|
1
|
Gousias F, Stylianaki I, Giannenas I, Kallitsis T, Papaioannou N, Chaitidis E, Squires C, Arsenos G, Tsiouris V, Papadopoulos GA. Effects of Milk Thistle Extract Supplementation on Performance, Egg Quality, and Liver Pathology of Laying Hens' Fed Diets Lacking Supplemental Choline Chloride. Vet Sci 2025; 12:77. [PMID: 40005837 PMCID: PMC11860362 DOI: 10.3390/vetsci12020077] [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: 10/17/2024] [Revised: 01/08/2025] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
The current study evaluated the effects of milk thistle extract supplementation in laying hens' fed diets lacking choline chloride addition. A total of 60 Isa-brown laying hens were randomly allocated into T1: control diet, 0% extract supplementation; T2: control diet with 1% extract; T3: control diet with 2.5% extract; and T4: control diet with 4% extract. Egg quality parameters, yolk lipid oxidation, malondialdehyde (MDA) content, and fatty acid profile were assessed. Livers were examined grossly and histologically to evaluate hepatocellular lesions such as vacuolization (lipidosis), reticular stromal architecture, the amount of collagenous connective tissue, and vascular wall changes. Groups T3 and T4 showed darker yolks compared to both control group and T2 (p = 0.001) and redness of the egg yolk (p < 0.001). The MDA was lowest in T2 group which had improved gross appearance with lower degrees of hepatic vacuolization than other groups. Liver discoloration was milder in T3 (43.8%) compared to the T1 and T4 groups (18.8% and 12.5%, respectively, p = 0.013). Reticulin loss was correlated with the degree of hepatic vacuolization (r = 0.751, p < 0.001). Supplementation with MT extract in diets lacking choline chloride may influence certain egg quality indices and liver gross macroscopic lesions in laying hens.
Collapse
Affiliation(s)
- Fotis Gousias
- Laboratory of Animal Husbandry, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (T.K.); (C.S.); (G.A.); (G.A.P.)
| | - Ioanna Stylianaki
- Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (I.S.); (N.P.); (E.C.)
| | - Ilias Giannenas
- Laboratory of Nutrition, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece;
| | - Theodoros Kallitsis
- Laboratory of Animal Husbandry, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (T.K.); (C.S.); (G.A.); (G.A.P.)
| | - Nikolaos Papaioannou
- Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (I.S.); (N.P.); (E.C.)
| | - Efstratios Chaitidis
- Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (I.S.); (N.P.); (E.C.)
| | - Clare Squires
- Laboratory of Animal Husbandry, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (T.K.); (C.S.); (G.A.); (G.A.P.)
| | - Georgios Arsenos
- Laboratory of Animal Husbandry, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (T.K.); (C.S.); (G.A.); (G.A.P.)
| | - Vasilios Tsiouris
- Unit of Avian Medicine, Clinic of Farm Animals, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 546 27 Thessaloniki, Greece;
| | - Georgios A. Papadopoulos
- Laboratory of Animal Husbandry, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (T.K.); (C.S.); (G.A.); (G.A.P.)
| |
Collapse
|
|
2
|
Selc M, Macova R, Babelova A. Novel Strategies Enhancing Bioavailability and Therapeutical Potential of Silibinin for Treatment of Liver Disorders. Drug Des Devel Ther 2024; 18:4629-4659. [PMID: 39444787 PMCID: PMC11498047 DOI: 10.2147/dddt.s483140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 10/02/2024] [Indexed: 10/25/2024] Open
Abstract
Silibinin, a bioactive component found in milk thistle extract (Silybum marianum), is known to have significant therapeutic potential in the treatment of various liver diseases. It is considered a key element of silymarin, which is traditionally used to support liver function. The main mechanisms of action of silibinin are attributed to its antioxidant properties protecting liver cells from damage caused by free radicals. Experimental studies conducted in vitro and in vivo have confirmed its ability to inhibit inflammatory and fibrotic processes, as well as promote the regeneration of damaged liver tissue. Therefore, silibinin represents a promising tool for the treatment of liver diseases. Since the silibinin molecule is insoluble in water and has poor bioavailability in vivo, new perspectives on solving this problem are being sought. The two most promising approaches are the water-soluble derivative silibinin-C-2',3-dihydrogen succinate, disodium salt, and the silibinin-phosphatidylcholine complex. Both drugs are currently under evaluation in liver disease clinical trials. Nevertheless, the mechanism underlying silibinin biological activity is still elusive and its more detailed understanding would undoubtedly increase its potential in the development of effective therapeutic strategies against liver diseases. This review is focused on the therapeutic potential of silibinin and its derivates, approaches to increase the bioavailability and the benefits in the treatment of liver diseases that have been achieved so far. The review discusses the relevant in vitro and in vivo studies that investigated the protective effects of silibinin in various forms of liver damage.
Collapse
Affiliation(s)
- Michal Selc
- Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Radka Macova
- Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Genetics, Faculty of Natural Sciences, Comenius University Bratislava, Bratislava, Slovakia
| | - Andrea Babelova
- Centre for Advanced Material Application, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| |
Collapse
|
|
3
|
Dagli Gul AS, Boyuk Ozcan G, Arihan O. Silibinin as a promising treatment for diabetes: Insights into behavioral and metabolic changes in an animal model. Food Sci Nutr 2024; 12:3336-3345. [PMID: 38726421 PMCID: PMC11077243 DOI: 10.1002/fsn3.3999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/25/2023] [Accepted: 01/17/2024] [Indexed: 05/12/2024] Open
Abstract
Diabetes mellitus is causing serious health problems in the chronic period. Silibinin is a flavonoid obtained from the milk thistle (Silybum marianum), which is among the herbal ethnopharmacological administrations. In studies with silibinin, it has been reported that it increases the activity of pancreatic beta cells and insulin sensitivity and has a hyperglycemia-reducing effect. However, behavioral parameters have not been evaluated together with insulin levels and liver function tests. Our aim in this study was to examine the effects of silibinin on insulin secretion, anxiety-like behaviors, and learning in a streptozotocin (STZ)-induced rat diabetes model. Wistar albino rats weighing 200-250 g were divided into 4 groups. Control: Saline solution, Diabetes: STZ 45 mg/kg, S 100: STZ 45 mg/kg + Silibinin 100 mg/kg, S 200: STZ 45 mg/kg + Silibinin 200 mg/kg. Administrations were continued for 21 days. On the 21st day, open field and elevated plus maze as unconditional anxiety tests; Barnes maze for learning and memory; and rotarod test for locomotor activity were conducted. Following behavioral tests, blood samples were taken under anesthesia. Blood glucose levels and ALT values were measured. Insulin levels were measured with an ELISA plate reader. Silibinin shortened the time to find the correct hole. Silibinin prevented the decrease in insulin due to STZ, exhibited a hyperglycemia-reducing effect and decreased the elevation of ALT.
Collapse
Affiliation(s)
- Asli San Dagli Gul
- Department of Physiology, Faculty of MedicineHacettepe UniversityAnkaraTurkey
| | - Gulbahar Boyuk Ozcan
- Department of Physiology, Faculty of MedicineAnkara Medipol UniversityAnkaraTurkey
| | - Okan Arihan
- Department of Physiology, Faculty of MedicineHacettepe UniversityAnkaraTurkey
| |
Collapse
|
|
4
|
Merenda T, Juszczak F, Ferier E, Duez P, Patris S, Declèves AÉ, Nachtergael A. Natural compounds proposed for the management of non-alcoholic fatty liver disease. NATURAL PRODUCTS AND BIOPROSPECTING 2024; 14:24. [PMID: 38556609 PMCID: PMC10982245 DOI: 10.1007/s13659-024-00445-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 03/20/2024] [Indexed: 04/02/2024]
Abstract
Although non-alcoholic fatty liver disease (NAFLD) presents as an intricate condition characterized by a growing prevalence, the often-recommended lifestyle interventions mostly lack high-level evidence of efficacy and there are currently no effective drugs proposed for this indication. The present review delves into NAFLD pathology, its diverse underlying physiopathological mechanisms and the available in vitro, in vivo, and clinical evidence regarding the use of natural compounds for its management, through three pivotal targets (oxidative stress, cellular inflammation, and insulin resistance). The promising perspectives that natural compounds offer for NAFLD management underscore the need for additional clinical and lifestyle intervention trials. Encouraging further research will contribute to establishing more robust evidence and practical recommendations tailored to patients with varying NAFLD grades.
Collapse
Affiliation(s)
- Théodora Merenda
- Unit of Clinical Pharmacy, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Florian Juszczak
- Department of Metabolic and Molecular Biochemistry, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Elisabeth Ferier
- Department of Metabolic and Molecular Biochemistry, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
- Unit of Therapeutic Chemistry and Pharmacognosy, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Pierre Duez
- Unit of Therapeutic Chemistry and Pharmacognosy, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Stéphanie Patris
- Unit of Clinical Pharmacy, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Anne-Émilie Declèves
- Department of Metabolic and Molecular Biochemistry, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Amandine Nachtergael
- Unit of Therapeutic Chemistry and Pharmacognosy, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium.
| |
Collapse
|
|
5
|
He T, Li X, Wang Z, Mao J, Mao Y, Sha R. Studies on the Changes of Fermentation Metabolites and the Protective Effect of Fermented Edible Grass on Stress Injury Induced by Acetaminophen in HepG2 Cells. Foods 2024; 13:470. [PMID: 38338605 PMCID: PMC10855311 DOI: 10.3390/foods13030470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 01/30/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024] Open
Abstract
In this study, gas chromatography-mass spectrometry (GC-MS) based untargeted metabolomics was used to describe the changes of metabolites in edible grass with Lactobacillus plantarum (Lp) fermentation durations of 0 and 7 days, and subsequently to investigate the protective effect of fermented edible grass on acetaminophen-induced stress injury in HepG2 cells. Results showed that 53 differential metabolites were identified, including 31 significantly increased and 22 significantly decreased metabolites in fermented edible grass. Fermented edible grass protected HepG2 cells against acetaminophen-induced stress injury, which profited from the reduction in lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels and the enhancement in superoxide dismutase (SOD) activity. Cell metabolomics analysis revealed that a total of 13 intracellular and 20 extracellular differential metabolites were detected. Fermented edible grass could regulate multiple cell metabolic pathways to exhibit protective effects on HepG2 cells. These findings provided theoretical guidance for the formation and regulation of bioactive metabolites in fermented edible grass and preliminarily confirmed the protective effects of fermented edible grass on drug-induced liver damage.
