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Sattari M, Shahaboddin ME, Akhavan Taheri M, Khalili E, Tabatabaei-Malazy O, Goodarzi G, Samavarchi Tehrani S, Meshkani R, Panahi G. Therapeutic potential of fisetin in hepatic steatosis: Insights into autophagy pathway regulation and endoplasmic reticulum stress alleviation in high-fat diet-fed mice. PLoS One 2025; 20:e0322335. [PMID: 40402993 PMCID: PMC12097571 DOI: 10.1371/journal.pone.0322335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Accepted: 03/19/2025] [Indexed: 05/24/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common condition with limited FDA-approved treatments due to its complex pathogenesis. Metabolic stress-induced lipotoxicity triggers the unfolded protein response, leading to the development of NAFLD through inflammation and apoptosis. Moreover, metabolic dysregulation compromises autophagic capacity, impairing effective ERphagy and lipophagy in the liver. Fisetin (FSN), a flavonoid present in various fruits and vegetables, has demonstrated the ability to regulate the processes mentioned above and possesses a range of biological properties. In this study using a high-fat diet-induced NAFLD mouse model, treatment with FSN at a dosage of 80 mg/kg per day for eight weeks resulted in reduced hepatic lipid accumulation. This effect was mediated by modulating ER stress through enhancing autophagic activity, as indicated by decreased expression of GRP78, elf2a, ATF4, and CHOP genes, along with increased AMPK phosphorylation, decreased mTOR expression, and elevated levels of ULK1, ATG5, and Beclin1. Additionally, there was an increase in the LCII/LC3I ratio and a reduction in p62 levels in hepatic tissue. Our findings suggest that FSN exerts its effects by activating the AMPK/mTOR signaling pathway and its downstream targets, underscoring its potential therapeutic advantages in managing NAFLD by targeting autophagy and ER stress pathways.
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Affiliation(s)
- Mahboobe Sattari
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Esmaeil Shahaboddin
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Akhavan Taheri
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Ehsan Khalili
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ozra Tabatabaei-Malazy
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Golnaz Goodarzi
- Department of Pathobiology and Laboratory Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Sadra Samavarchi Tehrani
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Science, Tehran, Iran
| | - Reza Meshkani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghodratollah Panahi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Gurusamy N, Almalki BMH, Katragadda S, Murray J, Speth RC, Robison LS. Epigenetic regulation by ketone bodies in cardiac diseases and repair. Can J Physiol Pharmacol 2025. [PMID: 40334279 DOI: 10.1139/cjpp-2024-0270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
Ketone bodies, particularly β-hydroxybutyrate (BHB), play an important role in the epigenetic regulation of gene expression in cardiac tissues, impacting both cardiac health and disease. This review explores the multifaceted influence of ketone bodies on epigenetic mechanisms, including histone acetylation, DNA methylation, ubiquitination, sirtuins activation, and RNA modulation. By acting as endogenous histone deacetylase inhibitors, ketone bodies enhance histone acetylation, thereby promoting the expression of genes involved in antioxidant defenses, anti-inflammatory responses, and metabolic regulation. Furthermore, BHB affects DNA methylation patterns by altering the availability of key metabolites such as S-adenosylmethionine. Ketogenic diet, which elevates BHB levels, has been shown to modulate gene expression, such as increasing FOXO3a and metallothionein 2, and improve cardiac function. This review highlights the therapeutic potential of ketone bodies in managing cardiac diseases through their epigenetic effects, underscoring the need for further research to elucidate the detailed molecular pathways and long-term impacts of these metabolic interventions.
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Affiliation(s)
- Narasimman Gurusamy
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Bandar Muteb H Almalki
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Sai Katragadda
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - James Murray
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Robert C Speth
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Lisa S Robison
- Department of Psychology and Neuroscience, College of Psychology, Nova Southeastern University, Fort Lauderdale, FL, USA
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Yu W, Zhao Y, Ilyas I, Wang L, Little PJ, Xu S. The natural polyphenol fisetin in atherosclerosis prevention: a mechanistic review. J Pharm Pharmacol 2025; 77:206-221. [PMID: 38733634 DOI: 10.1093/jpp/rgae053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 04/22/2024] [Indexed: 05/13/2024]
Abstract
The incidence and mortality rate of atherosclerotic cardiovascular disease (ASCVD) is increasing yearly worldwide. Recently, a growing body of evidence has unveiled the anti-atherosclerotic properties of fisetin, a natural polyphenol compound. In this article, we reviewed the pharmacologic actions of fisetin on experimental atherosclerosis and its protective effects on disease-relevant cell types such as endothelial cells, macrophages, vascular smooth muscle cells, and platelets. Based on its profound cardiovascular actions, fisetin holds potential for clinical translation and could be developed as a potential therapeutic option for atherosclerosis and its related complications. Large-scale randomized clinical trials are warranted to ascertain the safety and efficacy of fisetin in patients with or high risk for ASCVD.
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Affiliation(s)
- Wei Yu
- School of Materials Science and Engineering, Hefei University of Technology, Hefei, Anhui, 230009, China
- Anhui Renovo Pharmaceutical Co., Ltd, Hefei, Anhui, 230001, China
- Anhui Guozheng Pharmaceutical Co., Ltd, Hefei, Anhui, 230041, China
| | - Yaping Zhao
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Iqra Ilyas
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Peter J Little
- Department of Pharmacy, Guangzhou Xinhua University, No. 721, Guangshan Road 1, Tianhe District, Guangzhou, 510520, China
| | - Suowen Xu
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
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Cai Y, Fang L, Chen F, Zhong P, Zheng X, Xing H, Fan R, Yuan L, Peng W, Li X. Targeting AMPK related signaling pathways: A feasible approach for natural herbal medicines to intervene non-alcoholic fatty liver disease. J Pharm Anal 2025; 15:101052. [PMID: 40034684 PMCID: PMC11873010 DOI: 10.1016/j.jpha.2024.101052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 07/13/2024] [Accepted: 07/22/2024] [Indexed: 03/05/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease characterized by abnormal deposition of lipid in hepatocytes. If not intervened in time, NAFLD may develop into liver fibrosis or liver cancer, and ultimately threatening life. NAFLD has complicated etiology and pathogenesis, and there are no effective therapeutic means and specific drugs. Currently, insulin sensitizers, lipid-lowering agents and hepatoprotective agents are often used for clinical intervention, but these drugs have obvious side effects, and their effectiveness and safety need to be further confirmed. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a central role in maintaining energy homeostasis. Activated AMPK can enhance lipid degradation, alleviate insulin resistance (IR), suppress oxidative stress and inflammatory response, and regulate autophagy, thereby alleviating NAFLD. Natural herbal medicines have received extensive attention recently because of their regulatory effects on AMPK and low side effects. In this article, we reviewed the biologically active natural herbal medicines (such as natural herbal medicine formulas, extracts, polysaccharides, and monomers) that reported in recent years to treat NAFLD via regulating AMPK, which can serve as a foundation for subsequent development of candidate drugs for NAFLD.
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Affiliation(s)
- Yongqing Cai
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Lu Fang
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, 400016, China
| | - Fei Chen
- Department of Pharmacy, Dazhou Integrated Traditional Chinese Medicine and Western Medicine Hospital, Dazhou, Sichuan, 635000, China
| | - Peiling Zhong
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, 400016, China
| | - Xiangru Zheng
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China
| | - Haiyan Xing
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Rongrong Fan
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 14152, Sweden
| | - Lie Yuan
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, 400016, China
| | - Wei Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Xiaoli Li
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, 400016, China
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Choi J, Choi H, Jang Y, Paik HG, Kwon HS, Kwon J. Fermented Gold Kiwifruit Protects Mice Against Non-Alcoholic Fatty Liver Disease in a High-Fat Diet Model. APPLIED SCIENCES 2024; 14:11503. [DOI: 10.3390/app142411503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Gold kiwifruit is known for its high vitamin C content and various benefits. This study investigated the effects and molecular mechanisms of fermented gold kiwifruit (FGK) in a mouse model of high-fat diet (HFD)-induced obesity and hepatic steatosis. FGK powder was prepared using five strains of lactic acid bacteria: L. paracasei, Lc. lactis, L. acidophilus, L. casei, and L. helveticus. ICR mice were fed an HFD for 8 weeks to induce obesity and hepatic steatosis, and FGK supplementation was evaluated for its therapeutic potential. FGK administration significantly reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, triglyceride, and glucose compared to the HFD-only group. Histopathological analysis showed that FGK reduced lipid accumulation and hepatic lesions, as confirmed by hematoxylin and eosin (H&E) staining. Furthermore, administration of FGK activated the sirtuin 1(SIRT1)/adenosine monophosphate-activated protein kinase (AMPK) pathway and inhibited expression of the pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in liver tissue. These findings suggest that FGK could reduce the severity of non-alcoholic fatty liver disease (NAFLD) by inhibiting fat synthesis, promoting fat breakdown, and suppressing inflammation in HFD-induced obese mice.
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Affiliation(s)
- Jihye Choi
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Jeonbuk National University, Iksan-si 54596, Jeollabuk-do, Republic of Korea
| | - Hwal Choi
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Jeonbuk National University, Iksan-si 54596, Jeollabuk-do, Republic of Korea
| | - Yuseong Jang
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Jeonbuk National University, Iksan-si 54596, Jeollabuk-do, Republic of Korea
| | - Hyeon-Gi Paik
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Jeonbuk National University, Iksan-si 54596, Jeollabuk-do, Republic of Korea
| | - Hyuck-Se Kwon
- R&D Team, Food & Supplement Health Claims, Vitech, #602 Giyeon B/D 141 Anjeon-ro, Iseo-myeon, Wanju-gun 55365, Jeollabuk-do, Republic of Korea
| | - Jungkee Kwon
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Jeonbuk National University, Iksan-si 54596, Jeollabuk-do, Republic of Korea
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Chahal SK, Kabra A. Fisetin ameliorates polycystic ovary syndrome in rats via a mechanistic modulation of AMP-activated protein kinase and SIRT1 molecular pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:10017-10029. [PMID: 38963551 DOI: 10.1007/s00210-024-03257-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 06/23/2024] [Indexed: 07/05/2024]
Abstract
Fisetin, a polyphenolic flavonoid, exhibits numerous pharmacological activities against metabolic syndromes. The present research aims to explore the therapeutic efficacy of fisetin in experimental polycystic ovary syndrome (PCOS). Female Sprague-Dawley rats were administered mifepristone (20 mg/kg/day) to induce PCOS. PCOS rats were treated with fisetin (20 mg/kg and 40 mg/kg) and further compared with metformin HCl, the conventional drug for PCOS. The mechanism of fisetin was explored using dorsomorphin (an AMPK inhibitor). Then, rats were sacrificed for further analysis of biochemical and histological parameters. PCOS rats exhibited irregular estrous cycles, increased serum testosterone (4.72 ± 0.139 ng/ml), estradiol (750.2 ± 16.56 pg/ml), LH (30.33 ± 1.563 mIU/ml), HOMA-IR (1.115 ± 0.049), TNF-α (86.59 ± 3.93 pg/ml), IL-6 (55.34 ± 4.432 pg/ml), and TBARS (3.867 ± 0.193 µmol/mg) along with declined progesterone (11.67 ± 1.54 ng/ml), FSH (13.33 ± 1.256 mIU/ml), GSH (33.47 ± 1.348 µmol/mg) levels, and SOD (2.163 ± 0.298 U/mg) activity as compared to normal control group. Fisetin high dose significantly lowers testosterone (3.014 ± 0.234 ng/ml), estradiol (533.7 ± 15.39 pg/ml), LH (16.67 ± 1.62 mIU/ml), HOMA-IR (0.339 ± 0.20), TNF-α (46.02 ± 2.66 pg/ml), IL-6 (31.77 ± 3.47 pg/ml), and TBARS (1.747 ± 0.185 µmol/mg) and enhances progesterone (33.17 ± 1.447 ng/ml), FSH (27.17 ± 1.42 mIU/ml), GSH (60.35 ± 1.1.102 µmol/mg) levels, and SOD (4.513 ± 0.607 U/mg) activity. The histology of ovarian tissues shows a significant increase in cystic follicles in PCOS rats compared with the normal control group. These alterations were attenuated with fisetin treatment. Administration of dorsomorphin with fisetin can reverse the beneficial effects of fisetin in PCOS rats. Altogether, these present findings highlight the potential of fisetin as a promising therapeutic intervention for the management of PCOS by modulating AMPK/SIRT1 signaling in rats.
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Affiliation(s)
- Simerjeet Kaur Chahal
- University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali, 140413, Punjab, India
| | - Atul Kabra
- University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali, 140413, Punjab, India.
