Bioprotective Role of Phytocompounds Against the Pathogenesis of Non-alcoholic Fatty Liver Disease to Non-alcoholic Steatohepatitis: Unravelling Underlying Molecular Mechanisms

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.

Keywords

bioactive natural compounds - ethnomedicine - lipid metabolism - molecular targets - NAFLD - NASH

Publication History

Received: 22 December 2023

Accepted after revision: 07 March 2024

Accepted Manuscript online:
08 March 2024

Article published online:
15 April 2024

• References

• 1 Mcpherson S, Hardy T, Henderson E, Burt A, Day C, Anstee Q. Evidence of NAFLD Progression from Steatosis to Fibrosing-Steatohepatitis Using Paired Biopsies: Implications for Prognosis & Clinical Management. J Hepatol 2014; 62
• 2 Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67: 328-357
• 3 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease–Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64: 73-84
• 4 Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol 2017; 9: 715
• 5 Bikbov MM, Gilmanshin TR, Zainullin RM, Kazakbaeva GM, Iakupova EM, Fakhretdinova AA. Prevalence of non-alcoholic fatty liver disease in the Russian Ural Eye and Medical Study and the Ural Very Old Study. Sci Rep 2022; 12: 7842
• 6 Zhong F, Zhou X, Xu J, Gao L. Rodent Models of Nonalcoholic Fatty Liver Disease. Digestion 2020; 101: 522-535
• 7 Armstrong MJ, Adams LA, Canbay A, Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 2014; 59: 1174-1197
• 8 Sarkar A, Saha S, Paul A, Maji A, Roy P, Maity TK. Understanding stem cells and its pivotal role in regenerative medicine. Life Sci 2021; 273: 119270
• 9 Utzschneider KM, Kahn SE. The Role of Insulin Resistance in Nonalcoholic Fatty Liver Disease. J Clin Endocrinol Metab 2006; 91: 4753-4761
• 10 Tarantino G, Sinatti G, Citro V, Santini jr S, Balsano C. Sarcopenia, a condition shared by various diseases: can we alleviate or delay the progression?. Intern Emerg Med 2023; 18: 1887-1895
• 11 Bagherniya M, Nobili V, Blesso CN, Sahebkar A. Medicinal plants and bioactive natural compounds in the treatment of non-alcoholic fatty liver disease: A clinical review. Pharmacol Res 2018; 130: 213-240
• 12 Balato N, Napolitano M, Ayala F, Patruno C, Megna M, Tarantino G. Nonalcoholic fatty liver disease, spleen and psoriasis: New aspects of low-grade chronic inflammation. World J Gastroenterol 2015; 21: 6892-6897
• 13 Lian J, Fu J. Pioglitazone for NAFLD Patients With Prediabetes or Type 2 Diabetes Mellitus: A Meta-Analysis. Front Endocrinol 2021; 12
• 14 Bril F, Biernacki D, Kalavalapalli S, Lomonaco R, Subbarayan S, Lai J. Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial. Diabetes Care 2019; 42: dc190167
• 15 Lin C, Yu B, Chen L, Zhang Z, Ye W, Zhong H. Obeticholic Acid Induces Hepatoxicity Via FXR in the NAFLD Mice. Front Pharmacol 2022; 13
• 16 Cheng C, Li Z, Zhao X, Liao C, Quan J, Bode AM. Natural alkaloid and polyphenol compounds targeting lipid metabolism: Treatment implications in metabolic diseases. Eur J Pharmacol 2020; 870: 172922
• 17 Parthasarathy G, Revelo X, Malhi H. Pathogenesis of Nonalcoholic Steatohepatitis: An Overview. Hepatol Commun 2020; 4
• 18 Neuman MG, Cohen LB, Nanau RM. Biomarkers in Nonalcoholic Fatty Liver Disease. Can J Gastroenterol Hepatol 2014; 28: 607-618
• 19 Thibaut R, Gage M, Torra I, Chabrier G, Venteclef N, Alzaid F. Liver macrophages and inflammation in physiology and physiopathology of non‐alcoholic fatty liver disease. FEBS J 2021; 289
• 20 Shan Z, Ju C. Hepatic Macrophages in Liver Injury. Front Immunol 2020; 11
• 21 Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 2012; 18: 1028-1040
• 22 Arroyave-Ospina JC, Wu Z, Geng Y, Moshage H. Role of Oxidative Stress in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Implications for Prevention and Therapy. Antioxidants 2021; 10
• 23 Martín-Fernández M, Arroyo V, Carnicero C, Sigüenza R, Busta R, Mora N. Role of Oxidative Stress and Lipid Peroxidation in the Pathophysiology of NAFLD. Antioxidants (Basel) 2022; 11: 2217
• 24 Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res 2013; 8: 2003-2014
• 25 Mittal M, Siddiqui M, Tran KA, Pothireddy S, Malik A. Reactive Oxygen Species in Inflammation and Tissue Injury. Antioxid Redox Signal 2013; 20
• 26 Peverill W, Powell L, Skoien R. Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation. Int J Mol Sci 2014; 15: 8591-8638
• 27 Yin H, Price F, Rudnicki M. Satellite Cells and the Muscle Stem Cell Niche. Physiol Rev 2013; 93: 23-67
• 28 Basaranoglu M, Basaranoglu G, Bugianesi E. Carbohydrate intake and nonalcoholic fatty liver disease: Fructose as a weapon of mass destruction. Hepatobiliary Surg Nutr 2015; 4: 109-116
• 29 Valdes P, Cuevas-Ramos D, Aguilar-Salinas C. Metabolic syndrome and non-alcoholic fatty liver disease. Annals Hepatol 2009; 8. Suppl1:S18-24
• 30 Listenberger LL, Han X, Lewis SE, Cases S, Farese RV, Ory DS. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 2003; 100: 3077-3082
• 31 Bianco C, Casirati E, Malvestiti F, Valenti L. Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets. JHEP Rep 2021; 3: 100284
• 32 Dabravolski S, Bezsonov E, Baig M, Popkova T, Orekhov A. Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases. Int J Mol Sci 2021; 22: 6949
• 33 Herzig S, Shaw R. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 2017; 19
• 34 Fabbrini E, Sullivan S, Klein S. Obesity and Nonalcoholic Fatty Liver Disease: Biochemical, Metabolic, and Clinical Implications. Hepatology 2010; 51: 679-689
• 35 Ibrahim S, Hirsova P, Gores G. Non-alcoholic steatohepatitis pathogenesis: Sublethal hepatocyte injury as a driver of liver inflammation. Gut 2018; 67: gutjnl-2017
• 36 Zhang C-Y, Yuan W-G, He P, Lei J-H, Wang C-X. Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets. World J Gastroenterol 2016; 22: 10512
• 37 Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002; 35: 373-379
• 38 Zhang C, Zhou B, Sheng J, Chen Y, Cao Y, Chen C. Molecular mechanisms of hepatic insulin resistance in nonalcoholic fatty liver disease and potential treatment strategies. Pharmacol Res 2020; 159: 104984
• 39 Sarkar A, Saha R, Saha S, Bhowmik R, Chatterjee A, Paul A. Transesterification, GC-MS profiling, and in vitro antimicrobial potential of oil obtained from seeds of Citrus maxima (Burm.) Merr. Ind Crops Prod 2022; 189: 115764
• 40 Sarkar A, Banerjee T, Maji A, Paul A, Guria T. Mikania Species: Revealing Phytochemicals from the Pandoraʼs Box. In: Chakraborty R, Sen S, editors New Avenues in Drug Discovery and Bioactive Natural Products. BENTHAM SCIENCE PUBLISHERS; 2023: 149-167
• 41 Sarkar S, Kar A, Shaw P, DasGupta B, Keithellakpam OS, Mukherjee PK, Bhardwaj PK, Sharma N, Haldar PK, Sinha S. Hydroalcoholic root extracts of Houttuynia cordata (Thunb.) standardized by UPLC-Q-TOF-MS/MS promotes apoptosis in human hepatocarcinoma cell HepG2 via GSK-3β/β-catenin/PDL-1 axis. Fitoterapia 2023; 171: 105684
• 42 Tarantino G, Balsano C, Santini SJ, Brienza G, Clemente I, Cosimini B, Sinatti G. It Is High Time Physicians Thought of Natural Products for Alleviating NAFLD. Is There Sufficient Evidence to Use Them?. Int J Mol Sci 2021; 22: 13424
• 43 Zheng X, Wu F, Lin X, Shen L, Feng Y. Developments in drug delivery of bioactive alkaloids derived from traditional Chinese medicine. Drug Deliv 2018; 25: 398-416
• 44 Yang Y, Vong CT, Zeng S, Gao C, Chen Z, Fu C. Tracking evidences of Coptis chinensis for the treatment of inflammatory bowel disease from pharmacological, pharmacokinetic to clinical studies. J Ethnopharmacol 2021; 268: 113573