Collapse
Affiliation(s)
- Tao He
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, China
- Zhejiang Provincial Key Laboratory for Chemical & Biological Processing Technology of Farm Product, Hangzhou 310023, China
| | - Xianxiu Li
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, China
- Zhejiang Provincial Key Laboratory for Chemical & Biological Processing Technology of Farm Product, Hangzhou 310023, China
| | - Zhenzhen Wang
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, China
- Zhejiang Provincial Key Laboratory for Chemical & Biological Processing Technology of Farm Product, Hangzhou 310023, China
| | - Jianwei Mao
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, China
- Zhejiang Provincial Key Laboratory for Chemical & Biological Processing Technology of Farm Product, Hangzhou 310023, China
| | - Yangchen Mao
- School of Medicine, University of Southampton, Southampton SO17 1BJ, UK
| | - Ruyi Sha
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, China
- Zhejiang Provincial Key Laboratory for Chemical & Biological Processing Technology of Farm Product, Hangzhou 310023, China
| |
Collapse
|
|
6
|
Surai PF, Surai A, Earle-Payne K. Silymarin and Inflammation: Food for Thoughts. Antioxidants (Basel) 2024; 13:98. [PMID: 38247522 PMCID: PMC10812610 DOI: 10.3390/antiox13010098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/07/2024] [Accepted: 01/13/2024] [Indexed: 01/23/2024] Open
Abstract
Inflammation is a vital defense mechanism, creating hostile conditions for pathogens, preventing the spread of tissue infection and repairing damaged tissues in humans and animals. However, when inflammation resolution is delayed or compromised as a result of its misregulation, the process proceeds from the acute phase to chronic inflammation, leading to the development of various chronic illnesses. It is proven that redox balance disturbances and oxidative stress are among major factors inducing NF-κB and leading to over-inflammation. Therefore, the anti-inflammatory properties of various natural antioxidants have been widely tested in various in vitro and in vivo systems. Accumulating evidence indicates that silymarin (SM) and its main constituent silibinin/silybin (SB) have great potential as an anti-inflammation agent. The main anti-inflammatory mechanism of SM/SB action is attributed to the inhibition of TLR4/NF-κB-mediated signaling pathways and the downregulated expression of pro-inflammatory mediators, including TNF-α, IL-1β, IL-6, IL-12, IL-23, CCL4, CXCL10, etc. Of note, in the same model systems, SM/SB was able to upregulate anti-inflammatory cytokines (IL-4, IL-10, IL-13, TGF-β, etc.) and lipid mediators involved in the resolution of inflammation. The inflammatory properties of SM/SB were clearly demonstrated in model systems based on immune (macrophages and monocytes) and non-immune (epithelial, skin, bone, connective tissue and cancer) cells. At the same time, the anti-inflammatory action of SM/SB was confirmed in a number of in vivo models, including toxicity models, nonalcoholic fatty liver disease, ischemia/reperfusion models, stress-induced injuries, ageing and exercising models, wound healing and many other relevant model systems. It seems likely that the anti-inflammatory activities of SM/SB are key elements on the health-promoting properties of these phytochemicals.
Collapse
Affiliation(s)
- Peter F. Surai
- Vitagene and Health Research Centre, Bristol BS4 2RS, UK
- Faculty of Veterinary Medicine, Trakia University, 6000 Stara Zagora, Bulgaria
- Faculty of Agricultural and Environmental Sciences, Szent Istvan University, H-2103 Gödöllo, Hungary
- Biochemistry and Physiology Department, Saint-Petersburg State University of Veterinary Medicine, 196084 St. Petersburg, Russia
- Faculty of Veterinary Medicine, Sumy National Agrarian University, 40021 Sumy, Ukraine
- Faculty of Technology of Grain and Grain Business, Odessa National Technological University, 65039 Odessa, Ukraine
| | | | - Katie Earle-Payne
- NHS Greater Glasgow and Clyde, Renfrewshire Health and Social Care Centre, 10 Ferry Road, Renfrew PA4 8RU, UK
| |
Collapse
|
|
7
|
Lu C, Lei W, Sun M, Wu X, Liu Q, Liu J, Yang Y, Yang W, Zhang Z, Li X, Zhou Y, Deng C, Chen Y, Tian Y, Yang Y. Identification of CCR2 as a hub in septic myocardial injury and cardioprotection of silibinin. Free Radic Biol Med 2023; 197:46-57. [PMID: 36693441 DOI: 10.1016/j.freeradbiomed.2023.01.020] [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: 12/14/2022] [Revised: 01/14/2023] [Accepted: 01/20/2023] [Indexed: 01/22/2023]
Abstract
Myocardial injury is a serious complication of sepsis associated with high morbidity and mortality. Our previous work has confirmed that silibinin (SIL) alleviates septic myocardial injury, but the specific molecular mechanism has not been fully elucidated. This study aimed to identify its potential targets through network pharmacology combined with experimental verification. Firstly, a total of 29 overlapping genes between sepsis and SIL targets were obtained from RNA-seq analysis and the known databases. Subsequently, KEGG and GO analysis showed that these genes were enriched in immune response and cytokine-cytokine receptor interaction pathways. Notably, CCR2 was identified as an important candidate hub by protein-protein interaction analysis and molecular docking approach. In vivo experiments showed that SIL treatment significantly improved survival rate and cardiac function in septic mice, accompanied by decreased CCR2 expression. Moreover, in vitro experiments obtained the similar results. Especially, CCR2 siRNA attenuated inflammation response. In conclusion, this study systematically elucidated the key target of SIL in the treatment of septic myocardial injury. These findings provide valuable insights into the targets of sepsis and offer new avenues for exploring drug effect systematically.
Collapse
Affiliation(s)
- Chenxi Lu
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Wangrui Lei
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Meng Sun
- Department of Cardiology, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Xue Wu
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Qiong Liu
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Jie Liu
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Yaru Yang
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Wenwen Yang
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Zhe Zhang
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Xiaoru Li
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Yazhe Zhou
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Chao Deng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ying Chen
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ye Tian
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China.
| | - Yang Yang
- Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences and Medicine, Northwest University, Xi'an, China.
| |
Collapse
|
|
8
|
Surai PF. Silymarin as a vitagene modulator: effects on mitochondria integrity in stress conditions. MOLECULAR NUTRITION AND MITOCHONDRIA 2023:535-559. [DOI: 10.1016/b978-0-323-90256-4.00007-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
9
|
Awolaja OO, Lawal AO, Folorunso IM, Elekofehinti OO, Umar HI. Silibinin ameliorates the cardiovascular oxidative and inflammatory effects of type-2-diabetic rats exposed to air particulate matter. Polycycl Aromat Compd 2022. [DOI: 10.1080/10406638.2022.2123536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Affiliation(s)
- Olamide O. Awolaja
- Molecular Biology and Bioinformatics Unit, Department of Biochemistry, School of Sciences, Federal University of Technology, Akure, Nigeria
| | - Akeem O. Lawal
- Molecular Biology and Bioinformatics Unit, Department of Biochemistry, School of Sciences, Federal University of Technology, Akure, Nigeria
| | - Ibukun M. Folorunso
- Molecular Biology and Bioinformatics Unit, Department of Biochemistry, School of Sciences, Federal University of Technology, Akure, Nigeria
| | - Olusola O. Elekofehinti
- Molecular Biology and Bioinformatics Unit, Department of Biochemistry, School of Sciences, Federal University of Technology, Akure, Nigeria
| | - Haruna I. Umar
- Computer-Aided Therapeutic Discovery and Design Group, FUTA, Akure, Nigeria
| |
Collapse
|
|
10
|
Salvoza N, Giraudi PJ, Tiribelli C, Rosso N. Natural Compounds for Counteracting Nonalcoholic Fatty Liver Disease (NAFLD): Advantages and Limitations of the Suggested Candidates. Int J Mol Sci 2022; 23:2764. [PMID: 35269912 PMCID: PMC8911502 DOI: 10.3390/ijms23052764] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 02/23/2022] [Accepted: 02/27/2022] [Indexed: 12/20/2022] Open
Abstract
The booming prevalence of nonalcoholic fatty liver disease (NAFLD) in adults and children will threaten the health system in the upcoming years. The "multiple hit" hypothesis is the currently accepted explanation of the complex etiology and pathophysiology of the disease. Some of the critical pathological events associated with the development of NAFLD are insulin resistance, steatosis, oxidative stress, inflammation, and fibrosis. Hence, attenuating these events may help prevent or delay the progression of NAFLD. Despite an increasing understanding of the mechanisms involved in NAFLD, no approved standard pharmacological treatment is available. The only currently recommended alternative relies on lifestyle modifications, including diet and physical activity. However, the lack of compliance is still hampering this approach. Thus, there is an evident need to characterize new therapeutic alternatives. Studies of food bioactive compounds became an attractive approach to overcome the reticence toward lifestyle changes. The present study aimed to review some of the reported compounds with beneficial properties in NAFLD; namely, coffee (and its components), tormentic acid, verbascoside, and silymarin. We provide details about their protective effects, their mechanism of action in ameliorating the critical pathological events involved in NAFLD, and their clinical applications.
Collapse
Affiliation(s)
- Noel Salvoza
- Fondazione Italiana Fegato—ONLUS, Area Science Park Basovizza, SS14 km 163.5, 34149 Trieste, Italy; (N.S.); (P.J.G.)
- Philippine Council for Health Research and Development, DOST Compound, Bicutan, Taguig 1631, Philippines
| | - Pablo J. Giraudi
- Fondazione Italiana Fegato—ONLUS, Area Science Park Basovizza, SS14 km 163.5, 34149 Trieste, Italy; (N.S.); (P.J.G.)
| | - Claudio Tiribelli
- Fondazione Italiana Fegato—ONLUS, Area Science Park Basovizza, SS14 km 163.5, 34149 Trieste, Italy; (N.S.); (P.J.G.)
| | - Natalia Rosso
- Fondazione Italiana Fegato—ONLUS, Area Science Park Basovizza, SS14 km 163.5, 34149 Trieste, Italy; (N.S.); (P.J.G.)
| |
Collapse
|
|
11
|
A comprehensive review on phytochemicals for fatty liver: are they potential adjuvants? J Mol Med (Berl) 2022; 100:411-425. [PMID: 34993581 DOI: 10.1007/s00109-021-02170-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 12/18/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and, as such, is associated with obesity. With the current and growing epidemic of obesity, NAFLD is already considered the most common liver disease in the world. Currently, there is no official treatment for the disease besides weight loss. Although there are a few synthetic drugs currently being studied, there is also an abundance of herbal products that could also be used for treatment. With the World Health Organization (WHO) traditional medicine strategy (2014-2023) in mind, this review aims to analyze the mechanisms of action of some of these herbal products, as well as evaluate toxicity and herb-drug interactions available in literature.
Collapse
|
|
12
|
Islam A, Mishra A, Siddiqui MA, Siddiquie S. Recapitulation of Evidence of Phytochemical, Pharmacokinetic and Biomedical Application of Silybin. Drug Res (Stuttg) 2021; 71:489-503. [PMID: 34318464 DOI: 10.1055/a-1528-2721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Silymarin is a standardized extract obtained from seeds of Silybum marianum (SM) belonging to the family Asteraceae. It is a flavonolignan complex and consists of various compounds like silybin A silybin B, isosilybin A, isosilybin B, silydianin, silychristin and isosilychristin. Silybin is the major active component present in 60-70% of the silymarin extract. It has been used traditionally for the treatment of various liver disorders like cirrhosis, jaundice, and hepatitis. Silymarin possesses antioxidant and anti-inflammatory properties and is responsible for its antitumor activity. Other than hepatoprotective effect SM also possesses renoprotective, anti-diabetic, neuroprotective, hypolipidemic, anti-atherosclerosis and cardioprotective effects. Rather antimicrobial property of silymarin was observed against specific microbes, fungi, and viruses. This manuscript covered recent preclinical and clinical evidence of specific components silybin, responsible for its efficacy and about clinical studies has been conducted so far, which proven it's safety and offers mild effect like nausea, diarrhea and bloating. This review specifically focused on recent updates on its active components therapeutic applications against complicated ailments not covered in earlier reports.