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Sattari M, Amri J, Shahaboddin ME, Sattari M, Tabatabaei-Malazy O, Azmon M, Meshkani R, Panahi G. The protective effects of fisetin in metabolic disorders: a focus on oxidative stress and associated events. J Diabetes Metab Disord 2024; 23:1753-1771. [PMID: 39610486 PMCID: PMC11599505 DOI: 10.1007/s40200-024-01502-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 09/09/2024] [Indexed: 11/30/2024]
Abstract
Abstract Metabolic syndrome is increasingly recognized as a significant precursor to various chronic diseases, contributing to a growing public health concern. Its complex pathogenesis involves multiple interrelated mechanisms, with oxidative stress identified as a cornerstone that exacerbates other pathogenic pathways. This study elucidates the molecular mechanisms by which oxidative stress intensifies metabolic disturbances, particularly insulin resistance. Some recent research has focused on fisetin, a natural product known for its potential benefits in diabetes and its associated microvascular and macrovascular complications. This paper compiles a comprehensive collection of findings by reviewing studies conducted over the past decade, detailing dosages, investigated markers, and their respective outcomes. Notably, a recurrent finding was fisetin's ability to enhance Nrf2, a principal regulator of antioxidant defense, in both metabolic and non-metabolic diseases. Furthermore, intriguing results suggest that the effects of Nrf2 extend beyond oxidative stress modulation, demonstrating favorable impacts on tissue-specific functions in metabolic regulation. This highlights fisetin not only as an antioxidant but also as a potential therapeutic agent for improving metabolic health and mitigating the effects of metabolic syndrome. In conclusion, fisetin can enhance the body's antioxidant defenses by modulating the Nrf2 pathway while also improving metabolic health through its effects on inflammation, cell survival, and energy metabolism, offering a comprehensive approach to managing metabolic disorders. Graphical Abstract
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Affiliation(s)
- Mahboobe Sattari
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, I.R Iran
| | - Jamal Amri
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, I.R Iran
| | - Mohammad Esmaeil Shahaboddin
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohadese Sattari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ozra Tabatabaei-Malazy
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Marzyeh Azmon
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Meshkani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghodratollah Panahi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Zhang R, Liu M, Lu J, Lu S, Wang Y, Guan S. Fisetin Ameliorates Hepatocyte Lipid Droplet Accumulation via Targeting the Rhythmic Protein BMAL1 to Regulate Cell Death-Inducing DNA Fragmentation Factor-α-like Effector C-Mediated Lipid Droplet Fusion. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024. [PMID: 39563624 DOI: 10.1021/acs.jafc.4c06487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2024]
Abstract
High fat diet (HFD) induces the enlargement and accumulation of lipid droplets (LDs) in hepatocytes, thereby influencing the homeostasis of lipid metabolism. Cell death-inducing DNA fragmentation factor-α-like effector C (CIDEC), a surface protein of LDs, facilitates their fusion and growth, transforming small LDs into larger ones. Lipophagy, a selective form of autophagy, primarily targets small LDs for degradation. Fisetin (FIS), a natural dietary flavonoid present in various fruits and vegetables, has an unclear mechanism for reducing LD accumulation. In this study, we observed that FIS significantly ameliorated HFD-induced lipid accumulation in the hepatocytes of C57BL/6 mice. In further mechanistic studies, we revealed that FFA enhanced the expression of CIDEC, which promoted the fusion of LDs and caused them to become larger. The enlarged LDs could not be degraded by autophagy, which ultimately led to accumulation of LDs. Conversely, FIS alleviated LD accumulation by inhibiting CIDEC-mediated fusion, resulting in smaller LDs that facilitated lipophagy. Additionally, studies indicated that the dysfunction of circadian rhythms is closely related to lipid metabolism. In our study, we showed that HFD and FFA disrupted circadian rhythm in C57BL/6 mouse hepatocytes and AML12 cells, while FIS modified the rhythm disturbances and increased protein expression of the core clocks BMAL1 and CLOCK. We silenced the BMAL1 protein and revealed that si-BMAL1 upregulated CIDEC proteins. These data suggested that FIS might inhibit CIDEC-mediated LD fusion and enhance hepatocyte lipophagy by promoting the expression of rhythm protein BMAL1, thereby alleviating LD accumulation in C57BL/6 and AML12 cells caused by the HFD and FFA. The present study provided novel insights and potential targets for utilizing functional food factors to mitigate the accumulation of LD in hepatocytes.
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Affiliation(s)
- Ranran Zhang
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China
| | - Meitong Liu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China
| | - Jing Lu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Shujing Lu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China
| | - Yuanmeng Wang
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China
| | - Shuang Guan
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China
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Chen C, Liu XC, Deng B. Protective Effects of Berberine on Nonalcoholic Fatty Liver Disease in db/db Mice via AMPK/SIRT1 Pathway Activation. Curr Med Sci 2024; 44:902-911. [PMID: 39039374 DOI: 10.1007/s11596-024-2914-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 06/18/2024] [Indexed: 07/24/2024]
Abstract
OBJECTIVE Berberine (BBR) has emerged as a promising therapeutic agent for nonalcoholic fatty liver disease (NAFLD). This study aims to elucidate the underlying molecular mechanisms. METHODS In this study, db/db mice were chosen as an animal model for NAFLD. A total of 10 healthy C57BL/6J mice and 30 db/db mice were randomly allocated to one of 4 groups: the normal control (NC) group, the diabetic control (DC) group, the Metformin (MET) therapy group, and the BBR therapy group. The total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the serum were measured. The glutathione peroxidase (GSH-Px), glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), interleukin (IL)-1β, tumor necrosis factor (TNF)-α and monocyte chemotactic protein 1 (MCP-1) levels in liver tissue were measured. Hematoxylin and eosin (H&E), acid-Schiff (PAS) and TUNEL stanning was performed for histopathological analysis. Western blotting and immunohistochemistry were conducted to detect the expression levels of key proteins in the AMPK/SIRT1 pathway. RESULTS BBR could improve lipid metabolism, attenuate hepatic steatosis and alleviate liver injury significantly. The excessive oxidative stress, high levels of inflammation and abnormal apoptosis in db/db mice were reversed after BBR intervention. BBR clearly changed the expression of AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1), and their downstream proteins. CONCLUSION BBR could reverse NAFLD-related liver injury, likely by activating the AMPK/SIRT1 signaling pathway to inhibit oxidative stress, inflammation and apoptosis in hepatic tissue.
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Affiliation(s)
- Cheng Chen
- Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, 434020, China
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiao-Cui Liu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Bin Deng
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Mohammad SIS, Vasudevan A, Enwa FO, Bansal J, Chahar M, Eldesoqui M, Ullah MI, Gardanova ZR, Hulail HM, Zwamel AH. The Sirt1/Nrf2 pathway is a key factor for drug therapy in chemotherapy-induced cardiotoxicity: a Mini-Review. Med Oncol 2024; 41:244. [PMID: 39259412 DOI: 10.1007/s12032-024-02494-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 08/31/2024] [Indexed: 09/13/2024]
Abstract
The likelihood of survival for cancer patients has greatly improved due to chemotherapy medicines. However, these antitumor agents might also have unfavorable effects on the cardiovascular system, which could result in sudden or gradual cardiac failure. The production of free radicals that result in oxidative stress appears to be the key mechanism by which chemotherapy-induced cardiotoxicity (CIC) happens. Reports suggest that the Sirtuin-1 (Sirt1)/Nuclear factor E2-associated factor 2 (Nrf2) signaling pathway has been considered an alternative path for counteracting cardiotoxicity by suppressing oxidative stress, inflammation, and apoptosis. This review concludes recent knowledge about CIC with a special focus on the anti-oxidative regulation properties of the Sirt1/Nrf2 pathway.
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Affiliation(s)
- Suleiman Ibrahim Shelash Mohammad
- Research Follower, INTI International University, 71800, Nilai, Negeri Sembilan, Malaysia.
- Department of Business Administration, Business School, Al Al-Bayt University, Al-Mafraq, Jordan.
| | - Asokan Vasudevan
- Faculty of Business and Communications, INTI International University, 71800, Nilai, Negeri Sembilan, Malaysia
| | - Felix Oghenemaro Enwa
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Delta State University, Abraka, Delta State, Nigeria
| | - Jaya Bansal
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjeri, Mohali, Punjab, 140307, India
| | - Mamata Chahar
- Department of Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - Mamdouh Eldesoqui
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Diriyah, 13713, Riyadh, Saudi Arabia.
| | - Muhammad Ikram Ullah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, 72388, Sakaka, Aljouf, Saudi Arabia
| | - Zhanna R Gardanova
- Department of Psychotherapy, Pirogov Russian National Research Medical University, 117997, Moscow, Russia
- Department of Fundamental Disciplines, Independent Non-Profit Organization of Higher Education, "Medical University MGIMO-MED", Moscow, Russia
| | - Hanen Mahmod Hulail
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | - Ahmed Hussein Zwamel
- Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
- Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
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11
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Gostyńska A, Buzun K, Żółnowska I, Krajka-Kuźniak V, Mańkowska-Wierzbicka D, Jelińska A, Stawny M. Natural bioactive compounds-The promising candidates for the treatment of intestinal failure-associated liver disease. Clin Nutr 2024; 43:1952-1971. [PMID: 39032247 DOI: 10.1016/j.clnu.2024.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 07/01/2024] [Accepted: 07/09/2024] [Indexed: 07/23/2024]
Abstract
Parenteral nutrition (PN) is a life-saving procedure conducted to maintain a proper nutritional state in patients with severe intestinal failure who cannot be fed orally. A serious complication of PN therapy is liver failure, known as intestinal failure-associated liver disease (IFALD). The pathogenesis of IFALD is multifactorial and includes inhibition of the farnesoid X receptor (FXR) by PN components, bacteria translocation from impaired intestines, and intravenous line-associated bloodstream infection. Currently, the most frequently researched therapeutic option for IFALD is using lipid emulsions based on soy or fish oil and, therefore, free from phytosterols known as FXR antagonists. Nevertheless, the potential side effects of the lack of soybean oil delivery seem to outweigh the benefits, especially in the pediatric population. PN admixture provides all the necessary nutrients; however, it is deprived of exogenous natural bioactive compounds (NBCs) of plant origin, such as polyphenols, characterized by health-promoting properties. Among them, many substances have already been known to demonstrate the hepatoprotective effect in various liver diseases. Therefore, searching for new therapeutic options for IFALD among NBCs seems reasonable and potentially successful. This review summarizes the recent research on polyphenols and their use in treating various liver diseases, especially metabolic dysfunction-associated steatotic liver diseases (MASLD). Furthermore, based on scientific reports, we have described the molecular mechanism of action of selected NBCs that exert hepatoprotective properties. We also summarized the current knowledge on IFALD pathogenesis, described therapeutic options undergoing clinical trials, and presented the future perspective of the potential use of NBCs in PN therapy.
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Affiliation(s)
- Aleksandra Gostyńska
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | - Kamila Buzun
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland.
| | - Izabela Żółnowska
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; Doctoral School, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznan, Poland
| | - Violetta Krajka-Kuźniak
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | - Dorota Mańkowska-Wierzbicka
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznan, Poland
| | - Anna Jelińska
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | - Maciej Stawny
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
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12
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Maher P. The flavonoid fisetin reduces multiple physiological risk factors for dementia. Neurochem Int 2024; 178:105805. [PMID: 39004102 DOI: 10.1016/j.neuint.2024.105805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/05/2024] [Accepted: 07/11/2024] [Indexed: 07/16/2024]
Abstract
Dementia is a growing problem around the globe as the world's population continues to age. Multiple studies have identified potentially modifiable risk factors for the development of dementia suggesting that addressing some or all of these risk factors might have a significant impact on the aging population worldwide. However, this is not always as straightforward as it seems since many of these risk factors are currently treated with drugs specific to the risk factor. Moreover, since people can have multiple risk factors, addressing each of them individually could be highly problematic as it would likely lead to negative outcomes associated with polypharmacy and, in the long term, could do significant harm. A potential alternative is to identify compounds that have shown efficacy against a number of these different risk factors. As discussed in this review, there is strong evidence that the flavonol fisetin is one such compound. In animal studies it has shown efficacy against many of the risk factors that have been associated with an increased risk of developing dementia and also exhibits direct neuroprotective effects. Thus, further human research on fisetin in the context of dementia risk factors is clearly warranted.
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Affiliation(s)
- Pamela Maher
- Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
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13
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Nithyasree V, Magdalene P, Praveen Kumar PK, Preethi J, Gromiha MM. Role of HSP90 in Type 2 Diabetes Mellitus and Its Association with Liver Diseases. Mol Biotechnol 2024:10.1007/s12033-024-01251-1. [PMID: 39162909 DOI: 10.1007/s12033-024-01251-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 07/31/2024] [Indexed: 08/21/2024]
Abstract
Non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) are the fatal liver diseases which encompass a spectrum of disease severity associated with increased risk of type 2 diabetes mellitus (T2DM), a metabolic disorder. Heat shock proteins serve as markers in early prognosis and diagnosis of early stages of liver diseases associated with metabolic disorder. This review aims to comprehensively investigate the significance of HSP90 isoforms in T2DM and liver diseases. Additionally, we explore the collective knowledge on plant-based drug compounds that regulate HSP90 isoform targets, highlighting their potential in treating T2DM-associated liver diseases. Furthermore, this review focuses on the computational systems' biology and next-generation sequencing technology approaches that are used to unravel the potential medicine for the treatment of pleiotropy of these 2 diseases and to further elucidate the mechanism.
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Affiliation(s)
- V Nithyasree
- Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur Tk, Pennalur, Tamil Nadu, 602117, India
| | - P Magdalene
- Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur Tk, Pennalur, Tamil Nadu, 602117, India
| | - P K Praveen Kumar
- Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur Tk, Pennalur, Tamil Nadu, 602117, India.
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, 600036, India.
| | - J Preethi
- Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur Tk, Pennalur, Tamil Nadu, 602117, India
| | - M Michael Gromiha
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, 600036, India
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14
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Banerjee T, Sarkar A, Ali SZ, Bhowmik R, Karmakar S, Halder AK, Ghosh N. Bioprotective Role of Phytocompounds Against the Pathogenesis of Non-alcoholic Fatty Liver Disease to Non-alcoholic Steatohepatitis: Unravelling Underlying Molecular Mechanisms. PLANTA MEDICA 2024; 90:675-707. [PMID: 38458248 DOI: 10.1055/a-2277-4805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD), with a global prevalence of 25%, continues to escalate, creating noteworthy concerns towards the global health burden. NAFLD causes triglycerides and free fatty acids to build up in the liver. The excessive fat build-up causes inflammation and damages the healthy hepatocytes, leading to non-alcoholic steatohepatitis (NASH). Dietary habits, obesity, insulin resistance, type 2 diabetes, and dyslipidemia influence NAFLD progression. The disease burden is complicated due to the paucity of therapeutic interventions. Obeticholic acid is the only approved therapeutic agent for NAFLD. With more scientific enterprise being directed towards the understanding of the underlying mechanisms of NAFLD, novel targets like lipid synthase, farnesoid X receptor signalling, peroxisome proliferator-activated receptors associated with inflammatory signalling, and hepatocellular injury have played a crucial role in the progression of NAFLD to NASH. Phytocompounds have shown promising results in modulating hepatic lipid metabolism and de novo lipogenesis, suggesting their possible role in managing NAFLD. This review discusses the ameliorative role of different classes of phytochemicals with molecular mechanisms in different cell lines and established animal models. These compounds may lead to the development of novel therapeutic strategies for NAFLD progression to NASH. This review also deliberates on phytomolecules undergoing clinical trials for effective management of NAFLD.