• 45 Zhang Y, Ma J, Zhang W. Berberine for bone regeneration: Therapeutic potential and molecular mechanisms. J Ethnopharmacol 2021; 277: 114249
• 46 Guo T, Woo S-L, Guo X, Li H, Zheng J, Botchlett R. Berberine Ameliorates Hepatic Steatosis and Suppresses Liver and Adipose Tissue Inflammation in Mice with Diet-induced Obesity. Sci Rep 2016; 6: 22612
• 47 Li Y, Zhao X, Feng X, Liu X, Deng C, Hu C-H. Berberine Alleviates Olanzapine-Induced Adipogenesis via the AMPKα–SREBP Pathway in 3 T3-L1 Cells. Int J Mol Sci 2016; 17
• 48 Shan M, Dai Y, Ren X, Zheng J, Zhang K, Chen B. Berberine mitigates nonalcoholic hepatic steatosis by downregulating SIRT1-FoxO1-SREBP2 pathway for cholesterol synthesis. J Integr Med 2021; 19: 545-554
• 49 Liang H, Wang Y. Berberine alleviates hepatic lipid accumulation by increasing ABCA1 through the protein kinase C δ pathway. Biochem Biophys Res Commun 2018; 498: 473-480
• 50 Chang X, Wang Z, Zhang J, Yan H, Bian H, Xia M. Lipid profiling of the therapeutic effects of berberine in patients with nonalcoholic fatty liver disease. J Transl Med 2016; 14: 266
• 51 Day CR, Kempson SA. Betaine chemistry, roles, and potential use in liver disease. Biochim Biophys Acta 2016; 1860: 1098-1106
• 52 Deminice R, da Silva RP, Lamarre SG, Kelly KB, Jacobs RL, Brosnan ME. Betaine supplementation prevents fatty liver induced by a high-fat diet: effects on one-carbon metabolism. Amino Acids 2015; 47: 839-846
• 53 Xu G, Huang K, Zhou J. Hepatic AMP Kinase as a Potential Target for Treating Nonalcoholic Fatty Liver Disease: Evidence from Studies of Natural Products. Curr Med Chem 2018; 25: 889-907
• 54 Kim DH, Lee B, Kim MJ, Park MH, An HJ, Lee EK. Molecular Mechanism of Betaine on Hepatic Lipid Metabolism: Inhibition of Forkhead Box O1 (FoxO1) Binding to Peroxisome Proliferator-Activated Receptor Gamma (PPARγ). J Agric Food Chem 2016; 64: 6819-6825
• 55 Wang L, Chen L, Tan Y, Wei J, Chang Y, Jin T. Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter. Lipids Health Dis 2013; 12: 34
• 56 Xu L, Huang D, Hu Q, Wu J, Wang Y, Feng J. Betaine alleviates hepatic lipid accumulation via enhancing hepatic lipid export and fatty acid oxidation in rats fed with a high-fat diet. Br J Nutr 2015; 113: 1835-1843
• 57 Liu W, Yi D-D, Guo J-L, Xiang Z-X, Deng L-F, He L. Nuciferine, extracted from Nelumbo nucifera Gaertn, inhibits tumor-promoting effect of nicotine involving Wnt/β-catenin signaling in non-small cell lung cancer. J Ethnopharmacol 2015; 165: 83-93
• 58 Lu Y, He Y, Wang M, Zhang L, Yang L, Wang Z. Characterization of nuciferine metabolism by P450 enzymes and uridine diphosphate glucuronosyltransferases in liver microsomes from humans and animals. Acta Pharmacol Sin 2010; 31: 1635-1642
• 59 Ma C, Li G, He Y, Xu B, Mi X, Wang H. Pronuciferine and nuciferine inhibit lipogenesis in 3 T3-L1 adipocytes by activating the AMPK signaling pathway. Life Sci 2015; 136: 120-125
• 60 Zhang C, Deng J, Liu D, Tuo X, Xiao L, Lai B. Nuciferine ameliorates hepatic steatosis in high-fat diet/streptozocin-induced diabetic mice through PPARα/PGC1α pathway. Br J Pharmacol 2018; 175
• 61 Guo F, Yang X, Li X, Feng R, Guan C, Wang Y. Nuciferine Prevents Hepatic Steatosis and Injury Induced by a High-Fat Diet in Hamsters. PloS one 2013; 8: e63770
• 62 Gong X, Gao Y, Guo G, Vondran FWR, Schwartlander R, Efimova E. Effect of matrine on primary human hepatocytes in vitro. Cytotechnology 2015; 67: 255-265
• 63 Liu Z, Zhang Y, Tang Z, Xu J, Ma M, Pan S. Matrine attenuates cardiac fibrosis by affecting ATF6 signaling pathway in diabetic cardiomyopathy. Eur J Pharmacol 2017; 804: 21-30
• 64 Liu J, Zhao Y, Xia J, Qiu M. Matrine induces toxicity in mouse liver cells through an ROS-dependent mechanism. Res Vet Sci 2020; 132: 308-311
• 65 Zhang H-F, Shi L-J, Song G-Y, Cai Z-G, Wang C, An R-J. Protective effects of matrine against progression of high-fructose diet-induced steatohepatitis by enhancing antioxidant and anti-inflammatory defences involving Nrf2 translocation. Food Chem Toxicol 2013; 55: 70-77
• 66 Zeng X-Y, Wang H, Bai F, Zhou X, Li S-P, Ren L-P. Identification of matrine as a promising novel drug for hepatic steatosis and glucose intolerance with HSP72 as an upstream target. Br J Pharmacol 2015; 172: 4303-4318
• 67 Mahzari A, Li S, Zhou X, Li D, Fouda S, Alhomrani M. Matrine Protects Against MCD-Induced Development of NASH via Upregulating HSP72 and Downregulating mTOR in a Manner Distinctive From Metformin. Front Pharmacol 2019; 10
• 68 Fei Z-W, Qiu M-K, Qi X-Q, Dai Y-X, Wang S-Q, Quan Z-W. Oxymatrine suppresses proliferation and induces apoptosis of hemangioma cells through inhibition of HIF-1a signaling. Int J Immunopathol Pharmacol 2015; 28: 201-208
• 69 Shi L, Shi L, Zhang H, Hu Z, Wang C, Zhang D. Oxymatrine ameliorates non-alcoholic fatty liver disease in rats through peroxisome proliferator-activated receptor-α activation. Mol Med Rep 2013; 8: 439-445
• 70 Shi L, Shi L, Zhang H, Hu Z, Wang C, Zhang D. Oxymatrine ameliorates non-alcoholic fatty liver disease in rats through peroxisome proliferator-activated receptor-α activation. Mol Med Rep 2013; 8
• 71 Derosa G, Maffioli P, Sahebkar A. Piperine and Its Role in Chronic Diseases. In: Gupta SC, Prasad S, Aggarwal BB, editors Anti-inflammatory Nutraceuticals and Chronic Diseases. Cham: Springer International Publishing; 2016: 173-184
• 72 Park U-H, Jeong H-S, Jo E-Y, Park T, Yoon SK, Kim E-J. Piperine, a Component of Black Pepper, Inhibits Adipogenesis by Antagonizing PPARγ Activity in 3 T3-L1 Cells. J Agric Food Chem 2012; 60: 3853-3860
• 73 Kim KJ, Lee M-S, Jo K, Hwang J-K. Piperidine alkaloids from Piper retrofractum Vahl. protect against high-fat diet-induced obesity by regulating lipid metabolism and activating AMP-activated protein kinase. Biochem Biophys Res Commun 2011; 411: 219-225
• 74 Zhou J, Chan L, Zhou S. Trigonelline: A Plant Alkaloid with Therapeutic Potential for Diabetes and Central Nervous System Disease. Curr Med Chem 2012; 19: 3523-3531
• 75 Zia T, Hasnain SN, Hasan SK. Evaluation of the oral hypoglycaemic effect of Trigonella foenum-graecum L. (methi) in normal mice. J Ethnopharmacol 2001; 75: 191-195
• 76 Ilavenil S, Arasu MV, Lee J-C, Kim DH, Roh SG, Park HS. Trigonelline attenuates the adipocyte differentiation and lipid accumulation in 3 T3-L1 cells. Phytomedicine 2014; 21: 758-765
• 77 Zhang D-F, Zhang F, Zhang J, Zhang R-M, Li R. Protection effect of trigonelline on liver of rats with non-alcoholic fatty liver diseases. Asian Pac J Trop Med 2015; 8: 651-654
• 78 Song C-Y, Zeng X, Chen S-W, Hu P-F, Zheng Z-W, Ning B-F. Sophocarpine alleviates non-alcoholic steatohepatitis in rats. J Gastroenterol Hepatol 2011; 26: 765-774
• 79 Song C-Y, Shi J, Zeng X, Zhang Y, Xie W-F, Chen Y-X. Sophocarpine alleviates hepatocyte steatosis through activating AMPK signaling pathway. Toxicol In Vitro 2013; 27: 1065-1071
• 80 Lee W-Y, Lee C-Y, Lee J-S, Kim C-E. Identifying Candidate Flavonoids for Non-Alcoholic Fatty Liver Disease by Network-Based Strategy. Front Pharmacol 2022; 13
• 81 Wei D, Zhang G, Zhu Z, Zheng Y, Yan F, Pan C. Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells. Front Pharmacol 2019; 10
• 82 Yuk T, Kim Y, Yang J, Sung J, Jeong HS, Lee J. Nobiletin Inhibits Hepatic Lipogenesis via Activation of AMP-Activated Protein Kinase. Evid Based Complement Alternat Med 2018; 2018: 7420265
• 83 Bunbupha S, Pakdeechote P, Maneesai P, Prasarttong P. Nobiletin alleviates high-fat diet-induced nonalcoholic fatty liver disease by modulating AdipoR1 and gp91phox expression in rats. J Nutr Biochem 2021; 87: 108526