Collapse
Affiliation(s)
- Anas Islam
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Anuradha Mishra
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Md Aftab Siddiqui
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Saman Siddiquie
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| |
Collapse
|
|
13
|
Ali SA, Saifi MA, Godugu C, Talla V. Silibinin alleviates silica-induced pulmonary fibrosis: Potential role in modulating inflammation and epithelial-mesenchymal transition. Phytother Res 2021; 35:5290-5304. [PMID: 34250649 DOI: 10.1002/ptr.7210] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 12/25/2022]
Abstract
Pulmonary fibrosis (PF) is a devastating interstitial lung disease resulting from indefinite causes with very few limited, those too ineffective therapeutic options. Earlier evidence reported inflammation and epithelial-mesenchymal transition (EMT) are the major threats in PF. The present study was aimed to examine the anti-fibrotic activity of silibinin (SB) in PF. PF was induced by administering oropharyngeal 1.5 mg/mice silica on day 1, followed by treatment with and without oral SB for 14 days. Lung injury was assessed by x-ray analysis on day 14 and all the animals were sacrificed on day 15. The results showed that silica remarkably altered the histoarchitecture and induced the expression of inflammatory components in BALF and pulmonary tissue. Immunoblotting investigation quantified the expression of TGF-β, p-smad2/3, collagen-I, fibronectin, and α-SMA in the pulmonary tissue. To this end, treatment with SB alleviated inflammatory components, including IL-1β, IL-6, and TNF-α in the fibrotic tissue. Moreover, SB harnessed the tissue architecture, improved diffusive scattering of x-ray signals, and modulated epithelial-mesenchymal phenotypic alterations, including TGF-β, p-smad2/3, and collagen-I. Altogether, the significant reduction of inflammatory signaling, collagen deposition, and epithelial-mesenchymal transdifferentiation by SB suggested that it could be used as a potential therapeutic candidate to treat pulmonary inflammation and fibrosis.
Collapse
Affiliation(s)
- Syed Afroz Ali
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research-(NIPER), Hyderabad, India.,Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research-(NIPER), Hyderabad, India
| | - Mohd Aslam Saifi
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research-(NIPER), Hyderabad, India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research-(NIPER), Hyderabad, India
| | - Venu Talla
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research-(NIPER), Hyderabad, India
| |
Collapse
|
|
14
|
Andreadou I, Daiber A, Baxter GF, Brizzi MF, Di Lisa F, Kaludercic N, Lazou A, Varga ZV, Zuurbier CJ, Schulz R, Ferdinandy P. Influence of cardiometabolic comorbidities on myocardial function, infarction, and cardioprotection: Role of cardiac redox signaling. Free Radic Biol Med 2021; 166:33-52. [PMID: 33588049 DOI: 10.1016/j.freeradbiomed.2021.02.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/03/2021] [Accepted: 02/06/2021] [Indexed: 02/06/2023]
Abstract
The morbidity and mortality from cardiovascular diseases (CVD) remain high. Metabolic diseases such as obesity, hyperlipidemia, diabetes mellitus (DM), non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as well as hypertension are the most common comorbidities in patients with CVD. These comorbidities result in increased myocardial oxidative stress, mainly from increased activity of nicotinamide adenine dinucleotide phosphate oxidases, uncoupled endothelial nitric oxide synthase, mitochondria as well as downregulation of antioxidant defense systems. Oxidative and nitrosative stress play an important role in ischemia/reperfusion injury and may account for increased susceptibility of the myocardium to infarction and myocardial dysfunction in the presence of the comorbidities. Thus, while early reperfusion represents the most favorable therapeutic strategy to prevent ischemia/reperfusion injury, redox therapeutic strategies may provide additive benefits, especially in patients with heart failure. While oxidative and nitrosative stress are harmful, controlled release of reactive oxygen species is however important for cardioprotective signaling. In this review we summarize the current data on the effect of hypertension and major cardiometabolic comorbidities such as obesity, hyperlipidemia, DM, NAFLD/NASH on cardiac redox homeostasis as well as on ischemia/reperfusion injury and cardioprotection. We also review and discuss the therapeutic interventions that may restore the redox imbalance in the diseased myocardium in the presence of these comorbidities.
Collapse
Affiliation(s)
- Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
| | - Andreas Daiber
- Department of Cardiology 1, Molecular Cardiology, University Medical Center, Langenbeckstr. 1, 55131, Mainz, Germany; Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr, Germany.
| | - Gary F Baxter
- Division of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, United Kingdom
| | | | - Fabio Di Lisa
- Department of Biomedical Sciences, University of Padova, Italy; Neuroscience Institute, National Research Council of Italy (CNR), Padova, Italy
| | - Nina Kaludercic
- Neuroscience Institute, National Research Council of Italy (CNR), Padova, Italy
| | - Antigone Lazou
- Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
| | - Zoltán V Varga
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
| | - Coert J Zuurbier
- Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Rainer Schulz
- Institute of Physiology, Justus Liebig University Giessen, Giessen, Germany.
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary
| |
Collapse
|
|
15
|
Jakubczyk K, Skonieczna-Żydecka K, Kałduńska J, Stachowska E, Gutowska I, Janda K. Effects of Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease-A Meta-Analysis. Nutrients 2020; 12:nu12082435. [PMID: 32823621 PMCID: PMC7469003 DOI: 10.3390/nu12082435] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/08/2020] [Accepted: 08/11/2020] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is regarded as one of the most common liver pathologies in many societies. Resveratrol, as a phenolic compound with powerful antioxidant and anti-inflammatory properties exerting positive effects on the lipid profile and lipid accumulation and also on insulin resistance, appears to be an effective, natural, and safe complementary treatment option in NAFLD therapy. This meta-analysis was undertaken to evaluate the effects of resveratrol supplementation in NAFLD patients. To this end, scientific databases PubMed/Medline/Embase were searched up to 19 March 2020. We included seven randomized clinical trials (RCTs) with a total of 302 patients with NAFLD. In all the trials included in the analysis, resveratrol was administered daily over periods between 56 and 180 days in doses ranging from 500 mg to 3000 mg a day. The results of this meta-analysis reveal that resveratrol supplementation, irrespective of the dose or duration, did not affect the analyzed parameters (p < 0.05). The sole exception was an increase in alanine aminotransferase following the administration of resveratrol (p = 0.041). Currently available evidence is insufficient to confirm the efficacy of resveratrol in the management of NAFLD. Due to the inconsistencies between the existing scientific reports, a number of which found a positive effect on NAFLD-related parameters; further research in this area is needed.
Collapse
Affiliation(s)
- Karolina Jakubczyk
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 24 Broniewskiego Street, 71-460 Szczecin, Poland; (K.J.); (J.K.); (E.S.); (K.J.)
| | - Karolina Skonieczna-Żydecka
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 24 Broniewskiego Street, 71-460 Szczecin, Poland; (K.J.); (J.K.); (E.S.); (K.J.)
- Correspondence: ; Tel.: +48-91-441-4808
| | - Justyna Kałduńska
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 24 Broniewskiego Street, 71-460 Szczecin, Poland; (K.J.); (J.K.); (E.S.); (K.J.)
| | - Ewa Stachowska
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 24 Broniewskiego Street, 71-460 Szczecin, Poland; (K.J.); (J.K.); (E.S.); (K.J.)
| | - Izabela Gutowska
- Department of Medical Chemistry, Pomeranian Medical University, Powstancow Wlkp Street 72, 71-460 Szczecin, Poland;
| | - Katarzyna Janda
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 24 Broniewskiego Street, 71-460 Szczecin, Poland; (K.J.); (J.K.); (E.S.); (K.J.)
| |
Collapse
|
|
16
|
Singh A, Yau YF, Leung KS, El-Nezami H, Lee JCY. Interaction of Polyphenols as Antioxidant and Anti-Inflammatory Compounds in Brain-Liver-Gut Axis. Antioxidants (Basel) 2020; 9:antiox9080669. [PMID: 32722619 PMCID: PMC7465954 DOI: 10.3390/antiox9080669] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/23/2020] [Accepted: 07/24/2020] [Indexed: 02/08/2023] Open
Abstract
Oxidative stress plays an important role in the onset as well as the progression of inflammation. Without proper intervention, acute inflammation could progress to chronic inflammation, resulting in the development of inflammatory diseases. Antioxidants, such as polyphenols, have been known to possess anti-oxidative properties which promote redox homeostasis. This has encouraged research on polyphenols as potential therapeutics for inflammation through anti-oxidative and anti-inflammatory pathways. In this review, the ability of polyphenols to modulate the activation of major pathways of inflammation and oxidative stress, and their potential to regulate the activity of immune cells are examined. In addition, in this review, special emphasis has been placed on the effects of polyphenols on inflammation in the brain–liver–gut axis. The data derived from in vitro cell studies, animal models and human intervention studies are discussed.
Collapse
|
|
17
|
Li Y, Yang D, Wang Y, Li Z, Zhu C. Co-delivery doxorubicin and silybin for anti-hepatoma via enhanced oral hepatic-targeted efficiency. Int J Nanomedicine 2018; 14:301-315. [PMID: 30643408 PMCID: PMC6314320 DOI: 10.2147/ijn.s187888] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background To establish the combination of doxorubicin (DOX) and silybin (SLB) in oral hepatic-targeting liposomes with the goal of reducing cardiotoxic side effects and improve oral hepatoma treatment. Methods Distearoylphosphatidylethanolamine–polyethylene glycol–cholic acid-modified liposomes (CA-LP) were used to encapsulate DOX and SLB (CA-LP–DOX/SLB), and the hepatic targeting, efficacy against hepatoma and cardioprotective effects were evaluated by cell toxicity, scratch and apoptosis in vitro studies, and pharmacokinetics and pharmacodynamics in vivo studies. Results In vitro cell studies showed that CA-LP–DOX/SLB inhibited HepG2 cell proliferation and HCC97H cell migration, and protected H9c2 cells. In vivo pharmacokinetics demonstrated that the CA-LP–DOX/SLB-treated group showed higher liver accumulation and lower heart accumulation of DOX relative to those in the CA-LP–DOX and LP–DOX-treated groups. In vivo pharmacodynamic studies showed that the CA-LP–DOX/SLB-treated group not only efficiently inhibited growth but also induced significantly less tissue damage than that observed in the CA-LP–DOX-treated group. Conclusion Concurrent administration of DOX and SLB via CA-LP provided a viable strategy to mitigate acute DOX-induced cardiotoxicity.