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Affiliation(s)
- Tanmoy Banerjee
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
| | - Arnab Sarkar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
| | - Sk Zeeshan Ali
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
| | - Rudranil Bhowmik
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
| | - Sanmoy Karmakar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
| | - Amit Kumar Halder
- Dr. B. C. Roy College of Pharmacy and Allied Health Sciences, Dr. Meghnad Saha Sarani, Bidhannagar, Durgapur, West Bengal, India
| | - Nilanjan Ghosh
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
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15
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Khan H, Tiwari C, Kalra P, Vyas D, Grewal AK, Singh TG. Mechanistic correlation of molecular pathways in obesity-mediated stroke pathogenesis. Pharmacol Rep 2024; 76:463-474. [PMID: 38632185 DOI: 10.1007/s43440-024-00590-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 03/15/2024] [Accepted: 03/19/2024] [Indexed: 04/19/2024]
Abstract
Obesity, a prominent risk factor for the development of heart attacks and several cardiovascular ailments. Obesity ranks as the second most significant avoidable contributor to mortality, whereas stroke stands as the second leading cause of death on a global scale. While changes in lifestyle have been demonstrated to have significant impacts on weight management, the long-term weight loss remains challenging, and the global prevalence of obesity continues to rise. The pathophysiology of obesity has been extensively studied during the last few decades, and an increasing number of signal transduction pathways have been linked to obesity preclinically. This review is focused on signaling pathways, and their respective functions in regulating the consumption of fatty food as well as accumulation of adipose tissue, and the resulting morphological and cognitive changes in the brain of individuals with obesity. We have also emphasized the recent progress in the mechanisms behind the emergence of obesity, as elucidated by both experimental and clinical investigations. The mounting understanding of signaling transduction may shed light on the future course of obesity research as we move into a new era of precision medicine.
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Affiliation(s)
- Heena Khan
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Chanchal Tiwari
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Palak Kalra
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Daksha Vyas
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
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16
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Gu X, Xie Y, Cao Q, Hou Z, Zhang Y, Wang W. Fisetin alleviates cerebral ischemia/reperfusion injury by regulating Sirt1/Foxc1/Ubqln1 pathway-mediated proteostasis. Int Immunopharmacol 2024; 130:111742. [PMID: 38452414 DOI: 10.1016/j.intimp.2024.111742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/02/2024] [Accepted: 02/20/2024] [Indexed: 03/09/2024]
Abstract
BACKGROUND Cerebral ischemia/reperfusion injury (IRI) is pathologically associated with protein damage. The flavonoid fisetin has good therapeutic effects on cerebral IRI. However, the role of fisetin in regulating protein damage during cerebral IRI development remains unclear. This study investigated the pharmacological effects of fisetin on protein damage during cerebral IRI progression and defined the underlying mechanism of action. METHODS In vivo and in vitro models of cerebral IRI were established by middle cerebral artery occlusion/reperfusion (MACO/R) and oxygen-glucose deprivation/reperfusion (OGD/R) treatment, respectively. Triphenyl tetrazolium chloride staining was performed to detect cerebral infarct size, and the modified neurologic severity score was used to examine neurological deficits. LDH activity and protein damage were assessed using kits. HT22 cell vitality and apoptosis were examined using CCK-8 assay and TUNEL staining, respectively. Interactions between Foxc1, Ubqln1, Sirt1, and Ezh2 were analyzed using CoIP, ChIP and/or dual-luciferase reporter gene assays. RESULTS Fisetin alleviated protein damage and ubiquitinated protein aggregation and neuronal death caused by MCAO/R and OGD/R. Ubqln1 knockdown abrogated the inhibitory effect of fisetin on OGD/R-induced protein damage, ubiquitinated protein aggregation, and neuronal death in HT22 cells. Further experiments demonstrated that Foxc1 functions as a transcriptional activator of Ubqln1 and that Sirt1 promotes Foxc1 expression by deacetylating Ezh2 and inhibiting its activity. Furthermore, Sirt1 knockdown abrogated fisetin-mediated biological effects on OGD/R-treated HT22 cells. CONCLUSION Fisetin improved proteostasis during cerebral IRI by regulating the Sirt1/Foxc1/Ubqln1 signaling axis. Our findings strongly suggest that fisetin-mediated inhibition of protein damage after ischemic stroke is a part of the mechanism through which fisetin is neuroprotective in cerebral IRI.
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Affiliation(s)
- Xunhu Gu
- Department of Neurology, The Second Affliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Yuqin Xie
- Department of Laboratory Medicine, Nanchang medical College, Nanchang 330006, Jiangxi, China
| | - Qian Cao
- Department of Neurology, The Second Affliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Zhuo Hou
- Department of Neurology, The Second Affliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Yan Zhang
- Department of Neurosurgery, The Second Affliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China.
| | - Wei Wang
- Department of Neurology, The Second Affliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China.
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17
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Huang L, Tan L, Lv Z, Chen W, Wu J. Pharmacology of bioactive compounds from plant extracts for improving non-alcoholic fatty liver disease through endoplasmic reticulum stress modulation: A comprehensive review. Heliyon 2024; 10:e25053. [PMID: 38322838 PMCID: PMC10844061 DOI: 10.1016/j.heliyon.2024.e25053] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 02/08/2024] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition with significant clinical implications. Emerging research indicates endoplasmic reticulum (ER) stress as a critical pathogenic factor governing inflammatory responses, lipid metabolism and insulin signal transduction in patients with NAFLD. ER stress-associated activation of multiple signal transduction pathways, including the unfolded protein response, disrupts lipid homeostasis and substantially contributes to NAFLD development and progression. Targeting ER stress for liver function enhancement presents an innovative therapeutic strategy. Notably, the natural bioactive compounds of plant extracts have shown potential for treating NAFLD by reducing the level of ER stress marker proteins and mitigating inflammation, stress responses, and de novo lipogenesis. However, owing to limited comprehensive reviews, the effectiveness and pharmacology of these bioactive compounds remain uncertain. Objectives To address the abovementioned challenges, the current review categorizes the bioactive compounds of plant extracts by chemical structures and properties into flavonoids, phenols, terpenoids, glycosides, lipids and quinones and examines their ameliorative potential for NAFLD under ER stress. Methods This review systematically analyses the literature on the interactions of bioactive compounds from plant extracts with molecular targets under ER stress, providing a holistic view of NAFLD therapy. Results Bioactive compounds from plant extracts may improve NAFLD by alleviating ER stress; reducing lipid synthesis, inflammation, oxidative stress and apoptosis and enhancing fatty acid metabolism. This provides a multifaceted approach for treating NAFLD. Conclusion This review underscores the role of ER stress in NAFLD and the potential of plant bioactive compounds in treating this condition. The molecular mechanisms by which plant bioactive compounds interact with their ER stress targets provide a basis for further exploration in NAFLD management.
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Affiliation(s)
- Liying Huang
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Liping Tan
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Zhuo Lv
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Wenhui Chen
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Junzi Wu
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
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18
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Łanoszka K, Vlčková N. Natural Sirtuin1 Activators and Atherosclerosis: an Overview. Curr Atheroscler Rep 2023; 25:979-994. [PMID: 38038821 PMCID: PMC10770200 DOI: 10.1007/s11883-023-01165-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2023] [Indexed: 12/02/2023]
Abstract
PURPOSE OF REVIEW The purpose of this review is to summarize the most recent findings investigating the impact of several natural sirtuin (SIRT) activators, particularly SIRT1, on atherosclerosis. RECENT FINDINGS Sirtuins that belong to a family of class III histone deacetylases are believed to be novel therapeutic targets to treat age-related and chronic diseases. SIRT expression is regulated by small molecules called SIRT-activating compounds that can be found in natural food products. SIRT1 may exert protective effects in atherosclerosis, which is said to be a major cause of cardiovascular diseases. Most of the evidence supporting the beneficial effects of these natural compounds comes from in vitro or animal-based studies, while there have been particularly few or inconsistent human-based studies evaluating their long-term impact in recent years. SIRT1 activation has been demonstrated to mitigate or prevent atherosclerosis through various mechanisms. However, further research is required to determine the optimal SIRT activator dosage and to establish a stronger correlation between health effects and the administration of bioactive compounds. Additionally, conducting more human clinical trials is necessary to ensure the safety of these compounds for preventing atherosclerosis development.
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Affiliation(s)
- Karolina Łanoszka
- Department of Human Nutrition and Dietetics, Faculty of Food Technology, University of Agriculture in Krakow, 122 Balicka Street, 30-149, Krakow, Poland
| | - Nimasha Vlčková
- Department of Human Nutrition and Dietetics, Faculty of Food Technology, University of Agriculture in Krakow, 122 Balicka Street, 30-149, Krakow, Poland.
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Zakaria Z, Othman ZA, Nna VU, Mohamed M. The promising roles of medicinal plants and bioactive compounds on hepatic lipid metabolism in the treatment of non-alcoholic fatty liver disease in animal models: molecular targets. Arch Physiol Biochem 2023; 129:1262-1278. [PMID: 34153200 DOI: 10.1080/13813455.2021.1939387] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 06/01/2021] [Indexed: 12/13/2022]
Abstract
Imbalance in hepatic lipid metabolism can lead to an abnormal triglycerides deposition in the hepatocytes which can cause non-alcoholic fatty liver disease (NAFLD). Four main mechanisms responsible for regulating hepatic lipid metabolism are fatty acid uptake, de novo lipogenesis, lipolysis and fatty acid oxidation. Controlling the expression of transcription factors at molecular level plays a crucial role in NAFLD management. This paper reviews various medicinal plants and their bioactive compounds emphasising mechanisms involved in hepatic lipid metabolism, other important NAFLD pathological features, and their promising roles in managing NAFLD through regulating key transcription factors. Although there are many medicinal plants popularly investigated for NAFLD treatment, there is still little information and scientific evidence available and there has been no research on clinical trials scrutinised on this matter. This review also aims to provide molecular information of medicinal plants in NALFD treatment that might have potentials for future scientifically controlled studies.
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Affiliation(s)
- Zaida Zakaria
- Department of Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Zaidatul Akmal Othman
- Department of Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia
- Unit of Physiology, Faculty of Medicine, Universiti Sultan Zainal Abidin, Kuala Terengganu, Malaysia
| | - Victor Udo Nna
- Department of Physiology, Faculty of Basic Medical Sciences, College of Medical Sciences, University of Calabar, Calabar, Nigeria
| | - Mahaneem Mohamed
- Department of Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia
- Unit of Integrative Medicine, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia
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20
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Singuru G, Pulipaka S, Shaikh A, Balaji Andugulapati S, Thennati R, Kotamraju S. Therapeutic efficacy of mitochondria-targeted esculetin in the improvement of NAFLD-NASH via modulating AMPK-SIRT1 axis. Int Immunopharmacol 2023; 124:111070. [PMID: 37862737 DOI: 10.1016/j.intimp.2023.111070] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/06/2023] [Accepted: 10/10/2023] [Indexed: 10/22/2023]
Abstract
Mitochondrial dysfunction due to deregulated production of mitochondria-derived ROS is implicated in the development and progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Recently, we synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and investigated its dose-response therapeutic efficacy in mitigating high-fat diet (HFD)-induced NAFLD and NASH in Apoe-/- mice. Mito-Esc administration, compared to simvastatin and pioglitazone, dose-dependently caused a significant reduction in body weight, improved lipid profile, glucose homeostasis, and pro-inflammatory cytokines level. Mito-Esc administration reduced adipose tissue hypertrophy and lipid accumulation presumably by regulating the levels of CD36, PPAR-γ, EBP-α, and their target genes. Mechanistically, Mito-Esc-induced activation of the AMPK1α-SIRT1 axis inhibited pre-adipocyte differentiation. Conversely, Mito-Esc failed to regulate pre-adipocyte differentiation under AMPK/SIRT1 depleted conditions. In parallel, Mito-Esc administration ameliorated HFD-induced steatosis, fibrosis of the liver, and NAFLD-associated atheromatous plaque formation in the aorta. Importantly, Mito-Esc administration inhibited HFD-induced infiltration of macrophages, a marker of steatohepatitis, in the adipose and liver tissues. The results of the in vitro studies showed that Mito-Esc treatment significantly inhibits TGF-β-induced hepatic stellate cell differentiation as well as the fibrotic markers. Consistent with the above observations, Mito-Esc treatment by activating the AMPK-SIRT1 pathway markedly reversed palmitate-induced mitochondrial superoxide production, depolarization of mitochondrial membrane potential, and lipid accumulation in HepG2 cells. Together, the therapeutic efficacy of Mito-Esc in the mitigation of HFD-induced lipotoxicity, and the associated NASH is in part, mediated by potentiating the AMPK-SIRT1 axis.
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Affiliation(s)
- Gajalakshmi Singuru
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Sriravali Pulipaka
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Altab Shaikh
- Academy of Scientific and Innovative Research, Ghaziabad 201002, India; Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
| | - Sai Balaji Andugulapati
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Rajamannar Thennati
- High Impact Innovations-Sustainable Health Solutions (HISHS), Sun Pharmaceutical Industries Ltd., Vadodara 390012, India
| | - Srigiridhar Kotamraju
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad 201002, India.