• 84 Peng Z, Li X, Xing D, Du X, Wang Z, Liu G. Nobiletin alleviates palmitic acid-induced NLRP3 inflammasome activation in a sirtuin 1-dependent manner in AML-12 cells. Mol Med Rep 2018; 18: 5815-5822
• 85 Liu D, Mao Y, Ding L, Zeng X-A. Dihydromyricetin: A review on identification and quantification methods, biological activities, chemical stability, metabolism and approaches to enhance its bioavailability. Trends Food Sci Technol 2019; 91: 586-597
• 86 Xie C, Chen Z, Zhang C, Xu X, Jin J, Zhan W. Dihydromyricetin ameliorates oleic acid-induced lipid accumulation in L02 and HepG2 cells by inhibiting lipogenesis and oxidative stress. Life Sci 2016; 157: 131-139
• 87 Zeng X, Yang J, Hu O, Huang J, Ran L, Chen M. Dihydromyricetin Ameliorates Nonalcoholic Fatty Liver Disease by Improving Mitochondrial Respiratory Capacity and Redox Homeostasis Through Modulation of SIRT3 Signaling. Antioxid Redox Signal 2019; 30: 163-183
• 88 Guo L, Zhang H, Yan X. Protective effect of dihydromyricetin revents fatty liver through nuclear factor-κB/p 53/B-cell lymphoma 2-associated X protein signaling pathways in a rat model. Mol Med Rep 2019; 19: 1638-1644
• 89 Ganeshpurkar A, Saluja AK. The Pharmacological Potential of Rutin. Saudi Pharm J 2017; 25: 149-164
• 90 Liu Q, Pan R, Ding L, Zhang F, Hu L, Ding B. Rutin exhibits hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease by reducing hepatic lipid levels and mitigating lipid-induced oxidative injuries. Int Immunopharmacol 2017; 49: 132-141
• 91 Panchal SK, Poudyal H, Arumugam TV, Brown L. Rutin Attenuates Metabolic Changes, Nonalcoholic Steatohepatitis, and Cardiovascular Remodeling in High-Carbohydrate, High-Fat Diet-Fed Rats. J Nutr 2011; 141: 1062-1069
• 92 Sarkar A, Paul A, Banerjee T, Maji A, Saha S, Bishayee A. Therapeutic advancements in targeting BCL-2 family proteins by epigenetic regulators, natural, and synthetic agents in cancer. Eur J Pharmacol 2023; 944: 175588
• 93 Hernández-Aquino E, Muriel P. Beneficial effects of naringenin in liver diseases: Molecular mechanisms. World J Gastroenterol 2018; 24: 1679-1707
• 94 Zobeiri M, Belwal T, Parvizi F, Naseri R, Farzaei HM, Nabavi FS. Naringenin and its Nano-formulations for Fatty Liver: Cellular Modes of Action and Clinical Perspective. Curr Pharm Biotechnol 2018; 19: 196-205
• 95 Wang Q, Ou Y, Hu G, Wen C, Yue S, Chen C. Naringenin attenuates non-alcoholic fatty liver disease by down-regulating the NLRP3/NF-κB pathway in mice. Br J Pharmacol 2020; 177: 1806-1821
• 96 Chang H-H, Yi P-L, Cheng C-H, Lu C-Y, Hsiao Y-T, Tsai Y-F. Biphasic effects of baicalin, an active constituent of Scutellaria baicalensis Georgi, in the spontaneous sleep–wake regulation. J Ethnopharmacol 2011; 135: 359-368
• 97 Liu J, Yuan Y, Gong X, Zhang L, Zhou Q, Wu S. Baicalin and its nanoliposomes ameliorates nonalcoholic fatty liver disease via suppression of TLR4 signaling cascade in mice. Int Immunopharmacol 2020; 80: 106208
• 98 Hu Q, Zhang W, Wu Z, Tian X, Xiang J, Li L. Baicalin and the liver-gut system: Pharmacological bases explaining its therapeutic effects. Pharmacol Res 2021; 165: 105444
• 99 Zhong X, Liu H. Baicalin attenuates diet induced nonalcoholic steatohepatitis by inhibiting inflammation and oxidative stress via suppressing JNK signaling pathways. Biomed Pharmacother 2018; 98: 111-117
• 100 Banerjee R, Dasgupta B, Kar A, Bhardwaj PK, Sharma N, Haldar PK. Quality evaluation of different black rice varieties of northeastern region of India. Phytochem Anal 2023; 34: 507-517
• 101 Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S. Quercetin, Inflammation and Immunity. Nutrients 2016; 8
• 102 Yang H, Yang T, Heng C, Zhou Y, Jiang Z, Qian X. Quercetin improves nonalcoholic fatty liver by ameliorating inflammation, oxidative stress, and lipid metabolism in db/db mice. Phytother Res 2019; 33: 3140-3152
• 103 Yi H, Peng H, Wu X, Xu X, Kuang T, Zhang J. The Therapeutic Effects and Mechanisms of Quercetin on Metabolic Diseases: Pharmacological Data and Clinical Evidence. Oxid Med Cell Longev 2021; 2021: 6678662
• 104 Liu L, Gao C, Yao P, Gong Z. Quercetin Alleviates High-Fat Diet-Induced Oxidized Low-Density Lipoprotein Accumulation in the Liver: Implication for Autophagy Regulation. Biomed Res Int 2015; 2015: 607531
• 105 Lin Y, Shi R, Wang X, Shen H-M. Luteolin, a Flavonoid with Potential for Cancer Prevention and Therapy. Curr Cancer Drug Targets 2008; 8: 634-646
• 106 Liu X, Sun R, Li Z, Xiao R, Lv P, Sun X. Luteolin alleviates non-alcoholic fatty liver disease in rats via restoration of intestinal mucosal barrier damage and microbiota imbalance involving in gut-liver axis. Arch Biochem Biophys 2021; 711: 109019
• 107 Yin Y, Gao L, Lin H, Wu Y, Han X, Zhu Y. Luteolin improves non-alcoholic fatty liver disease in db/db mice by inhibition of liver X receptor activation to down-regulate expression of sterol regulatory element binding protein 1c. Biochem Biophys Res Commun 2017; 482: 720-726
• 108 Chen R, Chen X, Zhu T, Liu J, Xiang X, Yu J. Integrated Transcript and Metabolite Profiles Reveal That EbCHI Plays an Important Role in Scutellarin Accumulation in Erigeron breviscapus Hairy Roots. Front Plant Sci 2018; 9
• 109 Hua Fan, Xiande Ma, Peng Lin, Qiang Kang, Zhilong Zhao, Lina Wang. Scutellarin Prevents Nonalcoholic Fatty Liver Disease (NAFLD) and Hyperlipidemia via PI3K/AKT-Dependent Activation of Nuclear Factor (Erythroid-Derived 2)-Like 2 (Nrf2) in Rats. Med Sci Monit 2017; 23: 5599-5612
• 110 Zhang X, Ji R, Sun H, Peng J, Ma X, Wang C. Scutellarin ameliorates nonalcoholic fatty liver disease through the PPARγ/PGC-1α-Nrf2 pathway. Free Radic Res 2018; 52: 198-211
• 111 Xin X, Chen C, Hu Y-Y, Feng Q. Protective effect of genistein on nonalcoholic fatty liver disease (NAFLD). Biomed Pharmacother 2019; 117: 109047
• 112 Wang W, Chen J, Mao J, Li H, Wang M, Zhang H. Genistein Ameliorates Non-alcoholic Fatty Liver Disease by Targeting the Thromboxane A2 Pathway. J Agric Food Chem 2018; 66: 5853-5859
• 113 Seidemann L, Krüger A, Kegel-Hübner V, Seehofer D, Damm G. Influence of Genistein on Hepatic Lipid Metabolism in an In Vitro Model of Hepatic Steatosis. Molecules 2021; 26
• 114 Khan N, Syed DN, Ahmad N, Mukhtar H. Fisetin: A Dietary Antioxidant for Health Promotion. Antioxid Redox Signal 2013; 19: 151-162
• 115 Liou C-J, Wei C-H, Chen Y-L, Cheng C-Y, Wang C-L, Huang W-C. Fisetin Protects Against Hepatic Steatosis Through Regulation of the Sirt1/AMPK and Fatty Acid β-Oxidation Signaling Pathway in High-Fat Diet-Induced Obese Mice. Cell Physiol Biochem 2018; 49: 1870-1884
• 116 Dai X, Kuang Q, Sun Y, Xu M, Zhu L, Ge C. Fisetin represses oxidative stress and mitochondrial dysfunction in NAFLD through suppressing GRP78-mediated endoplasmic reticulum (ER) stress. J Funct Foods 2022; 90: 104954
• 117 Gaballah HH, El-Horany HE, Helal DS. Mitigative effects of the bioactive flavonol fisetin on high-fat/high-sucrose induced nonalcoholic fatty liver disease in rats. J Cell Biochem 2019; 120: 12762-12774
• 118 Brito-Arias M. Synthesis and Characterization of Glycosides. 2007
• 119 Leong XY, Thanikachalam PV, Pandey M, Ramamurthy S. A systematic review of the protective role of swertiamarin in cardiac and metabolic diseases. Biomed Pharmacother 2016; 84: 1051-1060
• 120 Patel TP, Rawal K, Soni S, Gupta S. Swertiamarin ameliorates oleic acid induced lipid accumulation and oxidative stress by attenuating gluconeogenesis and lipogenesis in hepatic steatosis. Biomed Pharmacother 2016; 83: 785-791
• 121 Xu L, Li D, Zhu Y, Cai S, Liang X, Tang Y. Swertiamarin supplementation prevents obesity-related chronic inflammation and insulin resistance in mice fed a high-fat diet. Adipocyte 2021; 10: 160-173