Collapse
Affiliation(s)
- Ying Li
- Drug Delivery Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, People's Republic of China,
| | - Dandan Yang
- Drug Delivery Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, People's Republic of China,
| | - Yian Wang
- Drug Delivery Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, People's Republic of China,
| | - Zhan Li
- Drug Delivery Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, People's Republic of China,
| | - Chunyan Zhu
- Drug Delivery Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, People's Republic of China,
| |
Collapse
|
|
18
|
Chu C, Li D, Zhang S, Ikejima T, Jia Y, Wang D, Xu F. Role of silibinin in the management of diabetes mellitus and its complications. Arch Pharm Res 2018; 41:785-796. [DOI: 10.1007/s12272-018-1047-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 06/16/2018] [Indexed: 02/07/2023]
|
|
19
|
Joshi AKR, Kandlakunta B, Kotturu SK, Ghosh S. Antiglucocorticoid potential of nutraceuticals: In silico molecular docking and in vitro assessment. J Food Biochem 2018. [DOI: 10.1111/jfbc.12522] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Apurva Kumar Ramesh Joshi
- Food Chemistry Division; National Institute of Nutrition, Jamai-Osmania; Telangana Hyderabad 500007 India
| | - Bhaskarachary Kandlakunta
- Food Chemistry Division; National Institute of Nutrition, Jamai-Osmania; Telangana Hyderabad 500007 India
| | - Sandeep Kumar Kotturu
- Division of Molecular Biology; National Institute of Nutrition, Jamai-Osmania; Telangana Hyderabad 500007 India
| | - Sudip Ghosh
- Division of Molecular Biology; National Institute of Nutrition, Jamai-Osmania; Telangana Hyderabad 500007 India
| |
Collapse
|
|
20
|
Song X, Liu B, Cui L, Zhou B, Liu W, Xu F, Hayashi T, Hattori S, Ushiki-Kaku Y, Tashiro SI, Ikejima T. Silibinin ameliorates anxiety/depression-like behaviors in amyloid β-treated rats by upregulating BDNF/TrkB pathway and attenuating autophagy in hippocampus. Physiol Behav 2017; 179:487-493. [DOI: 10.1016/j.physbeh.2017.07.023] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 07/15/2017] [Accepted: 07/18/2017] [Indexed: 02/07/2023]
|
|
21
|
Silibinin Restores NAD⁺ Levels and Induces the SIRT1/AMPK Pathway in Non-Alcoholic Fatty Liver. Nutrients 2017; 9:nu9101086. [PMID: 28973994 PMCID: PMC5691703 DOI: 10.3390/nu9101086] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 09/14/2017] [Accepted: 09/19/2017] [Indexed: 01/07/2023] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) homeostasis is emerging as a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and is tightly linked to the SIRT1/5’-AMP-activated protein kinase (AMPK) pathway. Silibinin, the main component of silymarin, has been proposed as a nutraceutical for the treatment of NAFLD. In this study, we aimed to identify whether silibinin may influence the NAD+/SIRT1 axis. To this end, C57BL/6 mice were fed a high fat diet (HFD) for 16 weeks, and were treated with silibinin or vehicle during the last 8 weeks. HepG2 cells were treated with 0.25 mM palmitate for 24 h with silibinin 25 µM or vehicle. HFD and palmitate administration led to oxidative stress, poly-(ADP-ribose)-polymerase (PARP) activation, NAD+ consumption, and lower SIRT1 activity. In mice fed the HFD, and in HepG2 treated with palmitate, we consistently observed lower levels of phospho-AMPKThr172 and phospho-acetyl-CoA carboxylaseSer79 and higher levels of nuclear sterol regulatory element-binding protein 1 activity, indicating de novo lipogenesis. Treatment of mice and HepG2 with silibinin abolished oxidative stress, and inhibited PARP activation thus restoring the NAD+ pool. In agreement with preserved NAD+ levels, SIRT1 activity and AMPK phosphorylation returned to control levels in mice and HepG2. Our results further indicate silibinin as a promising molecule for the treatment of NAFLD.
Collapse
|
|
22
|
Liu X, Xu Q, Liu W, Yao G, Zhao Y, Xu F, Hayashi T, Fujisaki H, Hattori S, Tashiro SI, Onodera S, Yamato M, Ikejima T. Enhanced migration of murine fibroblast-like 3T3-L1 preadipocytes on type I collagen-coated dish is reversed by silibinin treatment. Mol Cell Biochem 2017; 441:35-62. [PMID: 28933025 DOI: 10.1007/s11010-017-3173-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 09/01/2017] [Indexed: 12/24/2022]
Abstract
Migration of fibroblast-like preadipocytes is important for the development of adipose tissue, whereas excessive migration is often responsible for impaired adipose tissue related with obesity and fibrotic diseases. Type I collagen (collagen I) is the most abundant component of extracellular matrix and has been shown to regulate fibroblast migration in vitro, but its role in adipose tissue is not known. Silibinin is a bioactive natural flavonoid with antioxidant and antimetastasis activities. In this study, we found that type I collagen coating promoted the proliferation and migration of murine 3T3-L1 preadipocytes in a dose-dependent manner, implying that collagen I could be an extracellular signal. Regarding the mechanisms of collagen I-stimulated 3T3-L1 migration, we found that NF-κB p65 is activated, including the increased nuclear translocation of NF-κB p65 as well as the upregulation of NF-κB p65 phosphorylation and acetylation, accompanied by the increased expressions of proinflammatory factors and the generation of reactive oxygen species (ROS). Reduction of collagen I-enhanced migration of cells by treatment with silibinin was associated with suppression of NF-κB p65 activity and ROS generation, and negatively correlated with the increasing sirt1 expression. Taken together, the enhanced migration of 3T3-L1 cells induced on collagen I-coated dish is mediated by the activation of NF-κB p65 function and ROS generation that can be alleviated with silibinin by upregulation of sirt1, leading to the repression of NF-κB p65 function and ROS generation.
Collapse
Affiliation(s)
- Xiaoling Liu
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Qian Xu
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Weiwei Liu
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Guodong Yao
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
- Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang, China
| | - Yeli Zhao
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Fanxing Xu
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Toshihiko Hayashi
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Hitomi Fujisaki
- Nippi Research Institute of Biomatrix, Nippi, Incorporated, Toride, Japan
| | - Shunji Hattori
- Nippi Research Institute of Biomatrix, Nippi, Incorporated, Toride, Japan
| | - Shin-Ichi Tashiro
- Department of Medical Education and Primary Care, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Satoshi Onodera
- Department of Clinical and Pharmaceutical Sciences, Showa Pharmaceutical University, Tokyo, Japan
| | - Masayuki Yamato
- Waseda University Joint Institution for Advanced Biomedical Sciences, Tokyo Women's Medical University, Tokyo, Japan
| | - Takashi Ikejima
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China.
| |
Collapse
|
|
23
|
Marin V, Gazzin S, Gambaro SE, Dal Ben M, Calligaris S, Anese M, Raseni A, Avellini C, Giraudi PJ, Tiribelli C, Rosso N. Effects of Oral Administration of Silymarin in a Juvenile Murine Model of Non-alcoholic Steatohepatitis. Nutrients 2017; 9:nu9091006. [PMID: 28895929 PMCID: PMC5622766 DOI: 10.3390/nu9091006] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 09/07/2017] [Accepted: 09/09/2017] [Indexed: 12/29/2022] Open
Abstract
The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in adolescents is challenging the global care system. No therapeutic strategies have been defined so far, and changes in the lifestyle remain the only alternative. In this study, we assessed the protective effects of silymarin in a juvenile non-alcoholic steatohepatitis (NASH) model and the in vitro effects on fat-laden human hepatocytes. C57Bl/6 mice were exposed to HFHC diet immediately after weaning. After eight weeks, animals showed histological signs of NASH. Silymarin was added to the HFHC diet, the treatment continued for additional 12 weeks and the effects on BMI, hepatomegaly, visceral fat, lipid profile, transaminases, HOMA-IR, steatosis, inflammation, fibrosis, oxidative stress, and apoptosis were determined. The switch from HFHC to control diet was used to mimic life style changes. In vitro experiments were performed in parallel in human hepatocytes. HFHC diet supplemented with silymarin showed a significant improvement in glycemia, visceral fat, lipid profile, and liver fibrosis. Moreover, it reduced (both in vitro and in vivo) ALT, hepatic inflammation, oxidative stress, and apoptosis. Lifestyle changes restored the control group parameters. The data presented show the beneficial effects of the oral administration of silymarin in the absence of changes in the dietary habits in a juvenile model of NASH.
Collapse
Affiliation(s)
- Veronica Marin
- Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy.
| | - Silvia Gazzin
- Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy.
| | - Sabrina E Gambaro
- Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy.
| | - Matteo Dal Ben
- Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy.
| | - Sonia Calligaris
- Università di Udine, Dipartimento di Scienze AgroAlimentari, Ambientali e Animali, Via Sondrio 2/A, 33100 Udine, Italy.
| | - Monica Anese
- Università di Udine, Dipartimento di Scienze AgroAlimentari, Ambientali e Animali, Via Sondrio 2/A, 33100 Udine, Italy.
| | - Alan Raseni
- IRCCS Burlo Garofolo Paediatric Hospital, Clinical Chemistry Laboratory, 34100 Trieste, Italy.
| | - Claudio Avellini
- Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia", Dipartimento di Laboratorio, Istituto di Anatomia Patologica, 33100 Udine, Italy.
| | - Pablo J Giraudi
- Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy.
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy.
| | - Natalia Rosso
- Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy.
| |
Collapse
|
|
24
|
Coutinho PN, Pereira BP, Hertel Pereira AC, Porto ML, Monteiro de Assis ALE, Côgo Destefani A, Meyrelles SS, Vasquez EC, Nogueira BV, de Andrade TU, Endringer DC, Fronza M, Costa Pereira TM. Chronic administration of antioxidant resin from Virola oleifera attenuates atherogenesis in LDLr -/- mice. JOURNAL OF ETHNOPHARMACOLOGY 2017; 206:65-72. [PMID: 28502908 DOI: 10.1016/j.jep.2017.05.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 04/25/2017] [Accepted: 05/10/2017] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Virola oleifera (Schott) A. C. Smith, Myristicaceae has been largely used in traditional folk medicine in Brazil as an anti-inflammatory agent and our previous data indicated the antioxidant properties in other oxidative stress-related models. However, its effects on atherosclerosis (AT) are not yet investigated. AIMS OF THE STUDY To evaluate the influence of resin from Virola oleifera (RV) on progression of AT in LDLr-/- mice. MATERIALS AND METHODS LDLr-/- mice were divided into 4 groups: 1) The ND group received a normal diet without treatment. 2) The HD group received a high-fat diet without treatment. 3) The HD-V50 received a high-fat diet and was orally treated with RV at 50mg/Kg. 4) The HD-V300 received a high-fat diet and was orally treated with RV at 300mg/Kg. After 4 weeks, blood was collected to quantify biochemical parameters and ROS total and the aorta was removed to measure the lipid deposition by en face analysis. The liver was also collected to determine total lipids and lipid and protein oxidation. In order to investigate in more detail the contributions of RV in the vascular structure, we carried out the in vitro tests using four cellular types: macrophages, fibroblasts, vascular smooth muscle and endothelial cells. RESULTS We showed that the chronic treatment of RV at both doses reduced vascular lipid accumulation (~50%, p<0.05), probably through systemic and hepatic antioxidant effects, independent of dyslipidemia. Moreover, the in vitro assay results demonstrated that RV develops antioxidant properties on the vascular smooth muscle and endothelial cells, reinforcing the protective role of RV in progression of AT. LPS-stimulated macrophages treated with RV resulted in a significant reduction of NO production in a concentration-dependent manner. CONCLUSIONS Chronic treatment with RV diminishes lipid deposition in atherosclerotic mice, which may be justified, at least in part, by antioxidant systemic and local mechanisms, reinforcing the protective role this resin in the setting of vascular lipid deposition, independent of hypercholesterolemia.