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Xing X, Liang Y, Li Y, Zhao Y, Zhang Y, Li Z, Li Z, Wu Z. Fisetin Delays Postovulatory Oocyte Aging by Regulating Oxidative Stress and Mitochondrial Function through Sirt1 Pathway. Molecules 2023; 28:5533. [PMID: 37513404 PMCID: PMC10384696 DOI: 10.3390/molecules28145533] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/04/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
The quality of oocytes determines the development potential of an embryo and is dependent on their timely fertilization after ovulation. Postovulatory oocyte aging is an inevitable factor during some assisted reproduction technology procedures, which results in poor fertilization rates and impairs embryo development. We found that fisetin, a bioactive flavonol contained in fruits and vegetables, delayed postovulatory oocyte aging in mice. Fisetin improved the development of aged oocytes after fertilization and inhibited the Sirt1 reduction in aged oocytes. Fisetin increased the GSH level and Sod2 transcription level to inhibit ROS accumulation in aged oocytes. Meanwhile, fisetin attenuated aging-induced spindle abnormalities, mitochondrial dysfunction, and apoptosis. At the molecular level, fisetin decreased aging-induced aberrant expression of H3K9me3. In addition, fisetin increased the expression levels of the mitochondrial transcription factor Tfam and the mitochondrial genes Co2 and Atp8 by upregulating Sirt1 in aged oocytes. Finally, inhibition of Sirt1 reversed the anti-aging effects of fisetin. Taken together, fisetin delayed postovulatory oocyte aging by upregulating Sirt1.
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Affiliation(s)
- Xupeng Xing
- National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Gene Bank of GuangDong Local Livestock and Poultry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China
| | - Yalin Liang
- National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Gene Bank of GuangDong Local Livestock and Poultry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China
| | - Yanan Li
- National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Gene Bank of GuangDong Local Livestock and Poultry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China
| | - Yaolu Zhao
- National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Gene Bank of GuangDong Local Livestock and Poultry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China
| | - Yuxing Zhang
- National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Gene Bank of GuangDong Local Livestock and Poultry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China
| | - Zheng Li
- National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Gene Bank of GuangDong Local Livestock and Poultry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China
| | - Zicong Li
- National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Gene Bank of GuangDong Local Livestock and Poultry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China
| | - Zhenfang Wu
- National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Gene Bank of GuangDong Local Livestock and Poultry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China
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Shaer DFE, Halim HIAE. The Possible Ameliorating Role of Fisetin on Hepatic Changes Induced by Fluoxetine in Adult Male Albino Rats: Histological, Immunohistochemical, and Biochemical Study. J Microsc Ultrastruct 2023; 11:161-171. [PMID: 38025186 PMCID: PMC10679833 DOI: 10.4103/jmau.jmau_84_22] [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: 09/18/2022] [Revised: 11/30/2022] [Accepted: 12/01/2022] [Indexed: 02/09/2023] Open
Abstract
Background Fluoxetine (FLX) is one of the selective serotonin reuptake inhibitors, it is widely used to treat neuropsychiatric disorders including depression, but high doses can cause several adverse effects. Fisetin (FIS), a bioactive flavonoid presents in vegetables and fruits, has antioxidant, anti-inflammatory, and anticancer effects. Aim To evaluate the possible ameliorating effect of FIS on the hepatic alterations induced by FLX in adult male albino rats. Materials and Methods Our study was done, for 3-weeks, on 48 rats that were divided into four groups: Group I (control), Group II received FIS orally (100 mg/kg/day), Group III received FLX orally (10 mg/kg/day), and Group IV concomitantly received FLX and FIS at the same dose and manner of groups II and III. Blood and liver samples were obtained and prepared for histological, immunohistochemical, and biochemical studies. Results FLX group revealed disturbed liver architecture, hepatocytes with vacuolated cytoplasm, inflammatory cellular infiltration, blood extravasation, and congestion of blood vessels in addition to, a significant increase in the area percentage of caspase-3, inducible nitric oxide synthase and the number of glial fibrillary acidic protein-expressing cells as well as a significant decrease in the area percentage of periodic acid-Schiff stain. Moreover, FLX significantly increased aspartate-aminotransferase and alanine-aminotransferase levels in the serum. In addition, FLX increased malondialdehyde level and decreased superoxide dismutase, glutathione (GSH) peroxidase, and reduced GSH levels in liver tissue. The concomitant administration of FIS ameliorated these alterations. Conclusions Administration of FIS ameliorated the histological, immunohistochemical, and biochemical alterations induced by FLX in the liver of adult male albino rats.
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Affiliation(s)
- Dina Fouad El Shaer
- Department of Histology and Cell Biology, Faculty of Medicine, Tanta University, Tanta, Egypt
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Vakili O, Borji M, Saffari-Chaleshtori J, Shafiee SM. Ameliorative effects of bilirubin on cell culture model of non-alcoholic fatty liver disease. Mol Biol Rep 2023; 50:4411-4422. [PMID: 36971910 DOI: 10.1007/s11033-023-08339-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 02/15/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is defined as the most prevalent hepatic disorder that affects a significant population worldwide. There are several genes/proteins, involving in the modulation of NAFLD pathogenesis; sirtuin1 (SIRT1), TP53-inducible regulator gene (TIGAR), and autophagy-related gene 5 (Atg5) are considered a chief group of these modulators that principally act by regulating the hepatic lipid metabolism, as well as preventing the lipid accumulation. Surprisingly, bilirubin, especially in its unconjugated form, might be able to alleviate NAFLD progression by decreasing lipid accumulation and regulating the expression levels of the above-stated genes. METHODS AND RESULTS Herein, the interactions between bilirubin and the corresponding genes' products were first analyzed by docking assessments. Afterwards, HepG2 cells were cultured under the optimum conditions, and then were incubated with high concentrations of glucose to induce NAFLD. After treating normal and fatty liver cells with particular bilirubin concentrations for 24- and 48-hour periods, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay, colorimetric method, and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) were employed to assess cell viability status, intracellular triglycerides content, and mRNA expression levels of the genes, respectively. Intracellular lipid accumulation of HepG2 cells was significantly decreased after treating with bilirubin. Bilirubin also increased SIRT1 and Atg5 gene expression levels in fatty liver cells. TIGAR gene expression levels were variable upon the conditions and the cell type, suggesting a dual role for TIGAR during the NAFLD pathogenesis. CONCLUSION Our findings indicate the potential of bilirubin in the prevention from or amelioration of NAFLD through influencing SIRT1-related deacetylation and the process of lipophagy, as well as decreasing the intrahepatic lipid content. In vitro model of NAFLD was treated with unconjugated bilirubin under the optimal conditions.Desirably, bilirubin moderated the accumulation of triglycerides within the cells possibly through modulation of the expression of SIRT1, Atg5, and TIGAR genes. In the context, bilirubin was shown to increase the expression levels of SIRT1 and Atg5, while the expression of TIGAR was demonstrated to be either increased or decreased, depending on the treatment conditions. Created with BioRender.com.
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The Role of Selective Flavonoids on Triple-Negative Breast Cancer: An Update. SEPARATIONS 2023. [DOI: 10.3390/separations10030207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023] Open
Abstract
Among the many types of breast cancer (BC), Triple-Negative Breast Cancer (TNBC) is the most alarming. It lacks receptors for the three main biomarkers: estrogen, progesterone, and human epidermal growth factor, hence the name TNBC. This makes its treatment a challenge. Surgical procedures and chemotherapy, performed either alone or in combination, seem to be the primary therapeutic possibilities; however, they are accompanied by severe complications. Currently, the formulation of drugs using natural products has been playing an important role in the pharmaceutical industries, owing to the drugs’ increased efficacies and significantly lessened side effects. Hence, treating TNBC with chemotherapeutic drugs developed using natural products such as flavonoids in the near future is much warranted. Flavonoids are metabolic compounds largely present in all plants, vegetables, and fruits, such as blueberries, onions, (which are widely used to make red wine,) chocolates, etc. Flavonoids are known to have enormous health benefits, such as anticancer, antiviral, anti-inflammatory, and antiallergic properties. They are known to arrest the cell cycle of the tumor cells and induces apoptosis by modulating Bcl-2, Bax, and Caspase activity. They show a considerable effect on cell proliferation and viability and angiogenesis. Various studies were performed at both the biochemical and molecular levels. The importance of flavonoids in cancer treatment and its methods of extraction and purification to date have been reported as individual publications. However, this review article explains the potentiality of flavonoids against TNBC in the preclinical levels and also emphasizes their molecular mechanism of action, along with a brief introduction to its methods of extraction, isolation, and purification in general, emphasizing the fact that its quantum of yield if enhanced and its possible synergistic effects with existing chemotherapeutics may pave the way for better anticancer agents of natural origin and significantly lessened side-effects.
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Molinari S, Imbriano C, Moresi V, Renzini A, Belluti S, Lozanoska-Ochser B, Gigli G, Cedola A. Histone deacetylase functions and therapeutic implications for adult skeletal muscle metabolism. Front Mol Biosci 2023; 10:1130183. [PMID: 37006625 PMCID: PMC10050567 DOI: 10.3389/fmolb.2023.1130183] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/06/2023] [Indexed: 03/17/2023] Open
Abstract
Skeletal muscle is a highly adaptive organ that sustains continuous metabolic changes in response to different functional demands. Healthy skeletal muscle can adjust fuel utilization to the intensity of muscle activity, the availability of nutrients and the intrinsic characteristics of muscle fibers. This property is defined as metabolic flexibility. Importantly, impaired metabolic flexibility has been associated with, and likely contributes to the onset and progression of numerous pathologies, including sarcopenia and type 2 diabetes. Numerous studies involving genetic and pharmacological manipulations of histone deacetylases (HDACs) in vitro and in vivo have elucidated their multiple functions in regulating adult skeletal muscle metabolism and adaptation. Here, we briefly review HDAC classification and skeletal muscle metabolism in physiological conditions and upon metabolic stimuli. We then discuss HDAC functions in regulating skeletal muscle metabolism at baseline and following exercise. Finally, we give an overview of the literature regarding the activity of HDACs in skeletal muscle aging and their potential as therapeutic targets for the treatment of insulin resistance.
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Affiliation(s)
- Susanna Molinari
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Carol Imbriano
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Viviana Moresi
- Institute of Nanotechnology, Department of Physics, National Research Council (CNR-NANOTEC), Sapienza University of Rome, Rome, Italy
- *Correspondence: Viviana Moresi,
| | - Alessandra Renzini
- DAHFMO Unit of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy
| | - Silvia Belluti
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | | | - Giuseppe Gigli
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC), Lecce, Italy
| | - Alessia Cedola
- Institute of Nanotechnology, Department of Physics, National Research Council (CNR-NANOTEC), Sapienza University of Rome, Rome, Italy
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Lv H, Tao F, Peng L, Chen S, Ren Z, Chen J, Yu B, Wei H, Wan C. In Vitro Probiotic Properties of Bifidobacterium animalis subsp. lactis SF and Its Alleviating Effect on Non-Alcoholic Fatty Liver Disease. Nutrients 2023; 15:nu15061355. [PMID: 36986084 PMCID: PMC10053994 DOI: 10.3390/nu15061355] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/20/2023] [Accepted: 03/06/2023] [Indexed: 03/15/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease with many influencing factors. With the increasing role of the gut–liver axis in various liver diseases, research on the prevention and treatment of NAFLD with probiotics is increasing. In the present study, a Bifidobacterium animalis subsp. strain, B. lactis SF, was isolated from the feces of healthy infants and characterized by sequencing of the 16S rDNA. A systematic probiotic evaluation was carried out, and a diet-induced mouse model was constructed to study the effect and mechanism of B. lactis SF on diet-induced NAFLD. Results show that B. lactis SF has excellent gastrointestinal fluid tolerance and intestinal colonization, and strong antibacterial and antioxidant capabilities. In vivo, B. lactis SF modulated intestinal flora, restored the intestinal barrier, and inhibited LPS entrance into the portal circulation, which subsequently inhibited the TLR4/NF-κB and modulated the PI3K-Akt/AMPK signaling pathway, attenuated the inflammatory response, and reduced lipid accumulation. In addition, B. lactis SF attenuated oxidative stress and further alleviated autophagy, resulting in an ameliorative effect on NAFLD. Therefore, our study provides a new dietary method for the treatment of NAFLD.
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Affiliation(s)
- Huihui Lv
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (H.L.); (F.T.); (L.P.); (S.C.); (Z.R.); (J.C.); (H.W.)
| | - Feiyue Tao
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (H.L.); (F.T.); (L.P.); (S.C.); (Z.R.); (J.C.); (H.W.)
| | - Lingling Peng
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (H.L.); (F.T.); (L.P.); (S.C.); (Z.R.); (J.C.); (H.W.)
| | - Shufang Chen
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (H.L.); (F.T.); (L.P.); (S.C.); (Z.R.); (J.C.); (H.W.)
| | - Zhongyue Ren
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (H.L.); (F.T.); (L.P.); (S.C.); (Z.R.); (J.C.); (H.W.)
| | - Jiahui Chen
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (H.L.); (F.T.); (L.P.); (S.C.); (Z.R.); (J.C.); (H.W.)
| | - Bo Yu
- Jiangxi-OAI Joint Research Institute, Nanchang University, 235 Nanjing East Road, Nanchang 330047, China;
| | - Hua Wei
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (H.L.); (F.T.); (L.P.); (S.C.); (Z.R.); (J.C.); (H.W.)
