Synergistic Effects of Bavachinin in Combination With Either Ezetimibe or Atorvastatin on Liver Biomarkers: A Randomized Controlled Trial in Hyperlipidemic Rats With NAFLD
-
Seyed Amirhadi Hosseini
,
Yazdan Naderi
,
Seyedalireza Mirilavasani
,
Frits van Osch
,
Rasoul Samimi
,
Zohreh Abdolvahabi
,
Hossein Piri
Abstract
Bavachinin, a flavonoid derived from Psoralea corylifolia, exhibits antioxidant and anti-inflammatory properties and functions as a pan-agonist of PPAR nuclear receptors. This study aimed to evaluate the individual and combined effects of bavachinin with either ezetimibe or atorvastatin on liver function markers and hepatocyte apoptosis in a rat model of diet-induced hyperlipidemia. Thirty-five male Wistar rats were randomly assigned to seven groups: normal control (NC), hyperlipidemic control (HC), bavachinin (BAV), atorvastatin (ATV), ezetimibe (EZI), ATV+BAV, and EZI+BAV. Hyperlipidemia was induced in all groups except NC. Serum levels of AST, ALT, ALP, and IL-10 were measured before and after the 4-week intervention period. Liver tissue was assessed using TUNEL staining. Wilcoxon signed-rank tests showed significant within-group reductions in AST in all intervention groups (P<0.05). ALT significantly decreased in the BAV and ATV+BAV groups. IL-10 levels significantly increased in the EZI, BAV, ATV+BAV, and EZI+BAV groups. Kruskal-Wallis ANOVA revealed significant between-group differences in AST, ALT, and IL-10 levels across all groups (P<0.05). Post hoc Mann-Whitney U tests revealed that both combination groups (ATV+BAV and EZI+BAV) showed significant reductions in AST levels compared with the HC group, and the EZI+BAV group also demonstrated a significant reduction in ALT. IL-10 levels exhibited significant improvements in both combination groups compared with BAV alone. Additionally, TUNEL staining indicated reduced hepatocyte apoptosis in both combination groups as well as in the BAV group relative to the HC group. Bavachinin, in combination with ezetimibe or atorvastatin, demonstrated hepatoprotective and anti-inflammatory effects in a rat model of fatty liver disease. These findings suggest potential therapeutic roles for bavachinin. However, further studies, including complete lipid profiling and oxidative stress markers, are needed.
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2. Ge X, Zheng L, Wang M, Du Y, Jiang J. Prevalence trends in nonalcoholic fatty liver disease at the global, regional and national levels, 1990–2017: a population-based observational study. BMJ Open 2020;10:e036663.
3. Calzadilla Bertot L, Adams LA. The natural course of nonalcoholic fatty liver disease. Int J Mol Sci 2016;17.
4. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med 2018;24:908–22.
5. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356-62.
6. McCracken E, Monaghan M, Sreenivasan S. Pathophysiology of the metabolic syndrome. Clin Dermatol 2018;36:14-20.
7. Grundy SM. Metabolic syndrome update. Trends Cardiovasc Med 2016;26:364-73.
8. Rinella ME, Sanyal AJ. Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol 2016;13:196-205.
9. Tziomalos K, Athyros VG, Paschos P, Karagiannis A. Nonalcoholic fatty liver disease and statins. Metabolism 2015;64:1215-23.
10. Mantovani A, Dalbeni A. Treatments for NAFLD: State of Art. Int J Mol Sci 2021;22:2350.
11. Nascimbeni F, Pellegrini E, Lugari S, Mondelli A, Bursi S, Onfiani G, et al. Statins and nonalcoholic fatty liver disease in the era of precision medicine: more friends than foes. Atherosclerosis 2019;284:66-74.
12. Grundy SM. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov 2006;5:295-309.
13. Jiao B, Wang B, Liu B, Zhao J, Zhang Y. Potential impact of ezetimibe on patients with NAFLD/NASH: a meta-analysis of randomized controlled trials. Front Endocrinol 2024;15:1468476.