Collapse
Affiliation(s)
- Paola Nogueira Coutinho
- Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Vila Velha, ES, Brazil.
| | - Beatriz Peters Pereira
- Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Vila Velha, ES, Brazil.
| | | | - Marcella Leite Porto
- Federal Institute of Education, Science and Technology (IFES), Vila Velha, ES, Brazil.
| | - Arícia Leone Evangelista Monteiro de Assis
- Laboratory of Cellular Ultrastructure Carlos Alberto Redins (LUCCAR), Department of Morphology, UFES, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil.
| | - Afrânio Côgo Destefani
- Laboratory of Cellular Ultrastructure Carlos Alberto Redins (LUCCAR), Department of Morphology, UFES, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil.
| | - Silvana Santos Meyrelles
- Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil.
| | - Elisardo Corral Vasquez
- Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Vila Velha, ES, Brazil; Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil.
| | - Breno Valentim Nogueira
- Laboratory of Cellular Ultrastructure Carlos Alberto Redins (LUCCAR), Department of Morphology, UFES, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil.
| | - Tadeu Uggere de Andrade
- Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Vila Velha, ES, Brazil.
| | - Denise Coutinho Endringer
- Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Vila Velha, ES, Brazil; Federal Institute of Education, Science and Technology (IFES), Vila Velha, ES, Brazil.
| | - Marcio Fronza
- Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Vila Velha, ES, Brazil.
| | - Thiago Melo Costa Pereira
- Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Vila Velha, ES, Brazil; Federal Institute of Education, Science and Technology (IFES), Vila Velha, ES, Brazil.
| |
Collapse
|
|
25
|
Yun DG, Lee DG. Assessment of silibinin as a potential antifungal agent and investigation of its mechanism of action. IUBMB Life 2017. [DOI: 10.1002/iub.1647] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Dae Gyu Yun
- School of Life Sciences, BK 21 Plus KNU Creative BioResearch Group; College of Natural Sciences, Kyungpook National University; 80 Daehakro, Bukgu Daegu, 41566 Republic of Korea
| | - Dong Gun Lee
- School of Life Sciences, BK 21 Plus KNU Creative BioResearch Group; College of Natural Sciences, Kyungpook National University; 80 Daehakro, Bukgu Daegu, 41566 Republic of Korea
| |
Collapse
|
|
26
|
Spahis S, Delvin E, Borys JM, Levy E. Oxidative Stress as a Critical Factor in Nonalcoholic Fatty Liver Disease Pathogenesis. Antioxid Redox Signal 2017; 26:519-541. [PMID: 27452109 DOI: 10.1089/ars.2016.6776] [Citation(s) in RCA: 278] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
SIGNIFICANCE Nonalcoholic fatty liver disease (NAFLD), characterized by liver triacylglycerol build-up, has been growing in the global world in concert with the raised prevalence of cardiometabolic disorders, including obesity, diabetes, and hyperlipemia. Redox imbalance has been suggested to be highly relevant to NAFLD pathogenesis. Recent Advances: As a major health problem, NAFLD progresses to the more severe nonalcoholic steatohepatitis (NASH) condition and predisposes susceptible individuals to liver and cardiovascular disease. Although NAFLD represents the predominant cause of chronic liver disorders, the mechanisms of its development and progression remain incompletely understood, even if various scientific groups ascribed them to the occurrence of insulin resistance, dyslipidemia, inflammation, and apoptosis. Nevertheless, oxidative stress (OxS) more and more appears as the most important pathological event during NAFLD development and the hallmark between simple steatosis and NASH manifestation. CRITICAL ISSUES The purpose of this article is to summarize recent developments in the understanding of NAFLD, essentially focusing on OxS as a major pathogenetic mechanism. Various attempts to translate reactive oxygen species (ROS) scavenging by antioxidants into experimental and clinical studies have yielded mostly encouraging results. FUTURE DIRECTIONS Although augmented concentrations of ROS and faulty antioxidant defense have been associated to NAFLD and related complications, mechanisms of action and proofs of principle should be highlighted to support the causative role of OxS and to translate its concept into the clinic. Antioxid. Redox Signal. 26, 519-541.
Collapse
Affiliation(s)
- Schohraya Spahis
- 1 GI-Nutrition Unit, Research Centre, CHU Ste-Justine, Université de Montréal , Montreal, Quebec, Canada .,2 Department of Nutrition, Université de Montréal , Montreal, Quebec, Canada
| | - Edgard Delvin
- 1 GI-Nutrition Unit, Research Centre, CHU Ste-Justine, Université de Montréal , Montreal, Quebec, Canada .,3 Department of Biochemistry, Université de Montréal , Montreal, Quebec, Canada
| | | | - Emile Levy
- 1 GI-Nutrition Unit, Research Centre, CHU Ste-Justine, Université de Montréal , Montreal, Quebec, Canada .,2 Department of Nutrition, Université de Montréal , Montreal, Quebec, Canada .,4 EPODE International Network , Paris, France
| |
Collapse
|
|
27
|
Yun DG, Lee DG. Silymarin exerts antifungal effects via membrane-targeted mode of action by increasing permeability and inducing oxidative stress. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2017; 1859:467-474. [PMID: 28069415 DOI: 10.1016/j.bbamem.2017.01.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 01/03/2017] [Accepted: 01/05/2017] [Indexed: 12/19/2022]
Abstract
Silymarin, which is derived from the seeds of Silybum marianum, has been widely used to prevent and treat liver disorders. It is also consumed as a dietary supplement to improve liver function, as it does not exhibit any toxic effects in humans. Recently, silymarin has been reported to show antimicrobial effects against various pathogenic microorganisms, but the mode of action remains unknown. Thus, we investigated the antifungal activity of silymarin and aimed to determine the underlying mechanism. Initially, a propidium iodide assay was carried out; the results indicated that silymarin induced injury to the fungal plasma membrane. Subsequently, large unilamellar vesicles encapsulating calcein and fluorescein isothiocyanate-labeled dextrans (FDs) 4, 10, and 20 were prepared to analyze whether silymarin affects an artificial membrane model. The results indicated that silymarin increased membrane permeability by disturbing the membrane structure, thereby allowing free access to molecules smaller than FD20 (approximately 3.3nm). The accumulation of reactive oxygen species (ROS) results in deleterious effects to various cellular components. In particular, ROS easily react with the membrane lipids and induce lipid peroxidation, which increases membrane permeability and disturbs hydrophobic phospholipids. Using 2',7'-dichlorodihydrofluorescein diacetate and thiobarbituric acid, we confirmed that silymarin induced harmful effects on the plasma membrane. Membrane depolarization and K+ leakage, which were associated with an increase in membrane permeability, were also observed in Candida albicans cells. An assay using 1,6-diphenyl-1,3,5-hexatriene showed that silymarin decreased membrane fluidity. Taken together, we suggest that silymarin exerts its antifungal activity by targeting the C. albicans plasma membrane.
Collapse
Affiliation(s)
- Dae Gyu Yun
- School of Life Sciences, BK 21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, 80 Daehakro, Bukgu, Daegu, 41566, Republic of Korea
| | - Dong Gun Lee
- School of Life Sciences, BK 21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, 80 Daehakro, Bukgu, Daegu, 41566, Republic of Korea.
| |
Collapse
|
|
28
|
Stolf AM, Cardoso CC, Acco A. Effects of Silymarin on Diabetes Mellitus Complications: A Review. Phytother Res 2017; 31:366-374. [PMID: 28124457 DOI: 10.1002/ptr.5768] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 12/16/2016] [Accepted: 12/17/2016] [Indexed: 12/19/2022]
Abstract
Diabetes mellitus is a common metabolic disorder that is caused by a deficit in the production of (type 1) or response to (type 2) insulin. Diabetes mellitus is characterized by a state of chronic hyperglycemia and such symptoms as weight loss, thirst, polyuria, and blurred vision. These disturbances represent one of the major causes of morbidity and mortality nowadays, despite available treatments, such as insulin, insulin secretagogues, insulin sensitizers, and oral hypoglycemic agents. However, many efforts have been made to discover new drugs for diabetes treatment, including medicinal plant extracts. Silymarin is a powder extract of the seeds from Silybum marianum, a plant from the Asteraceae family. The major active ingredients include four isomers: silybin, isosilybin, silychristin, and silydianin. Silymarin is indicated for the treatment of hepatic disorders, such as cirrhosis, chronic hepatitis, and gallstones. Moreover, several studies of other pathologies, including diabetes, sepsis, osteoporosis, arthritis, hypercholesterolemia, cancer, viral infections, and Alzheimer's and Parkinson's diseases, have tested the effects of silymarin and reported promising results. This article reviews data from clinical, in vivo, and in vitro studies on the use of silymarin, with a focus on the complications of diabetes, including nephropathy, neuropathy, healing delays, oxidative stress, hepatotoxicity, and cardiomyopathy. Copyright © 2017 John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Aline Maria Stolf
- Department of Pharmacology, Federal University of Paraná, Curitiba, PR, Brazil
| | | | - Alexandra Acco
- Department of Pharmacology, Federal University of Paraná, Curitiba, PR, Brazil
| |
Collapse
|
|
29
|
Song X, Zhou B, Cui L, Lei D, Zhang P, Yao G, Xia M, Hayashi T, Hattori S, Ushiki-Kaku Y, Tashiro SI, Onodera S, Ikejima T. Silibinin ameliorates Aβ 25-35-induced memory deficits in rats by modulating autophagy and attenuating neuroinflammation as well as oxidative stress. Neurochem Res 2016; 42:1073-1083. [PMID: 28004303 DOI: 10.1007/s11064-016-2141-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 11/05/2016] [Accepted: 12/08/2016] [Indexed: 01/07/2023]
Abstract
Alzheimer's disease (AD) is a progressive, neurodegenerative disease. Accumulating evidence suggests that inflammatory response, oxidative stress and autophagy are involved in amyloid β (Aβ)-induced memory deficits. Silibinin (silybin), a flavonoid derived from the herb milk thistle, is well known for its hepatoprotective activities. In this study, we investigated the neuroprotective effect of silibinin on Aβ25-35-injected rats. Results demonstrated that silibinin significantly attenuated Aβ25-35-induced memory deficits in Morris water maze and novel object-recognition tests. Silibinin exerted anxiolytic effect in Aβ25-35-injected rats as determined in elevated plus maze test. Silibinin attenuated the inflammatory responses, increased glutathione (GSH) levels and decreased malondialdehyde (MDA) levels, and upregulated autophagy levels in the Aβ25-35-injected rats. In conclusion, silibinin is a potential candidate for AD treatment because of its anti-inflammatory, antioxidant and autophagy regulating activities.