- Jiangxi-OAI Joint Research Institute, Nanchang University, 235 Nanjing East Road, Nanchang 330047, China;
| | - Cuixiang Wan
- Jiangxi-OAI Joint Research Institute, Nanchang University, 235 Nanjing East Road, Nanchang 330047, China;
- Correspondence: ; Tel.: +86-791-8833-4578; Fax: +86-791-8833-3708
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Dzah CS, Asante-Donyinah D, Letsyo E, Dzikunoo J, Adams ZS. Dietary Polyphenols and Obesity: A Review of Polyphenol Effects on Lipid and Glucose Metabolism, Mitochondrial Homeostasis, and Starch Digestibility and Absorption. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2023; 78:1-12. [PMID: 36459308 DOI: 10.1007/s11130-022-01034-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/25/2022] [Indexed: 06/17/2023]
Abstract
Obesity is a major global public health concern, limiting socio-economic development and human productivity. As studies focus on finding sustainable solutions to this challenge, polyphenols have shown promising results and have become a research focus. This is mainly because of associated lower risks of side effects with their use, compared to synthetic pharmaceuticals. In this study, the anti-obesity potentials of dietary polyphenols have been reviewed. Using a narrative approach, the biological activities of polyphenols and their influence on energy metabolism and mechanisms are discussed. Specifically, their roles in insulin-dependent glucose uptake, insulin sensitivity, lipid metabolism and storage in adipocytes, starch digestibility, and regulation of mitophagy and mitogenesis in muscle cells and adipocytes, were considered. After considering the major findings of many related studies, it was confirmed that polyphenols can prevent and ameliorate obesity by fighting insulin resistance (IR) induced by pro-inflammatory cytokines, scavenging reactive oxygen species (ROS) and limiting their effects, and by regulating the expression and/or activity of key enzymes along relevant pathways. More human studies are needed to reveal more about the anti-obesity effects of dietary polyphenols and their effective doses in humans.
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Affiliation(s)
- Courage Sedem Dzah
- Department of Food Science and Technology, Faculty of Applied Sciences and Technology, Ho Technical University, P.O. Box HP217, Ho, Volta Region, Ghana.
| | - David Asante-Donyinah
- Department of Food Science and Technology, Faculty of Applied Sciences and Technology, Ho Technical University, P.O. Box HP217, Ho, Volta Region, Ghana
| | - Emmanuel Letsyo
- Department of Food Science and Technology, Faculty of Applied Sciences and Technology, Ho Technical University, P.O. Box HP217, Ho, Volta Region, Ghana
| | - John Dzikunoo
- Department of Food Science and Technology, Faculty of Applied Sciences and Technology, Ho Technical University, P.O. Box HP217, Ho, Volta Region, Ghana
| | - Zeenatu Suglo Adams
- Department of Food Science and Technology, Faculty of Applied Sciences and Technology, Ho Technical University, P.O. Box HP217, Ho, Volta Region, Ghana
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Lee JH, Woo KJ, Hong J, Han KI, Kim HS, Kim TJ. Heat-Killed Enterococcus faecalis Inhibit FL83B Hepatic Lipid Accumulation and High Fat Diet-Induced Fatty Liver Damage in Rats by Activating Lipolysis through the Regulation the AMPK Signaling Pathway. Int J Mol Sci 2023; 24:ijms24054486. [PMID: 36901915 PMCID: PMC10002555 DOI: 10.3390/ijms24054486] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/18/2023] [Accepted: 02/21/2023] [Indexed: 03/03/2023] Open
Abstract
Continuous consumption of high-calorie meals causes lipid accumulation in the liver and liver damage, leading to non-alcoholic fatty liver disease (NAFLD). A case study of the hepatic lipid accumulation model is needed to identify the mechanisms underlying lipid metabolism in the liver. In this study, the prevention mechanism of lipid accumulation in the liver of Enterococcus faecalis 2001 (EF-2001) was extended using FL83B cells (FL83Bs) and high-fat diet (HFD)-induced hepatic steatosis. EF-2001 treatment inhibited the oleic acid (OA) lipid accumulation in FL83B liver cells. Furthermore, we performed lipid reduction analysis to confirm the underlying mechanism of lipolysis. The results showed that EF-2001 downregulated proteins and upregulated AMP-activated protein kinase (AMPK) phosphorylation in the sterol regulatory element-binding protein 1c (SREBP-1c) and AMPK signaling pathways, respectively. The effect of EF-2001 on OA-induced hepatic lipid accumulation in FL83Bs enhanced the phosphorylation of acetyl-CoA carboxylase and reduced the levels of lipid accumulation proteins SREBP-1c and fatty acid synthase. EF-2001 treatment increased the levels of adipose triglyceride lipase and monoacylglycerol during lipase enzyme activation, which, when increased, contributed to increased liver lipolysis. In conclusion, EF-2001 inhibits OA-induced FL83B hepatic lipid accumulation and HFD-induced hepatic steatosis in rats through the AMPK signaling pathway.
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Affiliation(s)
- Jin-Ho Lee
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
| | - Keun-Jung Woo
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
| | - Joonpyo Hong
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
| | - Kwon-Il Han
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
- Research & Development Center, Bereum Co., Ltd., Wonju 26361, Republic of Korea
| | - Han Sung Kim
- Department of Biomedical Engineering, Yonsei University, Wonju 26493, Republic of Korea
| | - Tack-Joong Kim
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
- Research & Development Center, Doctor TJ Co., Ltd., Wonju 26493, Republic of Korea
- Correspondence: ; Tel.: +82-33-760-224
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Naringin reduces fat deposition by promoting the expression of lipolysis and β-oxidation related genes. Obes Res Clin Pract 2023; 17:74-81. [PMID: 36494293 DOI: 10.1016/j.orcp.2022.11.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 11/17/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022]
Abstract
AIMS Naringin, a flavonoid present in citrus fruits, has been known for the capacity to reduce lipid synthesis and anti-inflammatory. In this study, we investigated whether naringin increases lipolysis and fatty acid β-oxidation to change fat deposition. METHODS In in vivo experiment, obese adult mice (20-weeks-old, n = 18) were divided into control group fed with normal diet and naringin-treated group fed with naringin-supplemented diet (5 g/kg) for 60 days, respectively. In in vitro experiment, differentiated 3T3-L1 adipocytes were treated for four days with or without naringin (100 µg/mL). RESULTS Supplementing naringin significantly reduced the body weight, abdominal fat weight, blood total cholesterol content of mice, but did not affect food intake. In addition, naringin decreased levels of pro-inflammatory factors in adipose tissue including interleukin-1β (IL-1β), interleukin-6 (IL-6), and monocyte chemotactic protein 1 (MCP-1). Naringin increased the expression of AMP-activated protein kinase (AMPK), a key factor in cellular energy metabolism, and raised the ratio of p-AMPK/AMPK in mouse liver tissue. The protein expression of hormone-sensitive lipase (HSL), phospho-HSL563 (p-HSL563), p-HSL563/HSL, and adipocyte triglyceride lipase (ATGL) was significantly increased in the adipose tissue of naringin-treated mice. Furthermore, naringin enhanced the expression of fatty acid β-oxidation genes, including carnitine palmitoyl transferase 1 (CPT1), uncoupling protein 2 (UCP2), and acyl-coenzyme A oxidase 1 (AOX1) in mouse adipose tissue. In in vitro experiment, similar findings were observed in differentiated 3T3-L1 adipocytes with naringin treatment. The treatment remarkably reduced intracellular lipid content, increased the number of mitochondria and promoted the gene expression of HSL, ATGL, CPT1, AOX1, and UCP2 and the phosphorylation of HSL protein. CONCLUSION Naringin reduced body fat in obese mice and lipid content in differentiated 3T3-L1 adipocytes, which was associated with enhanced AMPK activation and upregulation of the expression of the lipolytic genes HSL, ATGL, and β-oxidation genes CPT1, AOX1, and UCP2.
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Rizk FH, Soliman NA, Abo-Elnasr SE, Mahmoud HA, Abdel Ghafar MT, Elkholy RA, ELshora OA, Mariah RA, Amin Mashal SS, El Saadany AA. Fisetin ameliorates oxidative glutamate testicular toxicity in rats via central and peripheral mechanisms involving SIRT1 activation. Redox Rep 2022; 27:177-185. [PMID: 36047349 PMCID: PMC9448439 DOI: 10.1080/13510002.2022.2116551] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Objectives This study aimed to evaluate the potential mitigating effect of fisetin on monosodium glutamate (MSG)-induced testicular toxicity and investigate the possible involvement of silent mating type information regulation 2 homolog 1 (SIRT1) in this effect. Methods Forty male rats were divided into normal control, fisetin-treated, MSG-treated, and fisetin + MSG-treated groups. Testosterone, GnRH, FSH, and LH were measured in plasma, as well as SIRT1 and phosphorylated AMP-activated protein kinase (pAMPK) levels in testicular tissues using ELISA. Hydrogen peroxide (H2O2), nitric oxide (NO), and reduced glutathione (GSH) were measured colorimetrically, while Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression was relatively quantified using RT–PCR in testicular tissues. Results After 30 days, fisetin could ameliorate MSG-induced testicular toxicity by acting centrally on the hypothalamic-pituitary-gonadal axis, increasing plasma levels of GnRH, FSH, LH, and testosterone. Peripheral actions of fisetin on the testis were indicated as it increased testicular SIRT1 and pAMPK. Furthermore, it antagonized glutamate-induced oxidative stress by significantly lowering H2O2, NO, and relative NOX4 expression while significantly increasing reduced GSH levels. It also improved the architecture of the seminiferous tubules, reduced sperm abnormality, and increased sperm count. Discussion Fisetin ameliorates MSG-induced testicular toxicity via central and peripheral mechanisms making it a promising therapeutic target for male infertility.
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Affiliation(s)
- Fatma H Rizk
- Department of Medical Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Nema A Soliman
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Suzan E Abo-Elnasr
- Department of Histology and Cell Biology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Heba A Mahmoud
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Rasha A Elkholy
- Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ola A ELshora
- Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Reham A Mariah
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Amira A El Saadany
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
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Cao W, Wang K, Liang C, Su Y, Liu S, Li J, Qing H, Zeng Z, Dai L, Song JL. Dietary tea seed saponin combined with aerobic exercise attenuated lipid metabolism and oxidative stress in mice fed a high-fat diet (HFD). J Food Biochem 2022; 46:e14461. [PMID: 36200661 DOI: 10.1111/jfbc.14461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/16/2022] [Accepted: 09/22/2022] [Indexed: 01/14/2023]
Abstract
Tea seed saponins (TSS) are oleanolane-type pentacyclic triterpenoid saponin mixtures with various pharmacological effects. We aimed to explore the effects of a total of 4 weeks intragastric administration of TSS (140 mg/kg·day) combined with aerobic exercise (AE) on lipid metabolism and its associated oxidative stress in HFD-induced obese mice and to investigate the possible molecular mechanisms. TSS + AE intervention significantly reduced body weight and the adiposity index (including subcutaneous, epididymal, perirenal, and abdominal adipose) in obese mice; improved dyslipidemia by lowering serum TC, TG, and LDL-c levels; and increased HDL-c levels. TSS + AE intervention significantly improved hepatic steatosis by inhibiting lipogenetic Acc, Srebp1c, and Scd1 and upregulating lipolysis genes (Pgc1α, Pgc1β, Pparα, and Cpt1). TSS + AE intervention increased the hepatic protein expression of p-AMPK, SIRT1, and PGC-1α, as well as PPAR-γ and GLUT-4 in skeletal muscle compared with expression in the HFD group. In addition, TSS + AE also modulated oxidative stress in obese mice, which was indicated by the increased serum and liver levels of SOD, GSH, and T-AOC and decreased ROS and MDA levels. These results suggest that TSS + AE intervention can reduce fat accumulation and improve HFD-induced lipid metabolism disorders and oxidative stress. PRACTICAL APPLICATIONS: Obesity is a metabolic disease induced by excess nutritional intake and insufficient energy expenditure. Dietary modifications combined with aerobic exercise are currently an effective method for weight loss. Tea seed saponins (TSS) are a variety of biologically active oleanolane-type pentacyclic triterpenoid saponins that naturally exist in tea seeds. Few articles have focused on the effects and mechanisms of TSS combined with aerobic exercise (AE) in regulating lipid metabolism and improving oxidative damage in vivo. Using an HFD-induced obese mice model to explore the mechanism of TSS + AE in regulating lipid metabolism and its associated oxidative stress damage will help provide reliable data for the application of dietary nutrition combined with AE in anti-obesity.
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Affiliation(s)
- Wenjing Cao
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.,School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Keying Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China
| | - Chanhua Liang
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.,School of Public Health, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China
| | - Yanming Su
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China
| | - Shuang Liu
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China
| | - Jiali Li
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China
| | - Huishan Qing
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China
| | - Zhen Zeng
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.,Department of Pediatrics and Maternal and Child Health, Xiangya College of Public Health, Central South University, Changsha, China
| | - Ling Dai
- Center of Mental Health Education and Counseling, Guilin Medical University, Guilin, China
| | - Jia-Le Song
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.,Department of Clinical Nutrition and Obstetrics, The Second Affiliated Hospital of Guilin Medical University, Guilin, China.,Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, Guilin Medical University, Guilin, China.,Guangxi Key Laboratory of Environmental Exposureomics and Entire Lifecycle Health, Guilin Medical University, Guilin, China
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Zakaria Z, Othman ZA, Suleiman JB, Mustaffa KMF, Jalil NAC, Ghazali WSW, Zulkipli NN, Mohamed M, Kamaruzaman KA. Therapeutic Effects of Heterotrigona itama (Stingless Bee) Bee Bread in Improving Hepatic Lipid Metabolism through theActivation of the Keap1/Nrf2 Signaling Pathway in an Obese Rat Model. Antioxidants (Basel) 2022; 11:2190. [PMID: 36358563 PMCID: PMC9686663 DOI: 10.3390/antiox11112190] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 10/29/2023] Open
Abstract
Bee bread (BB) has traditionally been used as a dietary supplement to treat liver problems. This study evaluated the therapeutic effects of Heterotrigona itama BB from Malaysia on obesity-induced hepatic lipid metabolism disorder via the regulation of the Keap1/Nrf2 pathway. Male Sprague Dawley rats were fed with either a normal diet or high-fat diet (HFD) for 6 weeks to induce obesity. Following 6 weeks, obese rats were treated either with distilled water (OB group), BB (0.5 g/kg body weight/day) (OB + BB group) or orlistat (10 mg/kg body weight/day) (OB + OR group) concurrent with HFD for another 6 weeks. BB treatment suppressed Keap1 and promoted Nrf2 cytoplasmic and nuclear translocations, leading to a reduction in oxidative stress, and promoted antioxidant enzyme activities in the liver. Furthermore, BB down-regulated lipid synthesis and its regulator levels (SIRT1, AMPK), and up-regulated fatty acid β-oxidation in the liver of obese rats, being consistent with alleviated lipid levels, improved hepatic histopathological changes (steatosis, hepatocellular hypertrophy, inflammation and glycogen expression) and prevented progression to non-alcoholic steatohepatitis. These results showed the therapeutic potentials of H. itama BB against oxidative stress and improved lipid metabolism in the liver of obese rats possibly by targeting the Keap1/Nrf2 pathway, hence proposing its role as a natural supplement capable of treating obesity-induced fatty liver disease.