• 122 Yang Y, Li J, Wei C, He Y, Cao Y, Zhang Y. Amelioration of nonalcoholic fatty liver disease by swertiamarin in fructose-fed mice. Phytomedicine 2019; 59: 152782
• 123 Wang J, Chen X, Wang W, Zhang Y, Yang Z, Jin Y. Glycyrrhizic acid as the antiviral component of Glycyrrhiza uralensis Fisch. against coxsackievirus A16 and enterovirus 71 of hand foot and mouth disease. J Ethnopharmacol 2013; 147: 114-121
• 124 Sun X, Duan X, Wang C, Liu Z, Sun P, Huo X. Protective effects of glycyrrhizic acid against non-alcoholic fatty liver disease in mice. Eur J Pharmacol 2017; 806: 75-82
• 125 Wang C, Duan X, Sun X, Liu Z, Sun P, Yang X. Protective effects of glycyrrhizic acid from edible botanical glycyrrhiza glabra against non-alcoholic steatohepatitis in mice. Food Funct 2016; 7: 3716-3723
• 126 Nabavi SF, Braidy N, Orhan IE, Badiee A, Daglia M, Nabavi SM. Rhodiola rosea L. and Alzheimerʼs Disease: From Farm to Pharmacy. Phytother Res 2016; 30: 532-539
• 127 Dou X, Ding Q, Lai S, Jiang F, Song Q, Zhao X. Salidroside alleviates lipotoxicity-induced cell death through inhibition of TLR4/MAPKs pathway, and independently of AMPK and autophagy in AML-12 mouse hepatocytes. J Funct Foods 2020; 65: 103691
• 128 Zheng T, Yang X, Li W, Wang Q, Chen L, Wu D. Salidroside Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease via AMPK-Dependent TXNIP/NLRP3 Pathway. Oxid Med Cell Longev 2018; 2018: 8597897
• 129 Li H, Ying H, Hu A, Li D, Hu Y. Salidroside Modulates Insulin Signaling in a Rat Model of Nonalcoholic Steatohepatitis. Evid Based Complement Alternat Med 2017; 2017: 9651371
• 130 Hung J-Y, Hsu Y-L, Ko Y-C, Tsai Y-M, Yang C-J, Huang M-S. Didymin, a dietary flavonoid glycoside from citrus fruits, induces Fas-mediated apoptotic pathway in human non-small-cell lung cancer cells in vitro and in vivo. Lung Cancer 2010; 68: 366-374
• 131 Yao Q, Lin M-T, Zhu Y-D, Xu H-L, Zhao Y-Z. Recent Trends in Potential Therapeutic Applications of the Dietary Flavonoid Didymin. Molecules 2018; 23
• 132 Feng Z, Pang L, Chen S, Pang X, Huang Y, Qiao Q. Didymin ameliorates dexamethasone-induced non-alcoholic fatty liver disease by inhibiting TLR4/NF-κB and PI3K/Akt pathways in C57BL/6 J mice. Int Immunopharmacol 2020; 88: 107003
• 133 Li Y, Li C, Xiong Y, Fang B, Lin X, Huang Q. Didymin Ameliorates Liver Fibrosis by Alleviating Endoplasmic Reticulum Stress and Glycerophospholipid Metabolism: Based on Transcriptomics and Metabolomics. Drug Des Devel Ther 2022; 16: 1713-1729
• 134 Tanase C, Coşarcă S, Muntean DL. A Critical Review of Phenolic Compounds Extracted from the Bark of Woody Vascular Plants and Their Potential Biological Activity. Molecules 2019; 24: 1182
• 135 Ganesan K, Xu B. A Critical Review on Polyphenols and Health Benefits of Black Soybeans. Nutrients 2017; 9: 455
• 136 Muruganandan S, Srinivasan K, Gupta S, Gupta PK, Lal J. Effect of mangiferin on hyperglycemia and atherogenicity in streptozotocin diabetic rats. J Ethnopharmacol 2005; 97: 497-501
• 137 Du S, Liu H, Lei T, Xie X, Wang H, He X. Mangiferin: An effective therapeutic agent against several disorders (Review). Mol Med Rep 2018; 18: 4775-4786
• 138 Yong Z, Ruiqi W, Hongji Y, Ning M, Chenzuo J, Yu Z. Mangiferin Ameliorates HFD-Induced NAFLD through Regulation of the AMPK and NLRP3 Inflammasome Signal Pathways. J Immunol Res 2021; 2021: 4084566
• 139 Wang H, Zhu Y-Y, Wang L, Teng T, Zhou M, Wang S-G. Mangiferin ameliorates fatty liver via modulation of autophagy and inflammation in high-fat-diet induced mice. Biomed Pharmacother 2017; 96: 328-335
• 140 Guo F, Huang C, Liao X, Wang Y, He Y, Feng R. Beneficial effects of mangiferin on hyperlipidemia in high-fat-fed hamsters. Mol Nutr Food Res 2011; 55: 1809-1818
• 141 Koushki M, Amiri-Dashatan N, Ahmadi N, Abbaszadeh HA, Rezaei-Tavirani M. Resveratrol: A miraculous natural compound for diseases treatment. Food Sci Nutr 2018; 6: 2473-2490
• 142 Tang LY, Chen Y, Rui BB, Hu CM. Resveratrol ameliorates lipid accumulation in HepG2 cells, associated with down-regulation of lipin1 expression. Can J Physiol Pharmacol 2016; 94: 185-189
• 143 Du F, Huang R, Lin D, Wang Y, Yang X, Huang X. Resveratrol Improves Liver Steatosis and Insulin Resistance in Non-alcoholic Fatty Liver Disease in Association With the Gut Microbiota. Front Microbiol 2021; 12
• 144 Ran G, Ying L, Li L, Yan Q, Yi W, Ying C. Resveratrol ameliorates diet-induced dysregulation of lipid metabolism in zebrafish (Danio rerio). PLOS ONE 2017; 12: e0180865
• 145 Booker A, Frommenwiler D, Johnston D, Umealajekwu C, Reich E, Heinrich M. Chemical variability along the value chains of turmeric (Curcuma longa): A comparison of nuclear magnetic resonance spectroscopy and high performance thin layer chromatography. J Ethnopharmacol 2014; 152: 292-301
• 146 Ghosh S, Banerjee S, Sil PC. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update. Food Chem Toxicol 2015; 83: 111-124
• 147 Lee DE, Lee SJ, Kim SJ, Lee HS, Kwon OS. Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of O-GlcNAcylation. Nutrients 2019; 11
• 148 Feng W, Kuang S, Tu C, Ma Z, Pang J, Wang Y. Natural products berberine and curcumin exhibited better ameliorative effects on rats with non-alcohol fatty liver disease than lovastatin. Biomed Pharmacother 2018; 99: 325-333
• 149 Kang O, Kim S, Seo Y, Joung D, Mun S, Choi J. Curcumin decreases oleic acid-induced lipid accumulation via AMPK phosphorylation in hepatocarcinoma cells. Eur Rev Med Pharmacol Sci 2013; 17: 2578-2586
• 150 Saadati S, Sadeghi A, Mansour A, Yari Z, Poustchi H, Hedayati M. Curcumin and inflammation in non-alcoholic fatty liver disease: a randomized, placebo controlled clinical trial. BMC Gastroenterol 2019; 19: 133
• 151 Xiao J, Ho CT, Liong EC, Nanji AA, Leung TM, Lau TYH. Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways. Eur J Nutr 2014; 53: 187-199
• 152 Kim JJY, Tan Y, Xiao L, Sun YL, Qu X. Green Tea Polyphenol Epigallocatechin-3-Gallate Enhance Glycogen Synthesis and Inhibit Lipogenesis in Hepatocytes. Biomed Res Int 2013; 2013: 920128
• 153 Huang J, Feng S, Liu A, Dai Z, Wang H, Reuhl K. Green Tea Polyphenol EGCG Alleviates Metabolic Abnormality and Fatty Liver by Decreasing Bile Acid and Lipid Absorption in Mice. Mol Nutr Food Res 2018; 62: 1700696
• 154 Vilaplana-Pérez C, Auñón D, García-Flores LA, Gil-Izquierdo A. Hydroxytyrosol and Potential Uses in Cardiovascular Diseases, Cancer, and AIDS. Front Nutr 2014; 1
• 155 Pirozzi C, Lama A, Simeoli R, Paciello O, Pagano TB, Mollica MP. Hydroxytyrosol prevents metabolic impairment reducing hepatic inflammation and restoring duodenal integrity in a rat model of NAFLD. J Nutr Biochem 2016; 30: 108-115
• 156 Valenzuela R, Illesca P, Echeverría F, Espinosa A, Rincón-Cervera MÁ, Ortiz M. Molecular adaptations underlying the beneficial effects of hydroxytyrosol in the pathogenic alterations induced by a high-fat diet in mouse liver: PPAR-α and Nrf2 activation, and NF-κB down-regulation. Food Funct 2017; 8: 1526-1537
• 157 Dong Y, Yu M, Wu Y, Xia T, Wang L, Song K. Hydroxytyrosol Promotes the Mitochondrial Function through Activating Mitophagy. Antioxidants 2022; 11
• 158 Hitl M, Kladar N, Gavarić N, Bozin B. Rosmarinic Acid–Human Pharmacokinetics and Health Benefits. Planta Med 2020; 87: 273-282
• 159 Balachander GJ, Subramanian S, Ilango K. Rosmarinic acid attenuates hepatic steatosis by modulating ER stress and autophagy in oleic acid-induced HepG2 cells. RSC Adv 2018; 8: 26656-26663
• 160 Luo C, Sun H, Peng J, Gao C, Bao L, Ji R. Rosmarinic acid exerts an antagonistic effect on nonalcoholic fatty liver disease by regulating the YAP1/TAZ-PPARγ/PGC-1α signaling pathway. Phytother Res 2021; 35: 1010-1022