Collapse
Affiliation(s)
- Xiaoyu Song
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Biao Zhou
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Lingyu Cui
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Di Lei
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Pingping Zhang
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Guodong Yao
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mingyu Xia
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Toshihiko Hayashi
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Shunji Hattori
- Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan
| | - Yuko Ushiki-Kaku
- Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan
| | - Shin-Ichi Tashiro
- Department of Medical Education & Primary Care, Kyoto Prefectural University of Medicine, Kajiicho 465, Kamikyo-ku, Kyoto City, Kyoto, 602-8566, Japan
| | - Satoshi Onodera
- Department of Clinical and Biomedical Sciences, Showa Pharmaceutical University, Tokyo, 194-8543, Japan
| | - Takashi Ikejima
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| |
Collapse
|
|
30
|
El Sohafy SM, Metwally AM, Omar AA, Amer ME, Radwan MM, Abdel-Kader MS, El Toumy SA, ElSohly MA. Cornigerin, a new sesqui-lignan from the hepatoprotective fractions of Cynara cornigera L. Fitoterapia 2016; 115:101-105. [PMID: 27693744 DOI: 10.1016/j.fitote.2016.09.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 09/21/2016] [Accepted: 09/26/2016] [Indexed: 01/23/2023]
Abstract
The ethanol extract of Cynara cornigera L. was fractionated and the fractions were subjected to hepatoprotective assays using Wistar albino rats at a dose of 500 and 250mg/kg. The liver injury was induced in rats using carbon tetrachloride. Biochemical parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin were estimated as reflections of the liver condition, with silymarin as a positive control. Phytochemical investigation and chromatographic separation of the hepatoprotective fractions led to the isolation of a new sesqui-lignan namely cornigerin (1), along with eight known compounds: apigenin (2), luteolin (3), β-sitosterol glycoside (4), apigenin 7-O-β-D-glucopyranoside (5), luteolin-7-O-β-D-glucopyranoside (6), apigenin-7-O-rutinoside (7), cynarin 1,5-di-O-caffeoylquinic acid (8), and apigenin-7-O-β-D-glucuronide (9). This is the first report for the isolation of 8 and 9 from this plant.
Collapse
Affiliation(s)
- Samah M El Sohafy
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria 21215, Egypt.
| | - Aly M Metwally
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria 21215, Egypt
| | - Abdalla A Omar
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria 21215, Egypt
| | - Masouda E Amer
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria 21215, Egypt
| | - Mohamed M Radwan
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria 21215, Egypt; National Center for Natural Products Research School of Pharmacy, University of Mississippi, University, MS 38677, USA
| | - Maged S Abdel-Kader
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria 21215, Egypt; Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin AbdulAziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
| | - Sayed A El Toumy
- Chemistry of Tannins Department, National Research Center, Dokki, 12622 Cairo, Egypt
| | - Mahmoud A ElSohly
- National Center for Natural Products Research School of Pharmacy, University of Mississippi, University, MS 38677, USA; Department of Pharmaceutics and Drug delivery, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
| |
Collapse
|
|
31
|
Chiba T, Suzuki S, Sato Y, Itoh T, Umegaki K. Evaluation of Methionine Content in a High-Fat and Choline-Deficient Diet on Body Weight Gain and the Development of Non-Alcoholic Steatohepatitis in Mice. PLoS One 2016; 11:e0164191. [PMID: 27723801 PMCID: PMC5056759 DOI: 10.1371/journal.pone.0164191] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023] Open
Abstract
Aim Non-alcoholic steatohepatitis (NASH) is a globally recognized liver disease. A methionine- and choline-deficient diet is used to induce NASH in mice; however, this diet also causes severe body weight loss. To resolve this issue, we examined the effects of methionine content in a high-fat and choline-deficient (HFCD) diet on body weight and the development of NASH in mice. Methods C57BL/6J mice (male, 10 weeks of age) were fed an L-amino acid rodent (control) diet, high-fat (HF) diet, or HFCD diet containing various amounts of methionine (0.1–0.6% (w/w)) for 12 weeks. Plasma lipid levels, hepatic lipid content and inflammatory marker gene expression were measured, and a pathological analysis was conducted to evaluate NASH. Results The 0.1% methionine in HFCD diet suppressed body weight gain, which was lower than that with control diet. On the other hand, the 0.2% methionine in HFCD diet yielded similar body weight gains as the control diet, while more than 0.4% methionine showed the same body weight gains as the HF diet. Liver weights and hepatic lipid contents were the greatest with 0.1% methionine and decreased in a methionine dose-dependent manner. Pathological analysis, NAFLD activity scores and gene expression levels in the liver revealed that 0.1% and 0.2% methionine for 12 weeks induced NASH, whereas 0.4% and 0.6% methionine attenuated the induction of NASH by HFCD diet. However, the 0.2% methionine in HFCD diet did not induce insulin resistance, despite the body weight gain. Conclusions The 0.2% methionine in HFCD diet for 12 weeks was able to induce NASH without weight loss.
Collapse
Affiliation(s)
- Tsuyoshi Chiba
- Information Center, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Shinjuku-ku, Tokyo, Japan
- * E-mail:
| | - Sachina Suzuki
- Information Center, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Shinjuku-ku, Tokyo, Japan
| | - Yoko Sato
- Information Center, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Shinjuku-ku, Tokyo, Japan
| | - Tatsuki Itoh
- Department of Food Science and Nutrition, Kinki University Faculty of Agriculture, Nakamachi, Nara, Japan
| | - Keizo Umegaki
- Information Center, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Shinjuku-ku, Tokyo, Japan
| |
Collapse
|
|
32
|
Clemente MG, Mandato C, Poeta M, Vajro P. Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions. World J Gastroenterol 2016; 22:8078-8093. [PMID: 27688650 PMCID: PMC5037077 DOI: 10.3748/wjg.v22.i36.8078] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 08/04/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A “multiple-hit” pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data (BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR (acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy (the “imperfect” gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention. Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended lifestyle changes. When morbid obesity prevails, bariatric surgery should be considered.
Collapse
|
|
33
|
Zhang C, Yuan W, Fang J, Wang W, He P, Lei J, Wang C. Efficacy of Resveratrol Supplementation against Non-Alcoholic Fatty Liver Disease: A Meta-Analysis of Placebo-Controlled Clinical Trials. PLoS One 2016; 11:e0161792. [PMID: 27560482 PMCID: PMC4999224 DOI: 10.1371/journal.pone.0161792] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 08/11/2016] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with rising prevalence. Increasing evidence has demonstrated that resveratrol, a dietary phytochemical, is capable of attenuating NAFLD development and progression; however, results from clinical studies are inconsistent and inconclusive. Here, we conducted a meta-analysis to evaluate the efficacy of resveratrol on NAFLD, using several parameters to provide new insights for clinical application. We systematically searched EMBASE, PubMed, Science Citation Index, Elsevier, and Cochrane Library databases for studies published up to date (July 2016), in English, to identify and screen eligible, relevant studies. Either a fixed-effect model or random model was used to estimate mean difference (MD) and 95% confidence intervals (CIs) for the effect of resveratrol on NAFLD. Four randomized, double-blinded, placebo-controlled trials involving 156 patients were included in the meta-analysis. Levels of low-density lipoprotein (MD = 0.47, 95% CI: 0.21, 0.74, P < 0.05) and total cholesterol (MD = 0.49, 95% CI: 0.18, 0.80, P < 0.05) were higher in the resveratrol treatment groups than in placebo control groups, whereas other parameters were not altered. Overall, this study indicates that resveratrol treatment has negligible effects on attenuating NAFLD, given the small improvement in NAFLD features. More high-quality clinical trials of resveratrol for NAFLD are required to confirm these results.
Collapse
Affiliation(s)
- Chongyang Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Weigang Yuan
- Department of Anthropotomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jianguo Fang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenqing Wang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Pei He
- Department of Obstetrics and Gynecology, Wuhan NO.1 Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiahui Lei
- Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chunxu Wang
- Department of Anthropotomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- * E-mail:
| |
Collapse
|
|
34
|
Palmeri R, Monteleone JI, Spagna G, Restuccia C, Raffaele M, Vanella L, Li Volti G, Barbagallo I. Olive Leaf Extract from Sicilian Cultivar Reduced Lipid Accumulation by Inducing Thermogenic Pathway during Adipogenesis. Front Pharmacol 2016; 7:143. [PMID: 27303302 PMCID: PMC4885843 DOI: 10.3389/fphar.2016.00143] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 05/17/2016] [Indexed: 12/22/2022] Open
Abstract
Olive leaves contain a wide variety of phenolic compounds belonging to phenolic acids, phenolic alcohols, flavonoids, and secoiridoids, and include also many other pharmacological active compounds. They could play an important role in human diet and health because of their ability to lower blood pressure, increase coronary arteries blood flow and decrease the risk of cardiovascular diseases. The aim of this study was to investigate the effect of olive leaf extract (OLE) from Sicilian cultivar on adipogenic differentiation of human adipose derived mesenchymal stem cells and its impact on lipid metabolism. We showed that OLE treatment during adipogenic differentiation reduces inflammation, lipid accumulation and induces thermogenesis by activation of uncoupling protein uncoupling protein 1, sirtuin 1, peroxisome proliferator-activated receptor alpha, and coactivator 1 alpha. Furthermore, OLE significantly decreases the expression of molecules involved in adipogenesis and upregulates the expression of mediators involved in thermogenesis and lipid metabolism. Taken together, our results suggest that OLE may promote the brown remodeling of white adipose tissue inducing thermogenesis and improving metabolic homeostasis.
Collapse
Affiliation(s)
- Rosa Palmeri
- Department of Agricultural, Food and Environment, University of CataniaCatania, Italy
| | - Julieta I. Monteleone
- Department of Agricultural, Food and Environment, University of CataniaCatania, Italy
| | - Giovanni Spagna
- Department of Agricultural, Food and Environment, University of CataniaCatania, Italy
| | - Cristina Restuccia
- Department of Agricultural, Food and Environment, University of CataniaCatania, Italy
| | - Marco Raffaele
- Biochemistry Section, Department of Drug Sciences, University of CataniaCatania, Italy
| | - Luca Vanella
- Biochemistry Section, Department of Drug Sciences, University of CataniaCatania, Italy
| | - Giovanni Li Volti
- Department of Biomedical and Biotechnological Sciences, University of CataniaCatania, Italy
- Euro-Mediterranean Institute of Science and TechnologyPalermo, Italy
| | - Ignazio Barbagallo
- Biochemistry Section, Department of Drug Sciences, University of CataniaCatania, Italy
- Euro-Mediterranean Institute of Science and TechnologyPalermo, Italy
| |
Collapse
|
|
35
|
Zelber-Sagi S, Godos J, Salomone F. Lifestyle changes for the treatment of nonalcoholic fatty liver disease: a review of observational studies and intervention trials. Therap Adv Gastroenterol 2016; 9:392-407. [PMID: 27134667 PMCID: PMC4830109 DOI: 10.1177/1756283x16638830] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is emerging as a major public health problem because of its association with increased cardiovascular and liver-related morbidity and mortality. Both genetic factors and lifestyle contribute to the pathogenesis of NAFLD. Lifestyle, including dietary habits and physical activity, is a modifiable risk factor and thus represents the main target for the prevention and treatment of NAFLD. In this review, we summarize the evidence regarding nutritional aspects (i.e. total energy intake, saturated fat and carbohydrates intake, certain foods or drinks and dietary patterns as a whole) in the treatment of NAFLD. In addition, we analyze the evidence concerning the independent effect of physical activity, including aerobic and resistance training, in the treatment of NAFLD. A therapeutic algorithm according to results from intervention trials is also provided for clinicians and other healthcare professionals involved in the management of NAFLD.