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Affiliation(s)
- Zaida Zakaria
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Zaidatul Akmal Othman
- Unit of Physiology, Universiti Sultan Zainal Abidin, Kuala Terengganu 20400, Terengganu, Malaysia
| | - Joseph Bagi Suleiman
- Department of Science Laboratory Technology, Akanu Ibiam Federal Polytechnic, Unwana P.O. Box 1007, Ebonyi State, Nigeria
| | - Khairul Mohd Fadzli Mustaffa
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Nur Asyilla Che Jalil
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Wan Syaheedah Wan Ghazali
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Ninie Nadia Zulkipli
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Mahaneem Mohamed
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
- Unit of Integrative Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Khaidatul Akmar Kamaruzaman
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
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Krishnakumar IM, Jaja-Chimedza A, Joseph A, Balakrishnan A, Maliakel B, Swick A. Enhanced bioavailability and pharmacokinetics of a novel hybrid-hydrogel formulation of fisetin orally administered in healthy individuals: a randomised double-blinded comparative crossover study. J Nutr Sci 2022; 11:e74. [PMID: 36304817 PMCID: PMC9574875 DOI: 10.1017/jns.2022.72] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 07/21/2022] [Indexed: 12/14/2022] Open
Abstract
Fisetin, a polyphenol found in several fruits and vegetables, has shown potential health benefits in many pre-clinical studies for neuroprotection, cardioprotection, chemoprevention, diabetes, inflammation and oxidative stress. However, the clinical effectiveness of fisetin may be limited by its poor bioavailability when ingested. Using a novel green technology of Hybrid-FENUMAT™, a food-grade fisetin formulation (FF-20) was developed through encapsulation of fisetin micelles into fenugreek galactomannan (FG) hydrogel scaffold to improve its physical characteristics and bioavailability. This is the first human pharmacokinetic study of fisetin following a single-dose, comparative, double-blinded, cross-over protocol, supplementing with FF-20 and unformulated fisetin (UF). Fifteen healthy volunteers were given a single dose of 1000 mg UF or 1000 mg FF-20 (delivering 192 mg fisetin) with a 10-d washout period between each dose. Blood samples were taken at 0⋅5, 1, 2, 3, 5, 8 and 12 h after both days of supplementation to quantify fisetin and geraldol, an active metabolite. The plasma concentration of fisetin when individuals consumed FF-20 was 26⋅9-fold greater than UF as determined by the area under the curve over 12 h [AUC0–12 h (FF-20) = 341⋅4 v . AUC0–12 h (UF) = 12⋅67]. The maximum plasma concentration (C max) was also more than twenty-three times higher when supplemented with FF-20 (238⋅2 ng/ml) compared to UF (9⋅97 ng/ml). The encapsulation also reduced the amount of conversion of fisetin to geraldol. No adverse events were reported during the study. Therefore, the encapsulation of fisetin into FG dietary fibre hydrogel scaffold could improve its delivery and bioavailability in human subjects.
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Affiliation(s)
| | | | - Ashil Joseph
- R & D Centre Akay Natural Ingredients, Ambunad, Malaidamthuruth P. O., Cochin, Kerala 683561, India
| | - Abhilash Balakrishnan
- R & D Centre Akay Natural Ingredients, Ambunad, Malaidamthuruth P. O., Cochin, Kerala 683561, India
| | - Balu Maliakel
- R & D Centre Akay Natural Ingredients, Ambunad, Malaidamthuruth P. O., Cochin, Kerala 683561, India
| | - Andrew Swick
- Life Extension, 3600 W Commercial Blvd, Fort Lauderdale, FL 33309, USA
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Liu Y, Li Y, Wang J, Yang L, Yu X, Huang P, Song H, Zheng P. Salvia-Nelumbinis naturalis improves lipid metabolism of NAFLD by regulating the SIRT1/AMPK signaling pathway. BMC Complement Med Ther 2022; 22:213. [PMID: 35945571 PMCID: PMC9361555 DOI: 10.1186/s12906-022-03697-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 08/04/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Salvia-Nelumbinis naturalis (SNN), the extract of Chinese herbal medicine, has shown effects on NAFLD. This study aims to explore the underlying mechanism of SNN for regulating the lipid metabolism disorder in NAFLD based on the SIRT1/AMPK signaling pathway.
Methods
Male C57BL/6J mice fed with a high-fat diet (HFD) were used to establish the NAFLD model. Dynamic changes of mice including body weight, liver weight, serological biochemical indexes, liver histopathological changes, and protein level of AMPK and SIRT1 were monitored. After18 weeks, SNN treatment was administrated to the NAFLD mice for another 4 weeks. Besides the aforementioned indices, TC and TG of liver tissues were also measured. Western blot and quantitative RT-PCR were used to detect the expression and/or activation of SIRT1 and AMPK, as well as the molecules associated with lipid synthesis and β-oxidation. Furthermore, AML12 cells with lipid accumulation induced by fatty acids were treated with LZG and EX527 (SIRT1 inhibitor) or Compound C (AMPK inhibitor ) to confirm the potential pharmacological mechanism.
Results
Dynamic observation found the mice induced by HFD with gradually increased body and liver weight, elevated serum cholesterol, hepatic lipid accumulation, and liver injury. After 16 weeks, these indicators have shown obvious changes. Additionally, the hepatic level of SIRT1 and AMPK activation was identified gradually decreased with NAFLD progress. The mice with SNN administration had lower body weight, liver weight, and serum level of LDL-c and ALT than those of the NAFLD model. Hepatosteatosis and hepatic TG content in the liver tissues of the SNN group were significantly reduced. When compared with control mice, the NAFLD mice had significantly decreased hepatic expression of SIRT1, p-AMPK, p-ACC, ACOX1, and increased total Acetylated-lysine, SUV39H2, and SREBP-1c. The administration of SNN reversed the expression of these molecules. In vitro experiments showed the effect of SNN in ameliorating hepatosteatosis and regulating the expression of lipid metabolism-related genes in AML12 cells, which were diminished by EX527 or Compound C co-incubation.
Conclusions
Taken together, the SIRT1/AMPK signaling pathway, involved in hepatic lipid synthesis and degradation, plays a pivotal role in the pathogenesis of NAFLD development. The regulation of SIRT1/AMPK signaling greatly contributes to the underlying therapeutic mechanism of SNN for NAFLD.
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Ketone Bodies and SIRT1, Synergic Epigenetic Regulators for Metabolic Health: A Narrative Review. Nutrients 2022; 14:nu14153145. [PMID: 35956321 PMCID: PMC9370141 DOI: 10.3390/nu14153145] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/21/2022] [Accepted: 07/27/2022] [Indexed: 11/17/2022] Open
Abstract
Ketone bodies (KBs) and Sirtuin-1 (SIRT1) have received increasing attention over the past two decades given their pivotal function in a variety of biological contexts, including transcriptional regulation, cell cycle progression, inflammation, metabolism, neurological and cardiovascular physiology, and cancer. As a consequence, the modulation of KBs and SIRT1 is considered a promising therapeutic option for many diseases. The direct regulation of gene expression can occur in vivo through histone modifications mediated by both SIRT1 and KBs during fasting or low-carbohydrate diets, and dietary metabolites may contribute to epigenetic regulation, leading to greater genomic plasticity. In this review, we provide an updated overview of the epigenetic interactions between KBs and SIRT1, with a particular glance at their central, synergistic roles for metabolic health.
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Amycenone reduces excess body weight and attenuates hyperlipidaemia by inhibiting lipogenesis and promoting lipolysis and fatty acid β-oxidation in KK- Ay obese diabetic mice. J Nutr Sci 2022; 11:e55. [PMID: 35836693 PMCID: PMC9274390 DOI: 10.1017/jns.2022.43] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 12/04/2022] Open
Abstract
Excess body weight and hyperlipidaemia cause severe health problems and have social implications. Amycenone is an active substance extracted from Yamabushitake mushrooms with no reports of its activity against excess body weight and hyperlipidaemia. This research clarifies the effects and mechanisms of action of amycenone on the inhibition of body weight excess and hyperlipidaemia attenuation using KK-Ay mice. Amycenone or water was administered to 8-week-old male KK-Ay mice by gavage for 8 weeks. Their body weight and food intake were recorded during the experiment. At the end of the experimental period, the mice were dissected, and blood samples, lipid metabolism-related organs and tissues were collected and stored for further analysis. Amycenone treatment suppressed body weight gain and improved serum levels of fasting blood glucose and non-esterified fatty acids. Additionally, serum and hepatic cholesterol and triacylglycerol levels were reduced after this treatment, whereas the phosphorylation levels of AMPK, PKA and HSL increased and the expression level of FAS decreased. The protein level of C/EBPβ and gene expression level of Cpt1 were higher in the perirenal adipose tissue of amycenone-treated KK-Ay mice. Furthermore, amycenone phosphorylated AMPK, PKA and ACC, and PPARγ expression was lower in the mesenteric adipose tissue. The phosphorylation levels of AMPK, LKB1, PKA and ACC were also induced, and FAS expression level was reduced in the liver of the amycenone-treated group. Amycenone could reduce excess body weight and attenuate hyperlipidaemia in KK-Ay mice by inhibiting lipogenesis and promoting lipolysis through lipid metabolism pathway stimulation and fatty acid β-oxidation acceleration.
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Prem PN, Sivakumar B, Boovarahan SR, Kurian GA. Recent advances in potential of Fisetin in the management of myocardial ischemia-reperfusion injury-A systematic review. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 101:154123. [PMID: 35533608 DOI: 10.1016/j.phymed.2022.154123] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 03/26/2022] [Accepted: 04/17/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND The primary therapeutic strategy in managing ischemic heart diseases is to restore the perfusion of the myocardial ischemic area by surgical methods that often result in an unavoidable injury called ischemia-reperfusion injury (IR). Fisetin is an effective flavonoid with antioxidant and anti-inflammatory properties, proven to be cardioprotective against IR injury in both in-vitro and invivo models, apart from its promising health benefits against cancer, diabetes, and neurodegenerative ailments. PURPOSE The potential of fisetin in attenuating myocardial IR is inconclusive as the effectiveness of fisetin needs more understanding in terms of its possible target sites and underlying different mechanisms. Considering the surge in recent scientific interests in fisetin as a pharmacological agent, this review not only updates the existing preclinical and clinical studies with fisetin and its underlying mechanisms but also summarizes its possible targets during IR protection. METHODS We performed a literature survey using search engines Pubmed, PMC, Science direct, Google, and research gate published across the years 2006-2021. The relevant studies were extracted from the databases with the combinations of the following keywords and summarized: myocardial ischemia-reperfusion injury, natural products, flavonoid, fisetin, PI3K, JAK-STAT, Nrf2, PKC, JNK, autophagy. RESULTS Fisetin is reported to be effective in attenuating IR injury by delaying the clotting time, preserving the mitochondrial function, reducing oxidative stress, and inhibiting GSK 3β. But it failed to protect diseased cardiomyocytes challenged to IR. As discussed in the current review, fisetin not only acts as a conventional antioxidant and anti-inflammatory agent to exert its biological effect but may also exert modulatory action on the cellular metabolism and adaptation via direct action on various signalling pathways that comprise PI3K, JAK-STAT, Nrf2, PKC, JNK, and autophagy. Moreover, the dosage of fisetin and co-morbidities like diabetes and obesity are found to be detrimental factors for cardioprotection. CONCLUSION For further evaluation and smooth clinical translation of the fisetin molecule in IR treatment, researchers should pay close attention to the potential of fisetin to possibly alter the key cardioprotective pathways and dosage, as the efficacy of fisetin is tissue and cell type-specific and varies with different doses.
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Affiliation(s)
- Priyanka N Prem
- Vascular Biology lab, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, India
| | - Bhavana Sivakumar
- Vascular Biology lab, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, India
| | - Sri Rahavi Boovarahan
- Vascular Biology lab, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, India
| | - Gino A Kurian
- Vascular Biology lab, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, India; School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, 613401, Tamil Nadu, India.
