
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Hajighasem A, Farzanegi P, Mazaheri Z, Naghizadeh M, Salehi G. Effects of resveratrol, exercises and their combination on Farnesoid X receptor, Liver X receptor and Sirtuin 1 gene expression and apoptosis in the liver of elderly rats with nonalcoholic fatty liver. PeerJ 2018; 6:e5522. [PMID: 30221089 PMCID: PMC6136396 DOI: 10.7717/peerj.5522] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 08/04/2018] [Indexed: 12/17/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. This study aims to consider effects of resveratrol, exercise and their combination on Farnesoid X receptor (Fxr), the liver X receptor (Lxr) and Sirtuin 1 (Sirt 1) genes expression in the liver of elderly rats with NAFLD. Methods Rats with NAFLD were randomly divided into seven groups including patient, saline, resveratrol (RSV), interval exercise, continuous exercise, interval exercise + RSV and continuous exercise + RSV. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in the liver tissue were measured using specific ELISA kits. A TUNEL assay kit was used for the assessment of hepatic cells apoptosis. Lipid profiles were considered by measuring the serum triglyceride, cholesterol, LDL, and HDL. Expression of Sirt1, Lxr and Fxr genes was considered using RT-PCR. Results Resveratrol administration alone or combined with exercise training significantly improved the expression of Sirt1, Lxr and Fxr genes (p < 0.05) in the hepatic tissue of rats with NAFLD, while levels of AST, ALT, ALP enzymes, as well as apoptotic cells were significantly decreased (p < 0.05). Discussion Although resveratrol alone improves the expression of Sirt1, Lxr and Fxr, as well as liver function, combined therapy with exercise training is more effective to improve NAFLD.
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Affiliation(s)
- Amir Hajighasem
- Department of Exercise Physiology, Sari Branch, Islamic Azad University, Sari, Iran
| | - Parvin Farzanegi
- Department of Exercise Physiology, Sari Branch, Islamic Azad University, Sari, Iran
| | - Zohreh Mazaheri
- Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Marjan Naghizadeh
- Department of Exercise Physiology, Sari Branch, Islamic Azad University, Sari, Iran
| | - Ghoncheh Salehi
- Department of Exercise Physiology, Sari Branch, Islamic Azad University, Sari, Iran
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Forner-Piquer I, Santangeli S, Maradonna F, Verde R, Piscitelli F, di Marzo V, Habibi HR, Carnevali O. Role of Bisphenol A on the Endocannabinoid System at central and peripheral levels: Effects on adult female zebrafish. CHEMOSPHERE 2018; 205:118-125. [PMID: 29689525 DOI: 10.1016/j.chemosphere.2018.04.078] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/12/2018] [Accepted: 04/13/2018] [Indexed: 06/08/2023]
Abstract
Bisphenol A (BPA), a widely used chemical to produce polycarbonate plastics, has become an ubiquitous pollutant due to its extensive use. Its endocrine disrupting properties have been documented in several studies, as well as its potential to induce metabolic and reproductive impairments at environmentally relevant concentrations. Recent insights highlighted the role of the Endocannabinoid System (ECS) in energy homeostasis and lipid metabolism. In fact, disruption of the ECS may induce metabolic alterations among other effects. Thus, the main objective of this study was to investigate the disruptive effects of environmentally relevant concentrations of BPA on the ECS of female zebrafish liver and brain. Adult female zebrafish were exposed for 3 weeks to three different concentrations of BPA (5 μg/L; 10 μg/L; 20 μg/L). We observed changes in the expression of a number of genes involved in the Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) metabolism in the liver and brain, as well as altered levels of endocannabinoids and endocannabinoid-like mediators. These changes were associated with greater presence of hepatic lipid vacuoles, following exposure to the highest concentration of BPA (20 μg/L) tested, although there were no changes in food intake and in the expression of the molecular markers for appetite. The overall results support the hypothesis that exposure to BPA induced changes in the central and hepatic ECS system of adult female zebrafish causing the increase of the area covered by lipids in the liver at the highest concentration tested, but not via food intake.
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Affiliation(s)
- Isabel Forner-Piquer
- Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Via Brecce Bianche, 60131, Ancona, Italy
| | - Stefania Santangeli
- Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Via Brecce Bianche, 60131, Ancona, Italy
| | - Francesca Maradonna
- Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Via Brecce Bianche, 60131, Ancona, Italy
| | - Roberta Verde
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei, 80078, Pozzuoli, Italy
| | - Fabiana Piscitelli
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei, 80078, Pozzuoli, Italy
| | - Vincenzo di Marzo
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei, 80078, Pozzuoli, Italy
| | - Hamid R Habibi
- Department of Biological Sciences, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
| | - Oliana Carnevali
- Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Via Brecce Bianche, 60131, Ancona, Italy.