14. Yang H, Suh DH, Jung ES, Lee Y, Liu KH, Do IG, et al. Ezetimibe modulates hepatic phospholipid metabolism to alleviate fat accumulation. Front Pharmacol 2024;15:1406493.
15. Chang F, Jaber LA, Berlie HD, O’Connell MB. Evolution of peroxisome proliferator-activated receptor agonists. Ann Pharmacother 2007;41:973-83.
16. Hong F, Pan S, Guo Y, Xu P, Zhai Y. PPARs as nuclear receptors for nutrient and energy metabolism. Molecules 2019;24 14:2545.
17. Kintz P, Ameline A, Gheddar L, Raul JS. Testing for GW501516 in human hair using LC/MS–MS and confirmation by LC/HRMS. Drug Test Anal 2020;12:980-6.
18. Wahli W, Michalik L. PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab 2012;23:351-63.
19. Zahran WE, Salah El-Dien KA, Kamel PG, El-Sawaby AS. Efficacy of TNF and IL-10 analysis in the follow-up of NAFLD progression. Indian J Clin Biochem 2013;28:141-6.
20. Yin J, Zhang H, Ye J. Traditional Chinese medicine in treatment of metabolic syndrome. Endocr Metab Immune Disord Drug Targets 2008;8:99-111.
21. Feng L, Luo H, Xu Z, Yang Z, Du G, Zhang Y, et al. Bavachinin as a natural pan-PPAR agonist shows synergistic effects with synthetic agonists. Diabetologia 2016;59:1276-86.
22. Mahdi C, Citrawati P, Hendrawan VF. The effect of rice bran on triglyceride levels and histopathologic aorta in rats. IOP Conf Ser Mater Sci Eng 2020.
23. Khosraviani S, Emami A, Keshavarz Hedayati S, Keshavarz Shahbaz S, Aali E, Naderi Y. Synergistic glucose-lowering effects of metformin and bavachinin on diabetic rats. Iran J Toxicol 2023;17:79-86.
24. Barsante MM, Roffê E, Yokoro CM, Tafuri WL, Souza DG, Pinho V, et al. Anti-inflammatory and analgesic effects of atorvastatin in arthritis. Eur J Pharmacol 2005;516:282-9.
25. Trocha M, Merwid-Ląd A, Chlebda E, Sozański T, Pieśniewska M, et al. Influence of ezetimibe on oxidative stress parameters in rat liver ischemia/reperfusion. Arch Med Sci 2014;10:817-24.
26. Majtnerová P, Roušar T. An overview of apoptosis assays detecting DNA fragmentation. Mol Biol Rep 2018;45:1469-78.
27. Povsic M, Wong OY, Perry R, Bottomley J. Epidemiology and disease burden of NASH. Adv Ther 2019;36:1574-94.
28. Attar BM, Van Thiel DH. Current concepts and management approaches in nonalcoholic fatty liver disease. Sci World J 2013;2013.
29. Parra-Vargas M, Rodriguez-Echevarria R, Jimenez-Chillaron JC. Nutritional approaches for NAFLD management. Nutrients 2020;12:3860.
30. Wu Y, Min L, Xu Y, Liu H, Zhou N, Hua Z, et al. Evaluation of salt-processed psoraleae fructus-induced hepatotoxicity. J Ethnopharmacol 2022;288:114955.
31. Kolodziejczyk AA, Zheng D, Shibolet O, Elinav E. Role of microbiome in NAFLD and NASH. EMBO Mol Med 2019;11.
32. Mocciaro G, Allison M, Jenkins B, Azzu V, Huang-Doran I, et al. Reduced PUFA transport in NAFLD. Mol Metab 2023;73:101728.
33. Guo Z, Li P, Wang C, Kang Q, Tu C, Jiang B, et al. Constituents contributing to hepatotoxicity via mitochondrial dysfunction. Front Pharmacol 2021;12:682823.