• 161 AlTamimi JZ, Alshammari GM, AlFaris NA, Alagal RI, Aljabryn DH, Albekairi NA, Alkhateeb MA, Yahya MA. Ellagic acid protects against non-alcoholic fatty liver disease in streptozotocin-diabetic rats by activating AMPK. Pharm Biol 2022; 60: 25-37
• 162 Zhang C, Hu J, Sheng L, Yuan M, Wu Y, Chen L. Ellagic acid ameliorates AKT-driven hepatic steatosis in mice by suppressing de novo lipogenesis via the AKT/SREBP-1/FASN pathway. Food Funct 2019; 10: 3410-3420
• 163 Polce SA, Burke C, França LM, Kramer B, de Andrade Paes AM, Carrillo-Sepulveda MA. Ellagic Acid Alleviates Hepatic Oxidative Stress and Insulin Resistance in Diabetic Female Rats. Nutrients 2018; 10
• 164 Goto T, Takahashi N, Hirai S, Kawada T. Various Terpenoids Derived from Herbal and Dietary Plants Function as PPAR Modulators and Regulate Carbohydrate and Lipid Metabolism. PPAR Res 2010; 2010: 483958
• 165 Cox-Georgian D, Ramadoss N, Dona C, Basu C. Therapeutic and Medicinal Uses of Terpenes. In: Joshee N, Dhekney SA, Parajuli P. editors Medicinal Plants: From Farm to Pharmacy. Cham: Springer International Publishing; 2019: 333-359
• 166 Kazmi I, Rahman M, Afzal M, Gupta G, Saleem S, Afzal O. Anti-diabetic potential of ursolic acid stearoyl glucoside: A new triterpenic gycosidic ester from Lantana camara. Fitoterapia 2012; 83: 142-146
• 167 Peng F, Zhang H, He X, Song Z. Effects of Ursolic Acid on Intestinal Health and Gut Bacteria Antibiotic Resistance in Mice. Front Physiol 2021; 12
• 168 Li J-S, Wang W-J, Sun Y, Zhang Y-H, Zheng L. Ursolic acid inhibits the development of nonalcoholic fatty liver disease by attenuating endoplasmic reticulum stress. Food Funct 2015; 6: 1643-1651
• 169 Li S, Meng F, Liao X, Wang Y, Sun Z, Guo F. Therapeutic Role of Ursolic Acid on Ameliorating Hepatic Steatosis and Improving Metabolic Disorders in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease Rats. PLOS ONE 2014; 9: e86724
• 170 Lin Y-N, Wang CCN, Chang H-Y, Chu F-Y, Hsu Y-A, Cheng W-K. Ursolic Acid, a Novel Liver X Receptor α (LXRα) Antagonist Inhibiting Ligand-Induced Nonalcoholic Fatty Liver and Drug-Induced Lipogenesis. J Agric Food Chem 2018; 66: 11647-11662
• 171 Ayeleso TB, Matumba MG, Mukwevho E. Oleanolic Acid and Its Derivatives: Biological Activities and Therapeutic Potential in Chronic Diseases. Molecules 2017; 22
• 172 Somova LI, Shode FO, Ramnanan P, Nadar A. Antihypertensive, antiatherosclerotic and antioxidant activity of triterpenoids isolated from Olea europaea, subspecies africana leaves. J Ethnopharmacol 2003; 84: 299-305
• 173 Nyakudya TT, Mukwevho E, Nkomozepi P, Erlwanger KH. Neonatal intake of oleanolic acid attenuates the subsequent development of high fructose diet-induced non-alcoholic fatty liver disease in rats. J Dev Orig Health Dis 2018; 9: 500-510
• 174 Gamede M, Mabuza-Mashaba L, Ngubane P, Khathi A. Plant-derived oleanolic acid ameliorates markers associated with non-alcoholic fatty liver disease in a diet-induced pre-diabetes rat model. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2019;Volume 12; 1953.  –  1962
• 175 Lin Y-N, Chang H-Y, Wang CCN, Chu F-Y, Shen H-Y, Chen C-J. Oleanolic Acid Inhibits Liver X Receptor Alpha and Pregnane X Receptor to Attenuate Ligand-Induced Lipogenesis. J Agric Food Chem 2018; 66: 10964-10976
• 176 Matumba MG, Ayeleso AO, Nyakudya T, Erlwanger K, Chegou NN, Mukwevho E. Long-Term Impact of Neonatal Intake of Oleanolic Acid on the Expression of AMP-Activated Protein Kinase, Adiponectin and Inflammatory Cytokines in Rats Fed with a High Fructose Diet. Nutrients 2019; 11
• 177 Fang Z, Zhang M, Liu J, Zhao X, Zhang Y, Fang L. Tanshinone IIA: A Review of its Anticancer Effects. Front Pharmacol 2021; 11
• 178 Maione F, De Feo V, Caiazzo E, De Martino L, Cicala C, Mascolo N. Tanshinone IIA, a major component of Salvia milthorriza Bunge, inhibits platelet activation via Erk-2 signaling pathway. J Ethnopharmacol 2014; 155: 1236-1242
• 179 Huang L, Ding W, Wang M-Q, Wang Z-G, Chen H-H, Chen W. Tanshinone IIA ameliorates non-alcoholic fatty liver disease through targeting peroxisome proliferator-activated receptor gamma and toll-like receptor 4. J Int Med Res 2019; 47: 5239-5255
• 180 Xu L, Liu X, Jia T, Sun Y, Du Y, Wei S. Tanshinone IIA Ameliorates Nonalcoholic Steatohepatitis in Mice by Modulating Neutrophil Extracellular Traps and Hepatocyte Apoptosis. Evid Based Complement Alternat Med 2022; 2022: 5769350
• 181 Yang G, Jia L, Wu J, Ma Y, Cao H, Song N. Effect of tanshinone IIA on oxidative stress and apoptosis in a rat model of fatty liver. Exp Ther Med 2017; 14: 4639-4646
• 182 Li L, Liu Z, Jiang H, Mao X. Biotechnological production of lycopene by microorganisms. Appl Microbiol Biotechnol 2020; 104: 10307-10324
• 183 Róvero Costa M, Leite Garcia J, Cristina Vágula de Almeida Silva C. Junio Togneri Ferron A, Valentini Francisqueti-Ferron F, Kurokawa Hasimoto F. Lycopene Modulates Pathophysiological Processes of Non-Alcoholic Fatty Liver Disease in Obese Rats. Antioxidants 2019; 8
• 184 Jiang W, Guo M-H, Hai X. Hepatoprotective and antioxidant effects of lycopene on non-alcoholic fatty liver disease in rat. World J Gastroenterol 2016; 22: 10180
• 185 Wang J, Geng T, Zou Q, Yang N, Zhao W, Li Y. Lycopene prevents lipid accumulation in hepatocytes by stimulating PPARα and improving mitochondrial function. J Funct Foods 2020; 67: 103857
• 186 Peng J, Yuan J-P, Wu C-F, Wang J-H. Fucoxanthin, a Marine Carotenoid Present in Brown Seaweeds and Diatoms: Metabolism and Bioactivities Relevant to Human Health. Mar Drugs 2011; 9: 1806-1828
• 187 Takatani N, Kono Y, Beppu F, Okamatsu-Ogura Y, Yamano Y, Miyashita K. Fucoxanthin inhibits hepatic oxidative stress, inflammation, and fibrosis in diet-induced nonalcoholic steatohepatitis model mice. Biochem Biophys Res Commun 2020; 528: 305-310
• 188 Ye J, Zheng J, Tian X, Xu B, Yuan F, Wang B. Fucoxanthin Attenuates Free Fatty Acid-Induced Nonalcoholic Fatty Liver Disease by Regulating Lipid Metabolism/Oxidative Stress/Inflammation via the AMPK/Nrf2/TLR4 Signaling Pathway. Mar Drugs 2022; 20
• 189 Shrikanth CB, Nandini CD. AMPK in microvascular complications of diabetes and the beneficial effects of AMPK activators from plants. Phytomedicine 2020; 73: 152808
• 190 Mu Q, Wang H, Tong L, Fang Q, Xiang M, Han L. Betulinic acid improves nonalcoholic fatty liver disease through YY1/FAS signaling pathway. FASEB J 2020; 34: 13033-13048
• 191 Quan HY, Kim DY, Kim SJ, Jo HK, Kim GW, Chung SH. Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK–mTOR–SREBP signaling pathway. Biochem Pharmacol 2013; 85: 1330-1340
• 192 Gu M, Zhao P, Zhang S, Fan S, Yang L, Tong Q. Betulinic acid alleviates endoplasmic reticulum stress-mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice. Br J Pharmacol 2019; 176: 847-863
• 193 Smeriglio A, Barreca D, Bellocco E, Trombetta D. Proanthocyanidins and hydrolysable tannins: occurrence, dietary intake and pharmacological effects. Br J Pharmacol 2017; 174: 1244-1262
• 194 Liman MS, Hassen A, McGaw LJ, Sutovsky P, Holm DE. Potential Use of Tannin Extracts as Additives in Semen Destined for Cryopreservation: A Review. Animals 2022; 12
• 195 Baldwin A, Booth BW. Biomedical applications of tannic acid. J Biomater Appl 2022; 36: 1503-1523
• 196 Chung M-Y, Song J-H, Lee J, Shin EJ, Park JH, Lee S-H. Tannic acid, a novel histone acetyltransferase inhibitor, prevents non-alcoholic fatty liver disease both in vivo and in vitro model. Mol Metab 2019; 19: 34-48
• 197 Li M, Liu P, Xue Y, Liang Y, Shi J, Han X. Tannic acid attenuates hepatic oxidative stress, apoptosis and inflammation by activating the Keap1-Nrf2/ARE signaling pathway in arsenic trioxide-toxicated rats. Oncol Rep 2020; 44: 2306-2316