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Oleoylethanolamide: A fat ally in the fight against obesity. Physiol Behav 2017; 176:50-58. [PMID: 28254531 DOI: 10.1016/j.physbeh.2017.02.034] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 02/22/2017] [Accepted: 02/23/2017] [Indexed: 01/24/2023]
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Sun X, Zhang Y, Xie M. Review. The role of peroxisome proliferator-activated receptor in the treatment of non-alcoholic fatty liver disease. ACTA PHARMACEUTICA 2017; 67:1-13. [PMID: 28231052 DOI: 10.1515/acph-2017-0007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/06/2016] [Indexed: 12/24/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has been defined as a spectrum of histological abnormalities and is characterized by significant and excessive accumulation of triglycerides in the hepatocytes in patients without alcohol consumption or other diseases. Current studies are targeting new molecular mechanisms that underlie NAFLD and associated metabolic disorders. Many therapeutic targets have been found and used in clinical studies. Peroxisome proliferator-activated receptors (PPARs) are among the potential targets and have been demonstrated to exert a pivotal role in modulation of NAFLD. Many drugs developed so far are targeted at PPARs. Thus, the aim of this paper is to summarize the roles of PPARs in the treatment of NAFLD.
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Affiliation(s)
- Xin Sun
- Department of Pharmacy Wuxi No. 2 People´s Hospital The Affiliated Hospital of Nanjing Medical University , Wuxi , Jiangsu 214002, China
| | - Yan Zhang
- Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital, The Affiliated Hospital of Nanjing Medical University , Wuxi , Jiangsu, 214002, China
- Department of Pharmacology College of Pharmaceutical Sciences Soochow University , Suzhou , Jiangsu 215123, China
| | - Meilin Xie
- Department of Pharmacology College of Pharmaceutical Sciences Soochow University , Suzhou , Jiangsu 215123, China
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Sesamin ameliorates hepatic steatosis and inflammation in rats on a high-fat diet via LXRα and PPARα. Nutr Res 2016; 36:1022-1030. [DOI: 10.1016/j.nutres.2016.06.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 06/18/2016] [Accepted: 06/24/2016] [Indexed: 11/20/2022]
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Schroeder F, McIntosh AL, Martin GG, Huang H, Landrock D, Chung S, Landrock KK, Dangott LJ, Li S, Kaczocha M, Murphy EJ, Atshaves BP, Kier AB. Fatty Acid Binding Protein-1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias. Lipids 2016; 51:655-76. [PMID: 27117865 PMCID: PMC5408584 DOI: 10.1007/s11745-016-4155-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 04/11/2016] [Indexed: 01/01/2023]
Abstract
The first discovered member of the mammalian FABP family, liver fatty acid binding protein (FABP1, L-FABP), occurs at high cytosolic concentration in liver, intestine, and in the case of humans also in kidney. While the rat FABP1 is well studied, the extent these findings translate to human FABP1 is not clear-especially in view of recent studies showing that endocannabinoids and cannabinoids represent novel rat FABP1 ligands and FABP1 gene ablation impacts the hepatic endocannabinoid system, known to be involved in non-alcoholic fatty liver (NAFLD) development. Although not detectable in brain, FABP1 ablation nevertheless also impacts brain endocannabinoids. Despite overall tertiary structure similarity, human FABP1 differs significantly from rat FABP1 in secondary structure, much larger ligand binding cavity, and affinities/specificities for some ligands. Moreover, while both mouse and human FABP1 mediate ligand induction of peroxisome proliferator activated receptor-α (PPARα), they differ markedly in pattern of genes induced. This is critically important because a highly prevalent human single nucleotide polymorphism (SNP) (26-38 % minor allele frequency and 8.3 ± 1.9 % homozygous) results in a FABP1 T94A substitution that further accentuates these species differences. The human FABP1 T94A variant is associated with altered body mass index (BMI), clinical dyslipidemias (elevated plasma triglycerides and LDL cholesterol), atherothrombotic cerebral infarction, and non-alcoholic fatty liver disease (NAFLD). Resolving human FABP1 and the T94A variant's impact on the endocannabinoid and cannabinoid system is an exciting challenge due to the importance of this system in hepatic lipid accumulation as well as behavior, pain, inflammation, and satiety.
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Affiliation(s)
- Friedhelm Schroeder
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA.
| | - Avery L McIntosh
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA
| | - Gregory G Martin
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA
| | - Huan Huang
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA
| | - Danilo Landrock
- Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA
| | - Sarah Chung
- Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA
| | - Kerstin K Landrock
- Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA
| | - Lawrence J Dangott
- Department of Biochemistry and Biophysics, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA
| | - Shengrong Li
- Avanti Polar Lipids, 700 Industrial Park Dr., Alabaster, AL, 35007-9105, USA
| | - Martin Kaczocha
- Department of Anesthesiology, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Eric J Murphy
- Department of Pharmacology, Physiology, and Therapeutics and Chemistry, University of North Dakota, Grand Forks, ND, 58202-9037, USA
| | - Barbara P Atshaves
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA
| | - Ann B Kier
- Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA
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Naowaboot J, Wannasiri S. Anti-lipogenic effect of Senna alata leaf extract in high-fat diet-induced obese mice. Asian Pac J Trop Biomed 2016. [DOI: 10.1016/j.apjtb.2015.12.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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