Collapse
Affiliation(s)
- Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa,Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Israel
| | - Justyna Godos
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | | |
Collapse
|
|
36
|
Sayin F, Buyukbas S, Basarali M, Alp H, Toy H, Ugurcu V. Effects of Silybum marianum Extract on High-Fat Diet Induced Metabolic Disorders in Rats. POL J FOOD NUTR SCI 2016. [DOI: 10.1515/pjfns-2015-0014] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
|
|
37
|
Song X, Zhou B, Zhang P, Lei D, Wang Y, Yao G, Hayashi T, Xia M, Tashiro SI, Onodera S, Ikejima T. Protective Effect of Silibinin on Learning and Memory Impairment in LPS-Treated Rats via ROS–BDNF–TrkB Pathway. Neurochem Res 2016; 41:1662-72. [DOI: 10.1007/s11064-016-1881-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Revised: 02/26/2016] [Accepted: 02/29/2016] [Indexed: 12/15/2022]
|
|
38
|
Hashem RM, Hassanin KM, Rashed LA, Mahmoud MO, Hassan MG. Effect of silibinin and vitamin E on the ASK1-p38 MAPK pathway in D-galactosamine/lipopolysaccharide induced hepatotoxicity. Exp Biol Med (Maywood) 2016; 241:1250-7. [PMID: 26941058 DOI: 10.1177/1535370216636719] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 02/02/2016] [Indexed: 11/15/2022] Open
Abstract
Apoptosis signal-regulating kinase 1 (ASK1), a redox-sensor mitogen-activated protein kinase kinase kinase (MAPKKK) that activates p38 MAPK pathways in oxidative stress-induced hepatotoxicity in D-galactosamine/lipopolysaccharide (D-GalN/LPS) model, is a key central pathway in which specific targeting of ASK1 deactivation is of a great therapeutic potential. We tested the effect of silibinin and vitamin E in curative and prophylactic manner of treatment on the negative modulators of ASK1, thioredoxin1 (Trx1), thioredoxin reductase1 (TrxR1), and the protein phosphatase (PP5), whereas they have previously proven to have hepatoprotective effect. Either curative or prophylactic silibinin and vitamin E groups significantly decreased ASK1 and p38 MAPK levels through increasing the gene expression of Trx1, TrxR1, and PP5 to reduce the oxidative stress as demonstrated by decreasing the levels of NADPH oxidase 4 (NOX4), TBARS and conjugated diene with a concomitant increase in the levels of GSH, CAT, and SOD. These results were confirmed by histopathology examination which illustrated progressive degenerative changes of hepatocytes such as hydropic degeneration, vacuolation, pyknosis, karyolysis, and loss of architecture of some cells in D-GalN/LPS treatment, and these features were alleviated with silibinin and vitamin E administration. In conclusion, silibinin and vitamin E decreased ASK1-p38 MAPK pathway through deactivating the upstream signalling ASK1 molecule via increasing the levels of Trx1 and TrxR1 as well as the PP5 to alleviate in D-GalN/LPS induced hepatotoxicity.
Collapse
Affiliation(s)
- Reem M Hashem
- Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Kamel Ma Hassanin
- Department of Biochemistry, Faculty of Veterinary Medicine, Minia University, El Minia, Egypt
| | - Laila A Rashed
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed O Mahmoud
- Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed G Hassan
- Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| |
Collapse
|
|
39
|
Nutritional therapy for nonalcoholic fatty liver disease. J Nutr Biochem 2016; 29:1-11. [DOI: 10.1016/j.jnutbio.2015.08.024] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 08/26/2015] [Accepted: 08/26/2015] [Indexed: 02/06/2023]
|
|
40
|
Hellerbrand C, Schattenberg JM, Peterburs P, Lechner A, Brignoli R. The potential of silymarin for the treatment of hepatic disorders. CLINICAL PHYTOSCIENCE 2016. [DOI: 10.1186/s40816-016-0019-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
|
|
41
|
Kim SB, Kang OH, Lee YS, Han SH, Ahn YS, Cha SW, Seo YS, Kong R, Kwon DY. Hepatoprotective Effect and Synergism of Bisdemethoycurcumin against MCD Diet-Induced Nonalcoholic Fatty Liver Disease in Mice. PLoS One 2016; 11:e0147745. [PMID: 26881746 PMCID: PMC4755614 DOI: 10.1371/journal.pone.0147745] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 01/07/2016] [Indexed: 12/14/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has become one of the most common causes of chronic liver disease over the last decade in developed countries. NAFLD includes a spectrum of pathological hepatic changes, such as steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Bisdemethoxycurcumin (BDMC) is polyphenolic compounds with a diarylheptanoid skeleton, curcumin close analogues, which is derived from the Curcumae Longae Rhizoma. While the rich bioavailability research of curcumin, BDMC is the poor studies. We investigated whether BDMC has the hepatoprotective effect and combinatory preventive effect with silymarin on methionine choline deficient (MCD)-diet-induced NAFLD in C57BL/6J mice. C57BL/6J mice were divided into five groups of normal (normal diet without any treatment), MCD diet (MCD diet only), MCD + silymarin (SIL) 100 mg/kg group, MCD + BDMC 100 mg/kg group, MCD + SIL 50 mg/kg + BDMC 50 mg/kg group. Body weight, liver weight, liver function tests, histological changes were assessed and quantitative real-time polymerase chain reaction and Western blot analyses were conducted after 4 weeks. Mice lost body weight on the MCD-diet, but BDMC did not lose less than the MCD-diet group. Liver weights decreased from BDMC, but they increased significantly in the MCD-diet groups. All liver function test values decreased from the MCD-diet, whereas those from the BDMC increased significantly. The MCD- diet induced severe hepatic fatty accumulation, but the fatty change was reduced in the BDMC. The BDMC showed an inhibitory effect on liver lipogenesis by reducing associated gene expression caused by the MCD-diet. In all experiments, the combinations of BDMC with SIL had a synergistic effect against MCD-diet models. In conclusion, our findings indicate that BDMC has a potential suppressive effect on NAFLD. Therefore, our data suggest that BDMC may act as a novel and potent therapeutic agent against NAFLD.
Collapse
Affiliation(s)
- Sung-Bae Kim
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University, Wonkwang Oriental Medicines Research Institute, Iksan, Jeonbuk, 570–749, Korea
| | - Ok-Hwa Kang
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University, Wonkwang Oriental Medicines Research Institute, Iksan, Jeonbuk, 570–749, Korea
| | - Young-Seob Lee
- BK21 Plus Team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk, 570–749, Korea
| | - Sin-Hee Han
- Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, RDA, 92 Bisanro, Eumsung, Chungbuk, 369–873, Korea
| | - Young-Sup Ahn
- Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, RDA, 92 Bisanro, Eumsung, Chungbuk, 369–873, Korea
| | - Seon-Woo Cha
- Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, RDA, 92 Bisanro, Eumsung, Chungbuk, 369–873, Korea
| | - Yun-Soo Seo
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University, Wonkwang Oriental Medicines Research Institute, Iksan, Jeonbuk, 570–749, Korea
| | - Ryong Kong
- BK21 Plus Team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk, 570–749, Korea
| | - Dong-Yeul Kwon
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University, Wonkwang Oriental Medicines Research Institute, Iksan, Jeonbuk, 570–749, Korea
- * E-mail:
| |
Collapse
|
|
42
|
Alcoholic Liver Disease: A Mouse Model Reveals Protection by Lactobacillus fermentum. Clin Transl Gastroenterol 2016; 7:e138. [PMID: 26795070 PMCID: PMC4737872 DOI: 10.1038/ctg.2015.66] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 12/04/2015] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVES Alcoholism is one of the most devastating diseases with high incidence, but knowledge of its pathology and treatment is still plagued with gaps mostly because of the inherent limitations of research with patients. We developed an animal model for studying liver histopathology, Hsp (heat-shock protein)-chaperones involvement, and response to treatment. METHODS The system was standardized using mice to which ethanol was orally administered alone or in combination with Lactobacillus fermentum following a precise schedule over time and applying, at predetermined intervals, a battery of techniques (histology, immunohistochemistry, western blotting, real-time PCR, immunoprecipitation, 3-nitrotyrosine labeling) to assess liver pathology (e.g., steatosis, fibrosis), and Hsp60 and iNOS (inducible form of nitric oxide synthase) gene expression and protein levels, and post-translational modifications. RESULTS Typical ethanol-induced liver pathology occurred and the effect of the probiotic could be reliably monitored. Steatosis score, iNOS levels, and nitrated proteins (e.g., Hsp60) decreased after probiotic intake. CONCLUSIONS We describe a mouse model useful for studying liver disease induced by chronic ethanol intake and for testing pertinent therapeutic agents, e.g., probiotics. We tested L. fermentum, which reduced considerably ethanol-induced tissue damage and deleterious post-translational modifications of the chaperone Hsp60. The model is available to test other agents and probiotics with therapeutic potential in alcoholic liver disease.
Collapse
|
|
43
|
Salomone F, Godos J, Zelber-Sagi S. Natural antioxidants for non-alcoholic fatty liver disease: molecular targets and clinical perspectives. Liver Int 2016; 36:5-20. [PMID: 26436447 DOI: 10.1111/liv.12975] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 09/18/2015] [Indexed: 12/11/2022]
Abstract
Non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), is emerging as a main health problem in industrialized countries. Lifestyle modifications are effective in the treatment of NAFLD; however, the long-term compliance is low. Therefore, several pharmacological treatments have been proposed but none has shown significant efficacy or long-term safety. Natural polyphenols are a heterogeneous class of polyphenolic compounds contained in vegetables, which are being proposed for the treatment of different metabolic disorders. Although the beneficial effect of these compounds has traditionally related to their antioxidant properties, they also exert several beneficial effects on hepatic and extra-hepatic glucose and lipid homeostasis. Furthermore, natural polyphenols exert antifibrogenic and antitumoural effects in animal models, which appear relevant from a clinical point of view because of the association of NASH with cirrhosis and hepatocellular carcinoma. Several polyphenols, such anthocyanins, curcumin and resveratrol and those present in coffee, tea, soy are available in the diet and their consumption can be proposed as part of a healthy diet for the treatment of NAFLD. Other phenolic compounds, such as silymarin, are commonly consumed worldwide as nutraceuticals or food supplements. Natural antioxidants are reported to have beneficial effects in preclinical models of NAFLD and in pilot clinical trials, and thus need clinical evaluation. In this review, we summarize the existing evidence regarding the potential role of natural antioxidants in the treatment of NAFLD and examine possible future clinical applications.