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Acacetin Protects against Non-Alcoholic Fatty Liver Disease by Regulating Lipid Accumulation and Inflammation in Mice. Int J Mol Sci 2022; 23:ijms23094687. [PMID: 35563076 PMCID: PMC9103759 DOI: 10.3390/ijms23094687] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 02/04/2023] Open
Abstract
We previously demonstrated that acacetin reduces adipogenesis in adipocytes, and decreases lipid accumulation in visceral adipocyte tissue. Here we investigated whether acacetin regulated the mechanisms of lipogenesis and inflammation in non-alcoholic fatty liver disease (NAFLD) in obese mice. Male C57BL/6 mice were fed a high-fat diet (HFD), and then administered acacetin by intraperitoneal injection. Acacetin reduced body weight and liver weight in obese mice. Acacetin-treated obese mice exhibited decreased lipid accumulation, increased glycogen accumulation, and improved hepatocyte steatosis. Acacetin regulated triglycerides and total cholesterol in the liver and serum. Acacetin decreased low-density lipoprotein and leptin concentrations, but increased high-density lipoprotein and adiponectin levels in obese mice. Acacetin effectively weakened the gene expressions of transcription factors related to lipogenesis, and promoted the expressions of genes related to lipolysis and fatty acid β-oxidation in liver. Acacetin also reduced expressions of inflammation-related cytokines in the serum and liver. Oleic acid induced lipid accumulation in murine FL83B hepatocytes, and the effects of acacetin treatment indicated that acacetin may regulate lipid metabolism through the AMPK pathway. Acacetin may protect against hepatic steatosis by modulating inflammation and AMPK expression.
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Li D, Liu X, Pi W, Zhang Y, Yu L, Xu C, Sun Z, Jiang J. Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation. Front Pharmacol 2022; 12:808480. [PMID: 35273493 PMCID: PMC8902236 DOI: 10.3389/fphar.2021.808480] [Citation(s) in RCA: 102] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/31/2021] [Indexed: 12/12/2022] Open
Abstract
Doxorubicin (DOX) is an anthracycline antibiotic that is used extensively for the management of carcinoma; however, its clinical application is limited due to its serious cardiotoxic side effects. Ferroptosis represents iron-dependent and reactive oxygen species (ROS)-related cell death and has been proven to contribute to the progression of DOX-induced cardiomyopathy. Fisetin is a natural flavonoid that is abundantly present in fruits and vegetables. It has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity in experimental rats. However, the underlying mechanisms remain unknown. The present study investigated the cardioprotective role of fisetin and the underlying molecular mechanism through experiments in the DOX-induced cardiomyopathy rat and H9c2 cell models. The results revealed that fisetin treatment could markedly abate DOX-induced cardiotoxicity by alleviating cardiac dysfunction, ameliorating myocardial fibrosis, mitigating cardiac hypertrophy in rats, and attenuating ferroptosis of cardiomyocytes by reversing the decline in the GPX4 level. Mechanistically, fisetin exerted its antioxidant effect by reducing the MDA and lipid ROS levels and increasing the glutathione (GSH) level. Moreover, fisetin exerted its protective effect by increasing the SIRT1 expression and the Nrf2 mRNA and protein levels and its nuclear translocation, which resulted in the activation of its downstream genes such as HO-1 and FTH1. Selective inhibition of SIRT1 attenuated the protective effects of fisetin in the H9c2 cells, which in turn decreased the GSH and GPX4 levels, as well as Nrf2, HO-1, and FTH1 expressions. In conclusion, fisetin exerts its therapeutic effects against DOX-induced cardiomyopathy by inhibiting ferroptosis via SIRT1/Nrf2 signaling pathway activation.
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Affiliation(s)
- Danlei Li
- Department of Cardiology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Xiaoman Liu
- Department of Cardiology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Wenhu Pi
- Key Laboratory of Radiation Oncology of Taizhou, Department of Radiation Oncology, Radiation Oncology Institute of Enze Medical Health Academy, Affiliated Taizhou Hospital of Wenzhou Medical University, Linhai, China
| | - Yang Zhang
- Department of Cardiology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Lei Yu
- Department of Cardiology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Cheng Xu
- Department of Cardiology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Zhenzhu Sun
- Department of Cardiology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Jianjun Jiang
- Department of Cardiology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
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Cominguez DC, Park YJ, Kang YM, Nugroho A, Kim S, An HJ. Clitorin ameliorates western diet-induced hepatic steatosis by regulating lipogenesis and fatty acid oxidation in vivo and in vitro. Sci Rep 2022; 12:4154. [PMID: 35264693 PMCID: PMC8907210 DOI: 10.1038/s41598-022-07937-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 02/28/2022] [Indexed: 12/02/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is usually correlated with metabolic diseases, such as obesity, insulin resistance, and hyperglycemia. Herein, we investigated the inhibitory effects and underlying governing mechanism of clitorin in a western diet (WD)-induced hepatic steatosis mouse model, and in oleic acid-stimulated HepG2 cells. Male C57BL/6 mice were fed a normal diet, WD, WD + 10 or 20 mg/kg orlistat, and WD + 10 or 20 mg/kg clitorin. HepG2 cells were treated with 1 mM oleic acid to induce lipid accumulation with or without clitorin. Clitorin significantly alleviated body weight gain and hepatic steatosis features (NAFLD activity score, micro-, and macro-vesicular steatosis) in WD-induced hepatic steatosis mice. Additionally, clitorin significantly decreased protein expressions of sterol regulatory element-binding protein 1 (SREBP1), peroxisome proliferator-activated receptor γ (PPARγ), and CCAAT/enhancer binding protein α (C/EBPα) in WD-induced hepatic steatosis mice. Moreover, clitorin significantly diminished the mRNA levels of SREBP1, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and enhanced the mRNA levels of peroxisome proliferator-activated receptor α (PPARα) and carnitine palmitoyltranserase-1 (CTP-1), as well as adenosine monophosphate-activated protein kinase (AMPK) in the liver of WD-induced hepatic steatosis mice and oleic acid-stimulated HepG2 cells. Overall, our findings demonstrated that clitorin can be a potentially efficacious candidate for NAFLD management.
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Affiliation(s)
- Divina C Cominguez
- Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju, Gangwon-do, 26339, Republic of Korea
| | - Yea-Jin Park
- Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju, Gangwon-do, 26339, Republic of Korea
| | - Yun-Mi Kang
- Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju, Gangwon-do, 26339, Republic of Korea
| | - Agung Nugroho
- Department of Agro-Industrial Technology, Lambung Mangkurat University, Banjarbaru, Indonesia
| | - Suhyun Kim
- Department of Obstetrics & Gynecology College of Korean Medicine, Sangji University, Wonju-si, Gangwon-do, 26339, Republic of Korea
| | - Hyo-Jin An
- Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju, Gangwon-do, 26339, Republic of Korea.
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Fan M, Choi YJ, Wedamulla NE, Tang Y, Han KI, Hwang JY, Kim EK. Heat-Killed Enterococcus faecalis EF-2001 Attenuate Lipid Accumulation in Diet-Induced Obese (DIO) Mice by Activating AMPK Signaling in Liver. Foods 2022; 11:575. [PMID: 35206052 PMCID: PMC8870772 DOI: 10.3390/foods11040575] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 02/04/2023] Open
Abstract
To explore the inhibitory mechanism of heat-killed Enterococcus faecalis, EF-2001 on hepatic lipid deposition, a diet-induced obese (DIO) animal model was established by high-fat diet (HFD). The DIO C57BL/6 mice were divided into four groups: the normal group without HFD (ND, n = 8), obesity group (HFD, n = 8), experimental group (HFD + EF-2001, 200 mg/kg, n = 8), and positive control group (HFD + Orlistat, 60 mg/kg, n = 8). After 4 weeks, liver and adipose tissue were fixed in 10% paraformaldehyde, followed by embedding in paraffin for tissue sectioning. The differences in body mass, body fat ratio, fatty cell area, and lipid profiling of the liver (TC, LDL, and HDL) were also determined. Moreover, Western blot was performed to analyze the expression of lipid accumulation-related proteins, including AMPK, PPARγ, SREBP-1, ACC, and FAS. Compared with the HFD group, the HFD + EF-2001 group exhibited decreased fat mass, liver index, adipocyte area, TC, and LDL, and an increased level of HDL. The results of liver hematoxylin and eosin (H&E), and oil red O staining showed that the mice in each intervention group were improved on hepatic lipid accumulation, and the mice in the HFD + EF-2001 group were the most similar to those in the normal group when compared with the HFD group. From the Western blot results, we proved that EF-2001 activated the AMPK signaling pathway. EF-2001 significantly upregulated the expressions of p-AMPK and p-ACC and downregulated PPARγ, SREBP-1, and FAS in murine liver. Taken together, these results suggest that EF-2001 decrease lipid accumulation in the DIO model mice through the AMPK pathway and ameliorate liver damage by HFD.
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Affiliation(s)
- Meiqi Fan
- Division of Food Bioscience, College of Biomedical and Health Sciences, Konkuk University, Chungju 27478, Korea;
| | - Young-Jin Choi
- Department of Food Science and Nutrition, College of Health Science, Dong-A University, Busan 49315, Korea; (Y.-J.C.); (N.E.W.)
- Center for Silver-Targeted Biomaterials, Brain Busan 21 Plus Program, Dong-A University, Busan 49315, Korea
- Department of Health Sciences, The Graduate School of Dong-A University, Busan 49315, Korea
| | - Nishala Erandi Wedamulla
- Department of Food Science and Nutrition, College of Health Science, Dong-A University, Busan 49315, Korea; (Y.-J.C.); (N.E.W.)
- Center for Silver-Targeted Biomaterials, Brain Busan 21 Plus Program, Dong-A University, Busan 49315, Korea
- Department of Health Sciences, The Graduate School of Dong-A University, Busan 49315, Korea
- Department of Export Agriculture, Faculty of Animal Science and Export Agriculture, Uva Wellassa University, Badulla 90000, Sri Lanka
| | - Yujiao Tang
- School of Bio-Science and Food Engineering, Changchun University of Science and Technology, Changchun 130600, China;
| | | | - Ji-Young Hwang
- Department of Food Science & Technology, Dong-Eui University, Busan 47340, Korea;
| | - Eun-Kyung Kim
- Department of Food Science and Nutrition, College of Health Science, Dong-A University, Busan 49315, Korea; (Y.-J.C.); (N.E.W.)
- Center for Silver-Targeted Biomaterials, Brain Busan 21 Plus Program, Dong-A University, Busan 49315, Korea
- Department of Health Sciences, The Graduate School of Dong-A University, Busan 49315, Korea
- Department of Export Agriculture, Faculty of Animal Science and Export Agriculture, Uva Wellassa University, Badulla 90000, Sri Lanka
- Center for Food & Bio Innovation, Dong-A University, Busan 49315, Korea
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Zhou ZS, Kong CF, Sun JR, Qu XK, Sun JH, Sun AT. Fisetin Ameliorates Alcohol-Induced Liver Injury through Regulating SIRT1 and SphK1 Pathway. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2022; 50:2171-2184. [DOI: 10.1142/s0192415x22500938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Alcoholic liver disease (ALD) often leads to hepatitis, hepatic cirrhosis, and even hepatocellular carcinoma. Fisetin has been shown to confer protection against liver injury. Herein, we investigated whether fisetin could prevent ethanol-induced hepatotoxicity. Mice were fed on 5% (v/v) Lieber–DeCarli ethanol diet. Human primary hepatic stellate cells (HSCs) co-cultured with ethanol were used to verify the therapeutic effect of fisetin. The results of alanine/aspartate aminotransferase (ALT/AST), Triglyceride (TG), total cholesterol (TC) in serum, Oil O Red and Masson staining revealed that fisetin (80[Formula: see text]mg/kg) ameliorated ethanol-induced mice liver injury and fibrosis. Besides, immunofluorescence results of [Formula: see text]-SMA revealed that fisetin suppressed HSCs activation. The suppression was dose-dependent. Furthermore, fisetin promoted SIRT1-mediated autophagy and inhibited Sphk1-mediated endoplasmic reticulum stress (ER stress) both in vitro and in vivo. Molecular docking results indicated potential interaction of fisetin with SIRT1 and SphK1. The inhibitory effect of fisetin on HSCs activation was reversed on co-culturing with EX-527, a specific inhibitor against STIR1 overexpression. Thus, fisetin has the potential to ameliorate alcohol-induced liver injury through suppression of HSCs activation, SIRT1-mediated autophagy and Sphk1-mediated ER stress.
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Affiliation(s)
- Zi-Shen Zhou
- School of Public Health, Jilin University, Jilin, P. R. China
| | - Chen-Fan Kong
- Department of Gastroenterology, Affiliated Shenzhen Hospital, Shanghai University of Traditional Chinese Medicine, Guangdong, P. R. China
| | - Jian-Rong Sun
- School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Xiang-Ke Qu
- School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Jin-Hui Sun
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - An-Tao Sun
- Department of Gastroenterology, Guang’anmen Hospital, Chinese Academy of Traditional Chinese Medicine, Beijing, P. R. China
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43
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Wang M, Wang K, Liao X, Hu H, Chen L, Meng L, Gao W, Li Q. Carnitine Palmitoyltransferase System: A New Target for Anti-Inflammatory and Anticancer Therapy? Front Pharmacol 2021; 12:760581. [PMID: 34764874 PMCID: PMC8576433 DOI: 10.3389/fphar.2021.760581] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/17/2021] [Indexed: 11/20/2022] Open
Abstract
Lipid metabolism involves multiple biological processes. As one of the most important lipid metabolic pathways, fatty acid oxidation (FAO) and its key rate-limiting enzyme, the carnitine palmitoyltransferase (CPT) system, regulate host immune responses and thus are of great clinical significance. The effect of the CPT system on different tissues or organs is complex: the deficiency or over-activation of CPT disrupts the immune homeostasis by causing energy metabolism disorder and inflammatory oxidative damage and therefore contributes to the development of various acute and chronic inflammatory disorders and cancer. Accordingly, agonists or antagonists targeting the CPT system may become novel approaches for the treatment of diseases. In this review, we first briefly describe the structure, distribution, and physiological action of the CPT system. We then summarize the pathophysiological role of the CPT system in chronic obstructive pulmonary disease, bronchial asthma, acute lung injury, chronic granulomatous disease, nonalcoholic fatty liver disease, hepatic ischemia–reperfusion injury, kidney fibrosis, acute kidney injury, cardiovascular disorders, and cancer. We are also concerned with the current knowledge in either preclinical or clinical studies of various CPT activators/inhibitors for the management of diseases. These compounds range from traditional Chinese medicines to novel nanodevices. Although great efforts have been made in studying the different kinds of CPT agonists/antagonists, only a few pharmaceuticals have been applied for clinical uses. Nevertheless, research on CPT activation or inhibition highlights the pharmacological modulation of CPT-dependent FAO, especially on different CPT isoforms, as a promising anti-inflammatory/antitumor therapeutic strategy for numerous disorders.