• 198 Yoon M, Kim J-S, Seo S, Lee K, Um MY, Lee J. Dieckol, a Major Marine Polyphenol, Enhances Non-Rapid Eye Movement Sleep in Mice via the GABAA-Benzodiazepine Receptor. Front Pharmacol 2020; 11
• 199 Byun K-A, Oh S, Son M, Park C-H, Son K, Byun K. Dieckol Decreases Caloric Intake and Attenuates Nonalcoholic Fatty Liver Disease and Hepatic Lymphatic Vessel Dysfunction in High-Fat-Diet-Fed Mice. Mar Drugs 2021; 19: 495
• 200 Eo H, Jeon Y, Lee M, Lim Y. Brown Alga Ecklonia cava Polyphenol Extract Ameliorates Hepatic Lipogenesis, Oxidative Stress, and Inflammation by Activation of AMPK and SIRT1 in High-Fat Diet-Induced Obese Mice. J Agric Food Chem 2015; 63: 349-359
• 201 Oh S, Son M, Byun K-A, Jang JT, Choi CH, Son KH. Attenuating Effects of Dieckol on High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease by Decreasing the NLRP3 Inflammasome and Pyroptosis. Mar Drugs 2021; 19
• 202 DellʼAgli M, Galli GV, Corbett Y, Taramelli D, Lucantoni L, Habluetzel A. Antiplasmodial activity of Punica granatum L. fruit rind. J Ethnopharmacol 2009; 125: 279-285
• 203 Feng L, Yin Y, Yang X, Tang H, Jiao Q. Dynamic Variations in Punicalagin and Related Metabolic Substances in Pomegranate Fruit and Leaves During Development Periods. Horticult J 2019; 88: 444-454
• 204 Yan C, Sun W, Wang X, Long J, Liu X, Feng Z. Punicalagin attenuates palmitate-induced lipotoxicity in HepG2 cells by activating the Keap1-Nrf2 antioxidant defense system. Mol Nutr Food Res 2016; 60: 1139-1149
• 205 Liu H, Zhan Q, Miao X, Xia X, Yang G, Peng X. Punicalagin Prevents Hepatic Steatosis through Improving Lipid Homeostasis and Inflammation in Liver and Adipose Tissue and Modulating Gut Microbiota in Western Diet-Fed Mice. Mol Nutr Food Res 2021; 65: 2001031
• 206 Zou X, Yan C, Shi Y, Cao K, Xu J, Wang X. Mitochondrial Dysfunction in Obesity-Associated Nonalcoholic Fatty Liver Disease: The Protective Effects of Pomegranate with Its Active Component Punicalagin. Antioxid Redox Signal 2014; 21: 1557-1570
• 207 Li X, Deng Y, Zheng Z, Huang W, Chen L, Tong Q. Corilagin, a promising medicinal herbal agent. Biomed Pharmacother 2018; 99: 43-50
• 208 Zhang R, Chu K, Zhao N, Wu J, Ma L, Zhu C. Corilagin Alleviates Nonalcoholic Fatty Liver Disease in High-Fat Diet-Induced C57BL/6 Mice by Ameliorating Oxidative Stress and Restoring Autophagic Flux. Front Pharmacol 2020; 10
• 209 Liao M, Zhang R, Wang Y, Mao Z, Wu J, Guo H. Corilagin prevents non-alcoholic fatty liver disease via improving lipid metabolism and glucose homeostasis in high fat diet-fed mice. Front Nutr 2022; 9
• 210 Liang L, Ye S, Jiang R, Zhou X, Zhou J, Meng S. Liensinine alleviates high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) through suppressing oxidative stress and inflammation via regulating TAK1/AMPK signaling. Int Immunopharmacol 2022; 104: 108306
• 211 Wang G-E, Li Y-F, Zhai Y-J, Gong L, Tian J-Y, Hong M. Theacrine protects against nonalcoholic fatty liver disease by regulating acylcarnitine metabolism. Metabolism 2018; 85: 227-239
• 212 Li G, Zhou F, Chen Y, Zhang W, Wang N. Kukoamine A attenuates insulin resistance and fatty liver through downregulation of Srebp-1c. Biomed Pharmacother 2017; 89: 536-543
• 213 Ohashi T, Nakade Y, Ibusuki M, Kitano R, Yamauchi T, Kimoto S. Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice. PLOS ONE 2019; 14: e0210068
• 214 Sylvester Darvin S, Toppo E, Esakkimuthu S, Ajeesh Krishna TP, Ceasar SA, Stalin A. Hepatoprotective effect of bisbenzylisoquinoline alkaloid tiliamosine from Tiliacora racemosa in high-fat diet/diethylnitrosamine-induced non-alcoholic steatohepatitis. Biomed Pharmacother 2018; 108: 963-973
• 215 Yue R, Jin G, Wei S, Huang H, Su L, Zhang C. Immunoregulatory Effect of Koumine on Nonalcoholic Fatty Liver Disease Rats. J Immunol Res 2019; 2019: 8325102
• 216 Wang LL, Zhang ZC, Hassan W, Li Y, Liu J, Shang J. Amelioration of free fatty acid-induced fatty liver by quercetin-3-O-β-D-glucuronide through modulation of peroxisome proliferator-activated receptor-alpha/sterol regulatory element-binding protein-1c signaling. Hepatol Res 2016; 46: 225-238
• 217 Park J-Y, Lim M-S, Kim S-I, Lee H, Kim S-S, Kwon Y-S. Quercetin-3-O-β-D-Glucuronide Suppresses Lipopolysaccharide-Induced JNK and ERK Phosphorylation in LPS-Challenged RAW264.7 Cells. Biomol Ther 2016; 24
• 218 Hur HJ, Jeong Y-H, Lee SH, Sung MJ. Quercitrin Ameliorates Hyperlipidemia and Hepatic Steatosis in Ovariectomized Mice. Life 2020; 10
• 219 PubChem. Quercitrin. https://pubchem.ncbi.nlm.nih.gov/compound/5280459 Accessed 29 Oct 2022
• 220 Kim JH, Lee BC, Kim JH, Sim GS, Lee DH, Lee KE. The isolation and antioxidative effects of vitexin fromAcer palmatum. Arch Pharm Res 2005; 28: 195-202
• 221 Inamdar S, Joshi A, Malik S, Boppana R, Ghaskadbi S. Vitexin alleviates non-alcoholic fatty liver disease by activating AMPK in high fat diet fed mice. Biochem Biophys Res Commun 2019; 519: 106-112
• 222 Sarkar MK, Kar A, Jayaraman A, Kar Mahapatra S, Vadivel V. Vitexin isolated from Prosopis cineraria leaves induce apoptosis in K-562 leukemia cells via inhibition of the BCR-ABL-Ras-Raf pathway. J Pharm Pharmacol 2022; 74: 103-111
• 223 Morissette M, Litim N, Paolo T. Natural Phytoestrogens: A Class of Promising Neuroprotective Agents for Parkinson Disease. In: Discovery and Development of Neuroprotective Agents from Natural Products: Natural Product Drug Discovery 2017: 9-61
• 224 Pai SA, Munshi RP, Panchal FH, Gaur I-S, Juvekar AR. Chrysin ameliorates nonalcoholic fatty liver disease in rats. Naunyn Schmiedebergs Arch Pharmacol 2019; 392: 1617-1628
• 225 Song Y, Wu W, Sheng L, Jiang B, Li X, Cai K. Chrysin ameliorates hepatic steatosis induced by a diet deficient in methionine and choline by inducing the secretion of hepatocyte nuclear factor 4α-dependent very low-density lipoprotein. J Biochem Mol Toxicol 2020; 34: e22497
• 226 Aloud AA, Chinnadurai V, Govindasamy C, Alsaif MA, Al-Numair KS. Galangin, a dietary flavonoid, ameliorates hyperglycaemia and lipid abnormalities in rats with streptozotocin-induced hyperglycaemia. Pharm Biol 2018; 56: 302-308
• 227 Zhang X, Deng Y, Xiang J, Liu H, Zhang J, Liao J. Galangin Improved Non-Alcoholic Fatty Liver Disease in Mice by Promoting Autophagy. Drug Des Devel Ther 2020; 14: 3393-3405
• 228 Hiramitsu M, Shimada Y, Kuroyanagi J, Inoue T, Katagiri T, Zang L. Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. Sci Rep 2014; 4: 3708
• 229 Kwon E-Y, Choi M-S. Eriocitrin Improves Adiposity and Related Metabolic Disorders in High-Fat Diet-Induced Obese Mice. J Med Food 2020; 23: 233-241
• 230 Karimi G, Vahabzadeh M, Lari P, Rashedinia M, Moshiri M. “Silymarin”, a Promising Pharmacological Agent for Treatment of Diseases. Iran J Basic Med Sci 2011; 14: 308-317
• 231 Salomone F, Barbagallo I, Godos J, Lembo V, Currenti W, Cinà D. Silibinin Restores NAD+ Levels and Induces the SIRT1/AMPK Pathway in Non-Alcoholic Fatty Liver. Nutrients 2017; 9
• 232 Sahin E, Bagci R, Bektur Aykanat NE, Kacar S, Sahinturk V. Silymarin attenuated nonalcoholic fatty liver disease through the regulation of endoplasmic reticulum stress proteins GRP78 and XBP-1 in mice. J Food Biochem 2020; 44: e13194
• 233 Geng Y, Wu Z, Buist-Homan M, Blokzijl H, Moshage H. Hesperetin protects against palmitate-induced cellular toxicity via induction of GRP78 in hepatocytes. Toxicol Appl Pharmacol 2020; 404: 115183
• 234 Li J, Wang T, Liu P, Yang F, Wang X, Zheng W. Hesperetin ameliorates hepatic oxidative stress and inflammation via the PI3K/AKT-Nrf2-ARE pathway in oleic acid-induced HepG2 cells and a rat model of high-fat diet-induced NAFLD. Food Funct 2021; 12: 3898-3918