Collapse
Affiliation(s)
- Federico Salomone
- Division of Gastroenterology, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania, Italy
| | - Justyna Godos
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Shira Zelber-Sagi
- The Liver Unit, Gastroenterology Department, Tel-Aviv Medical Center, Tel Aviv, Israel.,School of Public Health, University of Haifa, Haifa, Israel
| |
Collapse
|
|
44
|
Abstract
Associated with the obesity epidemic, non-alcoholic fatty liver disease (NAFLD) has become the leading liver disease in North America. Approximately 30 % of patients with NAFLD may develop non-alcoholic steatohepatitis (NASH) that can lead to cirrhosis and hepatocellular carcinoma (HCC). Frequently animal models are used to help identify underlying factors contributing to NAFLD including insulin resistance, dysregulated lipid metabolism and mitochondrial stress. However, studying the inflammatory, progressive nature of NASH in the context of obesity has proven to be a challenge in mice. Although the development of effective treatment strategies for NAFLD and NASH is gaining momentum, the field is hindered by a lack of a concise animal model that reflects the development of liver disease during obesity and the metabolic syndrome. Therefore, selecting an animal model to study NAFLD or NASH must be done carefully to ensure the optimal application. The most widely used animal models have been reviewed highlighting their advantages and disadvantages to studying NAFLD and NASH specifically in the context of obesity.
Collapse
|
|
45
|
Zhang DD, Zhang JG, Wu X, Liu Y, Gu SY, Zhu GH, Wang YZ, Liu GL, Li XY. Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG2 cells. Front Pharmacol 2015; 6:238. [PMID: 26539118 PMCID: PMC4612658 DOI: 10.3389/fphar.2015.00238] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 10/02/2015] [Indexed: 12/26/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disease associated with lipotoxicity, lipid peroxidation, oxidative stress, and inflammation. Nuciferine, an active ingredient extracted from the natural lotus leaf, has been reported to be effective for the prevention and treatment of NAFLD. Per-Arnt-Sim kinase (PASK) is a nutrient responsive protein kinase that regulates lipid and glucose metabolism, mitochondrial respiration, and gene expression. The aim of the present study was to investigate the protective effect of nuciferine against NAFLD and its inhibitory effect on PASK, exploring the possible underlying mechanism of nuciferine-mediated inhibition on NAFLD. Relevant biochemical parameters (lipid accumulation, extent of oxidative stress and release of inflammation cytokines) in oleic acid (OA)-induced HepG2 cells that mimicked steatosis in vitro were measured and compared with the control. It was found that nuciferine and silenced-PASK (siRNA PASK) both inhibited triglyceride (TG) accumulation and was effective in decreasing fatty acid (FFAs). The content of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) were increased respectively by nuciferine and siRNA PASK without increase in glutathione (GSH). Malondialdehyde (MDA) was decreased respectively by nuciferine and siRNA PASK. In addition, nuciferine decreased TNF-a, IL-6 and IL-8 as well as the siRNA PASK group. IL-10 was increased by nuciferine and siRNA PASK respectively. Further investigation revealed that nuciferine and siRNA PASK could respectively regulate the expression of target genes involved in lipogenesis and inflammation, suggesting that nuciferine may be a potential therapeutic treatment for NAFLD. Furthermore, the modulated effect of nuciferine on (OA)-induced HepG2 cells lipogenesis and inflammation, which was accompanied with PASK inhibition, was also consistent with siRNA PASK, implying that PASK might play a role in nuciferine-mediated regulation on NAFLD.
Collapse
Affiliation(s)
- Dan-Dan Zhang
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China
| | - Ji-Gang Zhang
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China
| | - Xin Wu
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China
| | - Ying Liu
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China
| | - Sheng-Ying Gu
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China
| | - Guan-Hua Zhu
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China
| | - Yu-Zhu Wang
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China
| | - Gao-Lin Liu
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China
| | - Xiao-Yu Li
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China
| |
Collapse
|
|
46
|
Polimeni L, Del Ben M, Baratta F, Perri L, Albanese F, Pastori D, Violi F, Angelico F. Oxidative stress: New insights on the association of non-alcoholic fatty liver disease and atherosclerosis. World J Hepatol 2015; 7:1325-1336. [PMID: 26052378 PMCID: PMC4450196 DOI: 10.4254/wjh.v7.i10.1325] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 12/01/2014] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the most common and emerging chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and more severe liver complications such as cirrhosis, hepatocellular carcinoma and liver mortality. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidaemia, and is now regarded as the liver manifestation of the metabolic syndrome. The increased mortality of patients with NAFLD is primarily a result of cardiovascular disease and, to a lesser extent, to liver related diseases. Increased oxidative stress has been reported in both patients with NAFLD and patient with cardiovascular risk factors. Thus, oxidative stress represents a shared pathophysiological disorder between the two conditions. Several therapeutic strategies targeting oxidative stress reduction in patients with NAFLD have been proposed, with conflicting results. In particular, vitamin E supplementation has been suggested for the treatment of non-diabetic, non-cirrhotic adults with active NASH, although this recommendation is based only on the results of a single randomized controlled trial. Other antioxidant treatments suggested are resveratrol, silybin, L-carnitine and pentoxiphylline. No trial so far, has evaluated the cardiovascular effects of antioxidant treatment in patients with NAFLD. New, large-scale studies including as end-point also the assessment of the atherosclerosis markers are needed.
Collapse
|
|
47
|
Farghali H, Canová NK, Zakhari S. Hepatoprotective properties of extensively studied medicinal plant active constituents: possible common mechanisms. PHARMACEUTICAL BIOLOGY 2015; 53:781-791. [PMID: 25489628 DOI: 10.3109/13880209.2014.950387] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
CONTEXT We focused on certain plant active constituents considered to be the most promising/studied for liver disease and that were critically investigated from the basic science point of view and, to some extent, the clinical one. Due to insufficient pharmacological data, most of the herbal formulations containing these molecules cannot be recommended for the treatment of liver disease. OBJECTIVE To present the most promising compounds tested experimentally and/or clinically and describe in brief popular models in experimental testing of potential hepatoprotective compounds. METHODS A literature search using Web of Science (WOS), PubMed, and Google search was performed. RESULTS Focusing on a few herbal hepatoprotective active constituents is useful to health professionals working in the field of therapeutics to develop evidence-based hepatoprotective agents by conducting research on pure chemical structures or on molecular modifications using computational chemistry. This review demonstrates that multi-pathways in the liver pathobiology can be interrupted at one or more levels by natural hepatoprotective studied, such as interference with the oxidative stress at multiple levels to reduce reactive oxygen/nitrogen species, resulting in ameliorating hepatotoxicity. CONCLUSION Hepatoprotective constituents of herbal medications are poorly absorbed after oral administration; methods that can improve their bioavailability are being developed. It is recommended that controlled prospective double-blind multicenter studies on isolated active plant constituents, or on related newly designed molecules after structural modifications, should be performed. This effort will lead to expanding the existing, limited drugs for the vast majority of liver diseases.
Collapse
Affiliation(s)
- Hassan Farghali
- First Faculty of Medicine, Institute of Pharmacology, Charles University in Prague , Czech Republic and
| | | | | |
Collapse
|
|
48
|
Van De Wier B, Koek GH, Bast A, Haenen GRMM. The potential of flavonoids in the treatment of non-alcoholic fatty liver disease. Crit Rev Food Sci Nutr 2015; 57:834-855. [DOI: 10.1080/10408398.2014.952399] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
49
|
Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives. Antioxidants (Basel) 2015; 4:204-47. [PMID: 26785346 PMCID: PMC4665566 DOI: 10.3390/antiox4010204] [Citation(s) in RCA: 372] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Revised: 02/06/2015] [Accepted: 03/09/2015] [Indexed: 12/16/2022] Open
Abstract
Silymarin (SM), an extract from the Silybum marianum (milk thistle) plant containing various flavonolignans (with silybin being the major one), has received a tremendous amount of attention over the last decade as a herbal remedy for liver treatment. In many cases, the antioxidant properties of SM are considered to be responsible for its protective actions. Possible antioxidant mechanisms of SM are evaluated in this review. (1) Direct scavenging free radicals and chelating free Fe and Cu are mainly effective in the gut. (2) Preventing free radical formation by inhibiting specific ROS-producing enzymes, or improving an integrity of mitochondria in stress conditions, are of great importance. (3) Maintaining an optimal redox balance in the cell by activating a range of antioxidant enzymes and non-enzymatic antioxidants, mainly via Nrf2 activation is probably the main driving force of antioxidant (AO) action of SM. (4) Decreasing inflammatory responses by inhibiting NF-κB pathways is an emerging mechanism of SM protective effects in liver toxicity and various liver diseases. (5) Activating vitagenes, responsible for synthesis of protective molecules, including heat shock proteins (HSPs), thioredoxin and sirtuins and providing additional protection in stress conditions deserves more attention. (6) Affecting the microenvironment of the gut, including SM-bacteria interactions, awaits future investigations. (7) In animal nutrition and disease prevention strategy, SM alone, or in combination with other hepatho-active compounds (carnitine, betaine, vitamin B12, etc.), might have similar hepatoprotective effects as described in human nutrition.
Collapse
|
|
50
|
Li HB, Yang YRY, Mo ZJ, Ding Y, Jiang WJ. Silibinin improves palmitate-induced insulin resistance in C2C12 myotubes by attenuating IRS-1/PI3K/Akt pathway inhibition. ACTA ACUST UNITED AC 2015; 48:440-6. [PMID: 25760026 PMCID: PMC4445668 DOI: 10.1590/1414-431x20144238] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 11/26/2014] [Indexed: 01/19/2023]
Abstract
The present study investigated the effect of silibinin, the principal potential
anti-inflammatory flavonoid contained in silymarin, a mixture of flavonolignans
extracted from Silybum marianum seeds, on palmitate-induced insulin
resistance in C2C12 myotubes and its potential molecular mechanisms. Silibinin
prevented the decrease of insulin-stimulated 2-NBDG
(2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) uptake and the
downregulation of glutamate transporter type 4 (GLUT4) translocation in C2C12
myotubes induced by palmitate. Meanwhile, silibinin suppressed the palmitate-induced
decrease of insulin-stimulated Akt Ser473 phosphorylation, which was reversed by
wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K). We also
found that palmitate downregulated insulin-stimulated Tyr632 phosphorylation of
insulin receptor substrate 1 (IRS-1) and up-regulated IRS-1 Ser307 phosphorylation.
These effects were rebalanced by silibinin. Considering several serine/threonine
kinases reported to phosphorylate IRS-1 at Ser307, treatment with silibinin
downregulated the phosphorylation of both c-Jun N-terminal kinase (JNK) and nuclear
factor-κB kinase β (IKKβ), which was increased by palmitate in C2C12 myotubes
mediating inflammatory status, whereas the phosphorylation of PKC-θ was not
significantly modulated by silibinin. Collectively, the results indicated that
silibinin prevented inhibition of the IRS-1/PI3K/Akt pathway, thus ameliorating
palmitate-induced insulin resistance in C2C12 myotubes.
Collapse
Affiliation(s)
- H B Li
- Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Y R Y Yang
- Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Z J Mo
- Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Y Ding
- Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - W J Jiang
- Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| |
Collapse
|