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Affiliation(s)
- Muyun Wang
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kun Wang
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ximing Liao
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Haiyang Hu
- Department of Vascular Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Liangzhi Chen
- Department of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Linlin Meng
- Department of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wei Gao
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiang Li
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Atractylodes chinensis Water Extract Ameliorates Obesity via Promotion of the SIRT1/AMPK Expression in High-Fat Diet-Induced Obese Mice. Nutrients 2021; 13:nu13092992. [PMID: 34578872 PMCID: PMC8470677 DOI: 10.3390/nu13092992] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/26/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022] Open
Abstract
Obesity remains a continuing global health concern, as it is associated with an increased risk of many chronic diseases. Atractylodes chinensis Koidz. (Ac) is traditionally used in the treatment of inflammatory diseases, such as arthritis, hepatitis, and gastric ulcers. Despite the diverse pharmacological activities of Ac, scientific evidence for the use of Ac in obesity is still limited. Therefore, the present study aimed to determine the anti-obesity effects of Ac. C57BL/6N mice were divided into five groups as follows: chow diet group (CON), 45% HFD group, HFD + oral administration of orlistat group, and HFD + oral administration of Ac groups. RT-PCR and western blotting were used to examine the expression of molecules relating to obesity progression. Ac-administered mice showed dramatically decreased body weight and weight gain compared to the high-fat diet (HFD)-fed mice. In addition, Ac administration attenuated the protein expression levels of adipogenic transcription factors in the white adipose tissue (WAT) and livers of HFD-fed mice. Furthermore, Ac administration declined the expression levels of lipogenic genes, while enhancing those of the fatty acid oxidation genes in the WAT of HFD-fed mice. Importantly, Ac administration highly upregulated the AMP-activated kinase (AMPK) and sirtuin 1 (SIRT1) expression levels in WAT of the HFD-induced obese mouse model. Our results provide evidence that Ac can effectively ameliorate weight gain and adipose tissue expansion.
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45
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Zhang P, Wang W, Mao M, Gao R, Shi W, Li D, Calderone R, Sui B, Tian X, Meng X. Similarities and Differences: A Comparative Review of the Molecular Mechanisms and Effectors of NAFLD and AFLD. Front Physiol 2021; 12:710285. [PMID: 34393826 PMCID: PMC8362097 DOI: 10.3389/fphys.2021.710285] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are the most prevalent metabolic liver diseases globally. Due to the complex pathogenic mechanisms of NAFLD and AFLD, no specific drugs were approved at present. Lipid accumulation, oxidative stress, insulin resistance, inflammation, and dietary habits are all closely related to the pathogenesis of NAFLD and AFLD. However, the mechanism that promotes disease progression has not been fully elucidated. Meanwhile, the gut microbiota and their metabolites also play an important role in the pathogenesis and development of NAFLD and AFLD. This article comparatively reviewed the shared and specific signaling pathways, clinical trials, and potential intervention effectors of NAFLD and AFLD, revealing their similarities and differences. By comparing the shared and specific molecular regulatory mechanisms, this paper provides mutual reference strategies for preventing and treating NAFLD, AFLD, and related metabolic diseases. Furthermore, it provides enlightenment for discovering novel therapies of safe and effective drugs targeting the metabolic liver disease.
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Affiliation(s)
- Pengyi Zhang
- School of Sports and Health, Shandong Sport University, Jinan, China
| | - Weiya Wang
- School of Sports and Health, Shandong Sport University, Jinan, China.,Shandong Academy of Pharmaceutical Science, Jinan, China
| | - Min Mao
- Department of Allied Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Ruolin Gao
- School of Sports and Health, Shandong Sport University, Jinan, China
| | - Wenting Shi
- School of Sports and Health, Shandong Sport University, Jinan, China
| | - Dongmei Li
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Richard Calderone
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bo Sui
- School of Sports and Health, Shandong Sport University, Jinan, China
| | - Xuewen Tian
- School of Sports and Health, Shandong Sport University, Jinan, China
| | - Xiangjing Meng
- Shandong Academy of Pharmaceutical Science, Jinan, China
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Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases. Int J Mol Sci 2021; 22:ijms22136949. [PMID: 34203309 PMCID: PMC8268967 DOI: 10.3390/ijms22136949] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/19/2021] [Accepted: 06/25/2021] [Indexed: 12/16/2022] Open
Abstract
The prevalence of NAFLD (non-alcoholic fatty liver disease) is a rapidly increasing problem, affecting a huge population around the globe. However, CVDs (cardiovascular diseases) are the most common cause of mortality in NAFLD patients. Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense LDL (low-density lipoprotein) particles, and decreased HDL-C (high-density lipoprotein cholesterol) levels, is often observed in NAFLD patients. In this review, we summarize recent genetic evidence, proving the diverse nature of metabolic pathways involved in NAFLD pathogenesis. Analysis of available genetic data suggests that the altered operation of fatty-acid β-oxidation in liver mitochondria is the key process, connecting NAFLD-mediated dyslipidemia and elevated CVD risk. In addition, we discuss several NAFLD-associated genes with documented anti-atherosclerotic or cardioprotective effects, and current pharmaceutical strategies focused on both NAFLD treatment and reduction of CVD risk.
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47
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Lorthongpanich C, Charoenwongpaiboon T, Supakun P, Klaewkla M, Kheolamai P, Issaragrisil S. Fisetin Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells via the Inhibition of YAP. Antioxidants (Basel) 2021; 10:antiox10060879. [PMID: 34070903 PMCID: PMC8226865 DOI: 10.3390/antiox10060879] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/27/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are self-renewal and capable of differentiating to various functional cell types, including osteocytes, adipocytes, myoblasts, and chondrocytes. They are, therefore, regarded as a potential source for stem cell therapy. Fisetin is a bioactive flavonoid known as an active antioxidant molecule that has been reported to inhibit cell growth in various cell types. Fisetin was shown to play a role in regulating osteogenic differentiation in animal-derived MSCs; however, its molecular mechanism is not well understood. We, therefore, studied the effect of fisetin on the biological properties of human MSCs derived from chorion tissue and its role in human osteogenesis using MSCs and osteoblast-like cells (SaOs-2) as a model. We found that fisetin inhibited proliferation, migration, and osteogenic differentiation of MSCs as well as human SaOs-2 cells. Fisetin could reduce Yes-associated protein (YAP) activity, which results in downregulation of osteogenic genes and upregulation of fibroblast genes. Further analysis using molecular docking and molecular dynamics simulations suggests that fisetin occupied the hydrophobic TEAD pocket preventing YAP from associating with TEA domain (TEAD). This finding supports the potential application of flavonoids like fisetin as a protein–protein interaction disruptor and also suggesting an implication of fisetin in regulating human osteogenesis.
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Affiliation(s)
- Chanchao Lorthongpanich
- Siriraj Center of Excellence for Stem Cell Research, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (P.S.); (S.I.)
- Correspondence:
| | | | - Prapasri Supakun
- Siriraj Center of Excellence for Stem Cell Research, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (P.S.); (S.I.)
| | - Methus Klaewkla
- Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Pakpoom Kheolamai
- Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathum Thani 10120, Thailand;
| | - Surapol Issaragrisil
- Siriraj Center of Excellence for Stem Cell Research, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (P.S.); (S.I.)
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48
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Su H, Liu D, Shao J, Li Y, Wang X, Gao Q. Aging Liver: Can Exercise be a Better Way to Delay the Process than Nutritional and Pharmacological Intervention? Focus on Lipid Metabolism. Curr Pharm Des 2021; 26:4982-4991. [PMID: 32503400 DOI: 10.2174/1381612826666200605111232] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 05/18/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Nowadays, the world is facing a common problem that the population aging process is accelerating. How to delay metabolic disorders in middle-aged and elderly people, has become a hot scientific and social issue worthy of attention. The liver plays an important role in lipid metabolism, and abnormal lipid metabolism may lead to liver diseases. Exercise is an easily controlled and implemented intervention, which has attracted extensive attention in improving the health of liver lipid metabolism in the elderly. This article reviewed the body aging process, changes of lipid metabolism in the aging liver, and the mechanism and effects of different interventions on lipid metabolism in the aging liver, especially focusing on exercise intervention. METHODS A literature search was performed using PubMed-NCBI, EBSCO Host and Web of Science, and also a report from WHO. In total, 143 studies were included from 1986 to 15 February 2020. CONCLUSION Nutritional and pharmacological interventions can improve liver disorders, and nutritional interventions are less risky relatively. Exercise intervention can prevent and improve age-related liver disease, especially the best high-intensity interval training intensity and duration is expected to be one of the research directions in the future.
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Affiliation(s)
- Hao Su
- The School of Sport Science, Beijing Sport University, Beijing, China
| | - Dongsen Liu
- The School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing, China
| | - Jia Shao
- The Graduate School, Beijing Sport University, Beijing, China
| | - Yinuo Li
- The Graduate School, Beijing Sport University, Beijing, China
| | - Xiaoxia Wang
- The School of Physical Education and Art Education, Beijing Technology and Business University, Beijing, China
| | - Qi Gao
- The School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing, China
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49
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Zhang L, Yang SY, Qi-Li FR, Liu XX, Zhang WT, Peng C, Wu P, Li P, Li P, Xu X. Administration of isoliquiritigenin prevents nonalcoholic fatty liver disease through a novel IQGAP2-CREB-SIRT1 axis. Phytother Res 2021; 35:3898-3915. [PMID: 33860590 DOI: 10.1002/ptr.7101] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/09/2021] [Accepted: 03/11/2021] [Indexed: 12/27/2022]
Abstract
Isoliquiritigenin (ISO) is a flavonoid extracted from the root of licorice, which serves various biological and pharmacological functions including antiinflammatory, antioxidation, liver protection, and heart protection. However, the mechanism of its action remains elusive and the direct target proteins of ISO have not been identified so far. Through cell-based screening, we identified ISO as a potent lipid-lowering compound. ISO treatment successfully ameliorated fatty acid-induced cellular lipid accumulation and improved nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) by increasing PPARα-dependent lipid oxidation and decreasing SREBPs-dependent lipid synthesis. Both these signaling required the activation of SIRT1. Knockdown of SIRT1 resulted in the reversal of ISO beneficiary effects suggesting that the lipid-lowering activity of ISO was regulated by SIRT1 expression. To identify the direct target of ISO, limited proteolysis combined with mass spectrometry (LiP-SMap) strategy was applied and IQGAP2 was identified as the direct target for ISO in regulating lipid homeostasis. In the presence of ISO, both mRNA and protein levels of SIRT1 were increased; however, this effect was abolished by blocking IQGAP2 expression using siRNA. To explore how IQGAP2 regulated the expression level of SIRT1, proteome profiler human phospho-kinase array kit was used to reveal possible phosphorylated kinases and signaling nodes that ISO affected. We found that through phosphorylation of CREB, ISO transduced signals from IQGAP2 to upregulate SIRT1 expression. Thus, we not only demonstrated the molecular basis of ISO in regulating lipid metabolism but also exhibited for the first time a novel IQGAP2-CREB-SIRT1 axis in treating NAFLD/NASH.
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Affiliation(s)
- Li Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.,Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China
| | - Sheng-Ye Yang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Feng-Rong Qi-Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Xiao-Xiao Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Wei-Tao Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Chao Peng
- National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, China.,Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, China
| | - Ping Wu
- National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, China.,Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, China
| | - Ping Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Pingping Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaojun Xu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.,Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China
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50
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Maissan P, Mooij EJ, Barberis M. Sirtuins-Mediated System-Level Regulation of Mammalian Tissues at the Interface between Metabolism and Cell Cycle: A Systematic Review. BIOLOGY 2021; 10:194. [PMID: 33806509 PMCID: PMC7999230 DOI: 10.3390/biology10030194] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/20/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023]
Abstract
Sirtuins are a family of highly conserved NAD+-dependent proteins and this dependency links Sirtuins directly to metabolism. Sirtuins' activity has been shown to extend the lifespan of several organisms and mainly through the post-translational modification of their many target proteins, with deacetylation being the most common modification. The seven mammalian Sirtuins, SIRT1 through SIRT7, have been implicated in regulating physiological responses to metabolism and stress by acting as nutrient sensors, linking environmental and nutrient signals to mammalian metabolic homeostasis. Furthermore, mammalian Sirtuins have been implicated in playing major roles in mammalian pathophysiological conditions such as inflammation, obesity and cancer. Mammalian Sirtuins are expressed heterogeneously among different organs and tissues, and the same holds true for their substrates. Thus, the function of mammalian Sirtuins together with their substrates is expected to vary among tissues. Any therapy depending on Sirtuins could therefore have different local as well as systemic effects. Here, an introduction to processes relevant for the actions of Sirtuins, such as metabolism and cell cycle, will be followed by reasoning on the system-level function of Sirtuins and their substrates in different mammalian tissues. Their involvement in the healthy metabolism and metabolic disorders will be reviewed and critically discussed.
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Affiliation(s)
- Parcival Maissan
- Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands;
| | - Eva J. Mooij
- Systems Biology, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, Surrey, UK;
- Centre for Mathematical and Computational Biology, CMCB, University of Surrey, Guildford GU2 7XH, Surrey, UK
| | - Matteo Barberis
- Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands;
- Systems Biology, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, Surrey, UK;
- Centre for Mathematical and Computational Biology, CMCB, University of Surrey, Guildford GU2 7XH, Surrey, UK
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