• 235 Wdowiak K, Walkowiak J, Pietrzak R, Bazan-Woźniak A, Cielecka-Piontek J. Bioavailability of Hesperidin and Its Aglycone Hesperetin–Compounds Found in Citrus Fruits as a Parameter Conditioning the Pro-Health Potential (Neuroprotective and Antidiabetic Activity)–Mini-Review. Nutrients 2022; 14
• 236 Stanisic D, Liu LHB, dos Santos RV, Costa AF, Durán N, Tasic L. New Sustainable Process for Hesperidin Isolation and Anti-Ageing Effects of Hesperidin Nanocrystals. Molecules 2020; 25
• 237 Chen H, Nie T, Zhang P, Ma J, Shan A. Hesperidin attenuates hepatic lipid accumulation in mice fed high-fat diet and oleic acid induced HepG2 via AMPK activation. Life Sci 2022; 296: 120428
• 238 Zarmouh NO, Mazzio EA, Elshami FM, Messeha SS, Eyunni SVK, Soliman KFA. Evaluation of the Inhibitory Effects of Bavachinin and Bavachin on Human Monoamine Oxidases A and B. Evid Based Complement Alternat Med 2015; 2015: 852194
• 239 Dong X, Zhu Y, Wang S, Luo Y, Lu S, Nan F. Bavachinin inhibits cholesterol synthesis enzyme FDFT1 expression via AKT/mTOR/SREBP-2 pathway. Int Immunopharmacol 2020; 88: 106865
• 240 Ali MY, Zaib S, Rahman MM, Jannat S, Iqbal J, Park SK. Didymin, a dietary citrus flavonoid exhibits anti-diabetic complications and promotes glucose uptake through the activation of PI3K/Akt signaling pathway in insulin-resistant HepG2 cells. Chem Biol Interact 2019; 305: 180-194
• 241 Chang T-C, Chiou W-C, Lai W-H, Huang H-C, Huang Y-L, Liu H-K. Ugonin J improves metabolic disorder and ameliorates nonalcoholic fatty liver disease by regulating the AMPK/AKT signaling pathway. Pharmacol Res 2021; 163: 105298
• 242 Sun B, Zhang R, Liang Z, Fan A, Kang D. Hyperoside attenuates non-alcoholic fatty liver disease through targeting Nr 4A1 in macrophages. Int Immunopharmacol 2021; 94: 107438
• 243 Wang S, Sheng F, Zou L, Xiao J, Li P. Hyperoside attenuates non-alcoholic fatty liver disease in rats via cholesterol metabolism and bile acid metabolism. J Adv Res 2021; 34: 109-122
• 244 Lin W, Jin Y, Hu X, Huang E, Zhu Q. AMPK/PGC-1α/GLUT4-Mediated Effect of Icariin on Hyperlipidemia-Induced Non-Alcoholic Fatty Liver Disease and Lipid Metabolism Disorder in Mice. Biochemistry (Mosc) 2021; 86: 1407-1417
• 245 Dietz BM, Kang Y-H, Liu G, Eggler AL, Yao P, Chadwick LR. Xanthohumol Isolated from Humulus lupulus Inhibits Menadione-Induced DNA Damage through Induction of Quinone Reductase. Chem Res Toxicol 2005; 18: 1296-1305
• 246 Zhang Y, Bobe G, Miranda CL, Lowry MB, Hsu VL, Lohr CV. Tetrahydroxanthohumol, a xanthohumol derivative, attenuates high-fat diet-induced hepatic steatosis by antagonizing PPARγ . eLife 2021; 10: e66398
• 247 Wang W, Chen Z, Zheng T, Zhang M. Xanthohumol alleviates T2DM-induced liver steatosis and fibrosis by mediating the NRF2/RAGE/NF-κB signaling pathway. Future Med Chem 2021; 13: 2069-2081
• 248 Gao J, Chen G, He H, Liu C, Xiong X, Li J. Therapeutic Effects of Breviscapine in Cardiovascular Diseases: A Review. Front Pharmacol 2017; 8
• 249 Lan T, Jiang S, Zhang J, Weng Q, Yu Y, Li H. Breviscapine alleviates NASH by inhibiting TGF-β-activated kinase 1-dependent signaling. Hepatology 2022; 76: 155-171
• 250 Xia S-F, Le G-W, Wang P, Qiu Y-Y, Jiang Y-Y, Tang X. Regressive Effect of Myricetin on Hepatic Steatosis in Mice Fed a High-Fat Diet. Nutrients 2016; 8
• 251 de Lima M de FR, Cavalcante LA, Costa ECT de A, Veras B, da Silva MV, Cavalcanti LN, Araújo RM. Bioactivity flavonoids from roots of Euphorbia tirucalli L. Phytochem Lett 2021; 41: 186-192
• 252 Choi H-N, Shin J-Y, Kim J-I. Ameliorative Effect of Myricetin on Nonalcoholic Fatty Liver Disease in ob/ob Mice. J Med Food 2021; 24: 1092-1099
• 253 Fu Y, Liu B, Liu J, Liu Z, Liang D, Li F. Geniposide, from Gardenia jasminoides Ellis, inhibits the inflammatory response in the primary mouse macrophages and mouse models. Int Immunopharmacol 2012; 14: 792-798
• 254 Shen B, Feng H, Cheng J, Li Z, Jin M, Zhao L. Geniposide alleviates non-alcohol fatty liver disease via regulating Nrf2/AMPK/mTOR signalling pathways. J Cell Mol Med 2020; 24: 5097-5108
• 255 Cominguez DC, Park Y-J, Kang Y-M, Nugroho A, Kim S, An H-J. Clitorin ameliorates western diet-induced hepatic steatosis by regulating lipogenesis and fatty acid oxidation in vivo and in vitro. Sci Rep 2022; 12: 4154
• 256 Jin M, Feng H, Wang Y, Yan S, Shen B, Li Z. Gentiopicroside Ameliorates Oxidative Stress and Lipid Accumulation through Nuclear Factor Erythroid 2-Related Factor 2 Activation. Oxid Med Cell Longev 2020; 2020: 2940746
• 257 Cheng S, Liang S, Liu Q, Deng Z, Zhang Y, Du J. Diosgenin prevents high-fat diet-induced rat non-alcoholic fatty liver disease through the AMPK and LXR signaling pathways. Int J Mol Med 2018; 41: 1089-1095
• 258 Liu M, Zhang G, Wu S, Song M, Wang J, Cai W. Schaftoside alleviates HFD-induced hepatic lipid accumulation in mice via upregulating farnesoid X receptor. J Ethnopharmacol 2020; 255: 112776
• 259 Yu Q, Liu Y, Wu Y, Chen Y. Dihydrocurcumin ameliorates the lipid accumulation, oxidative stress and insulin resistance in oleic acid-induced L02 and HepG2 cells. Biomed Pharmacother 2018; 103: 1327-1336
• 260 Kim M, Yoo G, Randy A, Kim HS, Nho CW. Chicoric acid attenuate a nonalcoholic steatohepatitis by inhibiting key regulators of lipid metabolism, fibrosis, oxidation, and inflammation in mice with methionine and choline deficiency. Mol Nutr Food Res 2017; 61: 1600632
• 261 Ma J, Li M, Kalavagunta PK, Li J, He Q, Zhang Y. Protective effects of cichoric acid on H2O2-induced oxidative injury in hepatocytes and larval zebrafish models. Biomed Pharmacother 2018; 104: 679-685
• 262 Ding X, Jian T, Li J, Lv H, Tong B, Li J. Chicoric Acid Ameliorates Nonalcoholic Fatty Liver Disease via the AMPK/Nrf2/NFκB Signaling Pathway and Restores Gut Microbiota in High-Fat-Diet-Fed Mice. Oxid Med Cell Longev 2020; 2020: 9734560
• 263 Minh TN, Xuan TD, Tran H-D, Van TM, Andriana Y, Khanh TD. Isolation and Purification of Bioactive Compounds from the Stem Bark of Jatropha podagrica. Molecules 2019; 24
• 264 Fanaei H, Mard SA, Sarkaki A, Goudarzi G, Khorsandi L. Gallic acid protects the liver against NAFLD induced by dust exposure and high-fat diet through inhibiting oxidative stress and repressing the inflammatory signaling pathways NF-κβ/TNF-α/IL-6 in Wistar rats. Avicenna J Phytomed 2021; 11: 527-540
• 265 Ismail BS, Abdel-Reheim ES, Soliman HA, Mahmoud B. Protective Effect of Gallic Acid against Nonalcoholic Fatty Liver Disease Induced by High Fat Diet. J Pharm Res Int 2021; 378-397
• 266 Cha S-H, Hwang Y, Heo S-J, Jun H-S. Diphlorethohydroxycarmalol Attenuates Palmitate-Induced Hepatic Lipogenesis and Inflammation. Mar Drugs 2020; 18
• 267 Vazquez Prieto MA, Bettaieb A, Rodriguez Lanzi C, Soto VC, Perdicaro DJ, Galmarini CR. Catechin and quercetin attenuate adipose inflammation in fructose-fed rats and 3 T3-L1 adipocytes. Mol Nutr Food Res 2015; 59: 622-633
• 268 Hodges JK, Sasaki GY, Bruno RS. Anti-inflammatory activities of green tea catechins along the gut–liver axis in nonalcoholic fatty liver disease: lessons learned from preclinical and human studies. J Nutr Biochem 2020; 85: 108478
• 269 Suárez-Quiroz ML, Campos AA, Alfaro GV, González-Ríos O, Villeneuve P, Figueroa-Espinoza MC. Isolation of green coffee chlorogenic acids using activated carbon. J Food Compost Anal 2014; 33: 55-58
• 270 Jin S, Chang C, Zhang L, Liu Y, Huang X, Chen Z. Chlorogenic Acid Improves Late Diabetes through Adiponectin Receptor Signaling Pathways in db/db Mice. PLOS ONE 2015; 10: e0120842
• 271 Wang Z, Lam K-L, Hu J, Ge S, Zhou A, Zheng B. Chlorogenic acid alleviates obesity and modulates gut microbiota in high-fat-fed mice. Food Sci Nutr 2019; 7: 579-588
• 272 Ding C, Zhao Y, Shi X, Zhang N, Zu G, Li Z. New insights into salvianolic acid A action: Regulation of the TXNIP/NLRP3 and TXNIP/ChREBP pathways ameliorates HFD-induced NAFLD in rats. Sci Rep 2016; 6: 28734
• 273 Li S, Qian Q, Ying N, Lai J, Feng L, Zheng S. Activation of the AMPK-SIRT1 pathway contributes to protective effects of Salvianolic acid A against lipotoxicity in hepatocytes and NAFLD in mice. Front Pharmacol 2020; 11
• 274 Li J, Wang S, Yao L, Ma P, Chen Z, Han T-L. 6-gingerol ameliorates age-related hepatic steatosis: Association with regulating lipogenesis, fatty acid oxidation, oxidative stress and mitochondrial dysfunction. Toxicol Appl Pharmacol 2019; 362: 125-135
• 275 Sarrafan A, Ghobeh M, Yaghmaei P. The effect of 6-gingerol on biochemical and histological parameters in cholesterol-induced nonalcoholic fatty liver disease in NMRI mice. Braz J Pharm Sci 2021; 57: e18020
• 276 Chen F, Yang L, Zhai L, Huang Y, Chen F, Duan W. Methyl brevifolincarboxylate, a novel influenza virus PB2 inhibitor from Canarium Album (Lour.) Raeusch. Chem Biol Drug Des 2020; 96: 1280-1291
• 277 Geethangili M, Lin C-W, Mersmann HJ, Ding S-T. Methyl Brevifolincarboxylate Attenuates Free Fatty Acid-Induced Lipid Metabolism and Inflammation in Hepatocytes through AMPK/NF-κB Signaling Pathway. Int J Mol Sci 2021; 22
• 278 Li H-B, Jiang Y, Chen F. Isolation and Purification of Lutein from the Microalga Chlorella vulgaris by Extraction after Saponification. J Agric Food Chem 2002; 50: 1070-1072
• 279 Kim JE, Clark RM, Park Y, Lee J, Fernandez ML. Lutein decreases oxidative stress and inflammation in liver and eyes of guinea pigs fed a hypercholesterolemic diet. Nutr Res Pract 2012; 6: 113-119
• 280 Qiu X, Gao D-H, Xiang X, Xiong Y-F, Zhu T-S, Liu L-G. Ameliorative effects of lutein on non-alcoholic fatty liver disease in rats. World J Gastroenterol 2015; 21: 8061-8072
• 281 Shah MdMR, Liang Y, Cheng JJ, Daroch M. Astaxanthin-Producing Green Microalga Haematococcus pluvialis: From Single Cell to High Value Commercial Products. Front Plant Sci 2016; 7
• 282 Wu L, Mo W, Feng J, Li J, Yu Q, Li S. et al. Astaxanthin attenuates hepatic damage and mitochondrial dysfunction in non-alcoholic fatty liver disease by up-regulating the FGF21/PGC-1α pathway. Br J Pharmacol 2020; 177: 3760-3777
• 283 Li Y, Liu J, Ye B, Cui Y, Geng R, Liu S. Astaxanthin Alleviates Nonalcoholic Fatty Liver Disease by Regulating the Intestinal Flora and Targeting the AMPK/Nrf2 Signal Axis. J Agric Food Chem 2022; 70: 10620-10634
• 284 Kobori M, Ni Y, Takahashi Y, Watanabe N, Sugiura M, Ogawa K. β-Cryptoxanthin Alleviates Diet-Induced Nonalcoholic Steatohepatitis by Suppressing Inflammatory Gene Expression in Mice. PLOS ONE 2014; 9: e98294
• 285 Lim JY, Liu C, Hu K-Q, Smith DE, Wu D, Lamon-Fava S. Dietary β-Cryptoxanthin Inhibits High-Refined Carbohydrate Diet–Induced Fatty Liver via Differential Protective Mechanisms Depending on Carotenoid Cleavage Enzymes in Male Mice. J Nutr 2019; 149: 1553-1564
• 286 Islam MT. Andrographolide, a New Hope in the Prevention and Treatment of Metabolic Syndrome. Front Pharmacol 2017; 8: 571
• 287 Cabrera D, Wree A, Povero D, Solís N, Hernandez A, Pizarro M. Andrographolide Ameliorates Inflammation and Fibrogenesis and Attenuates Inflammasome Activation in Experimental Non-Alcoholic Steatohepatitis. Sci Rep 2017; 7: 3491
• 288 Ran L-S, Wu Y-Z, Gan Y-W, Wang H-L, Wu L-J, Zheng C-M. Andrographolide ameliorates hepatic steatosis by suppressing FATP2-mediated fatty acid uptake in mice with nonalcoholic fatty liver disease. J Nat Med. 2022
• 289 Chen H-J, Liu J. Actein ameliorates hepatic steatosis and fibrosis in high fat diet-induced NAFLD by regulation of insulin and leptin resistant. Biomed Pharmacother 2018; 97: 1386-1396
• 290 Gao X. Efficacy and Safety of Berberine in Non-alcoholic Steatohepatitis: a Multicentre, Randomised, Placebo-controlled Trial. 2020. https://clinicaltrials.gov/ct2/show/NCT03198572 Accessed 21 Aug 2022
• 291 Mahadeva S. A Randomised, Double-blind, Placebo-controlled, Phase II, Single-centre Study to Assess the Safety and Efficacy of Silymarin 700 mg Capsules TID for the Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD). 2016. https://clinicaltrials.gov/ct2/show/NCT02006498 Accessed 25 Sep 2022
• 292 Reddy KR, Navarro V, Afdhal N, Fried M. Single and Multiple Dose Escalation Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Orally Administered Silymarin (Legalon) in Non-Cirrhotic Subjects With Chronic Hepatitis C or Non-Alcoholic Fatty Liver Disease. 2008. https://clinicaltrials.gov/ct2/show/NCT00389376 Accessed 25 Aug 2022
• 293 Fried M, Navarro V, Afdhal N, Reddy KR, Belle SH, Harrison SA. A Multicenter, Randomized, Placebo Controlled Study to Assess the Safety and Efficacy of Orally Administered Silymarin Preparation (Legalon) for the Treatment of Non-Cirrhotic Patients With Non-Alcoholic Steatohepatitis. 2019. https://clinicaltrials.gov/ct2/show/NCT00680407 Accessed 11 Sep 2022
• 294 Hauser G. Silymarin^® – Efficacy in Treatment of Non-alcoholic Fatty Liver Disease (NAFLD) Controlled by Laboratory and and Elastographic Parameters. 2020. https://clinicaltrials.gov/ct2/show/NCT02973295 Accessed 18 Sep 2022
• 295 Wicklow B. Safety and Efficacy of Resveratrol for the Treatment of Non-Alcoholic Fatty Liver Disease and Associated Insulin Resistance in Overweight and Obese Adolescents. 2017. https://clinicaltrials.gov/ct2/show/NCT02216552 Accessed 12 Oct 2022
• 296 Nielsen S. Long-term Investigation of Resveratrol on Lipid Turnover in Obese Men With Nonalcoholic Fatty Liver Disease. Effects on Liver Fat Content and Basal and Insulin Stimulated FFA and VLDL-triglyceride Metabolism. 2014. https://clinicaltrials.gov/ct2/show/NCT01446276 Accessed 22 Sep 2022
• 297 Hekmatdoost A. The Effects of Resveratrol Supplement on Lipid Profile, Liver Enzymes, Inflammatory Factors and Hepatic Fibrosis in Patients With Nonalcoholic Steatohepatitis. 2014. https://clinicaltrials.gov/ct2/show/NCT02030977 Accessed 20 Oct 2022
• 298 Grønbæk H. Long-term Investigation of Resveratrol on Management of Metabolic Syndrome, Osteoporosis and Inflammation, and Identification of Plant Derived Anti-inflammatory Compounds, Study 3. 2015. https://clinicaltrials.gov/ct2/show/NCT01464801 Accessed 14 Oct 2022
• 299 Jørgensen JOL. Potential Beneficial Effects of Resveratrol on Obesity, Metabolic Syndrome and Inflammation – Emphasis on Description of the Molecular Biology Underpinning the Interplay Between Calorie Restriction, SIRT1, STAT5 and the GH/IGF-I Axis. 2012. https://clinicaltrials.gov/ct2/show/NCT01150955 Accessed 11 Sep 2022
• 300 Hellmann PH. The Effect of Curcumin on Liver Fat Content in Obese Subjects. 2021. https://clinicaltrials.gov/ct2/show/NCT03864783 Accessed 14 Oct 2022
• 301 Hekmatdoost A. The Effect of Curcumin Supplement on Metabolic Factors and Hepatic Fibrosis in Nonalcoholic Fatty Liver Patients. 2020. https://clinicaltrials.gov/ct2/show/NCT02908152 Accessed 30 Aug 2022
• 302 Nobili V. Hydroxytyrosol and Vitamin E in the Treatment of Children With Biopsy-proven NASH. 2018. https://clinicaltrials.gov/ct2/show/NCT02842567 Accessed 27 Sep 2022
• 303 Ling W. Effects of Purified Anthocyanin on Oxidative and Inflammatory Markers in Subjects With Nonalcoholic Fatty Liver Disease: A Randomized, Double-Blinded, Placebo-Controlled Trial. 2014. https://clinicaltrials.gov/ct2/show/NCT01940263 Accessed 11 Oct 2022