34. Wang S, Wang M, Wang M, Tian Y, Sun X, Sun G, et al. Bavachinin induces oxidative damage via p38/JNK MAPK. Toxins 2018;10:154.
35. Chen CH, Hwang TL, Chen LC, Chang TH, Wei CS, Chen JJ. Isoflavones and anti-inflammatory constituents from Psoralea corylifolia. Phytochemistry 2017;143:186-93.
36. Haraguchi H, Inoue J, Tamura Y, Mizutani K. Antioxidative components of Psoralea corylifolia. Phytother Res 2002;16:539-44.
37. Dong X, Zhu Y, Wang S, Luo Y, Lu S, Nan F, et al. Bavachinin inhibits cholesterol synthesis via AKT/mTOR/SREBP-2. Int Immunopharmacol 2020;88:106865.
38. Seo E, Oh YS, Jun HS. Psoralea corylifolia seed extract attenuates NAFLD. Nutrients 2016;8:83.
39. Lee SW, Yun BR, Kim MH, Park CS, Lee WS, Oh HM, et al. Phenolics inhibit STAT3 activation. Planta Med 2012;78:903-6.
40. Chen X, Shen Y, Liang Q, Flavell R, Hong Z, Yin Z, et al. Effects of bavachinin on T-cell differentiation. Int Immunopharmacol 2014;19:399-404.
41. Kim DH, Li H, Han YE, Jeong JH, Lee HJ, Ryu JH. Prenylated chalcones inhibit iNOS expression. Molecules 2018;23.
42. Lee MH, Kim JY, Ryu JH. Prenylflavones inhibit nitric oxide synthase. Biol Pharm Bull 2005;28:2253-7.
43. Nepal M, Choi HJ, Choi BY, Kim SL, Ryu JH, Kim DH, et al. Anti-tumor activity of bavachinin. Eur J Pharmacol 2012;691:28-37.
44. Wang J, Jiang Z, Ji J, Li Y, Chen M, Wang Y, et al. Hepatotoxicity and cholestasis induced by Fructus Psoraleae. J Ethnopharmacol 2012;144:73-81.
45. Liu B, Liu X, Ning Q, Zhong R, Xia Z, Li J, et al. Toxicity and anti-osteoporosis effect of Psoraleae flavonoids. J Funct Foods 2020;75:104262.
46. Torres-Peña JD, Martín-Piedra L, Fuentes-Jiménez F. Statins in NASH. Front Cardiovasc Med 2021;8:777131.
47. Nakade Y, Murotani K, Inoue T, Kobayashi Y, Yamamoto T, Ishii N, et al. Ezetimibe for NAFLD: meta-analysis. Hepatol Res 2017;47:1417-28.
48. Li X, Li M. Cholesterol metabolism targets and natural product interventions in MASLD. Pharmaceuticals 2024;17:1073.
49. Park HS, Jang JE, Ko MS, Woo SH, Kim BJ, Kim HS, et al. Statins increase FA oxidation and prevent NASH. Diabetes Metab J 2016;40:376-85.
50. Samy W, Hassanian MA. Paraoxonase-1 activity in NAFLD and effect of atorvastatin. Arab J Gastroenterol 2011;12:80-5.
51. Kimura Y, Hyogo H, Yamagishi SI, Takeuchi M, Ishitobi T, Nabeshima Y, et al. Atorvastatin decreases AGEs in NASH. J Gastroenterol 2010;45:750-7.
52. Yoshida M. Role of NPC1L1 in hepatic metabolism: contribution of ezetimibe. Curr Vasc Pharmacol 2011;9:121-3.
53. Yoneda M, Fujita K, Nozaki Y, Endo H, Takahashi H, Hosono K, et al. Efficacy of ezetimibe in NASH: open-label pilot study. Hepatol Res 2010;40:566-73.
2. Ge X, Zheng L, Wang M, Du Y, Jiang J. Prevalence trends in nonalcoholic fatty liver disease at the global, regional and national levels, 1990–2017: a population-based observational study. BMJ Open 2020;10:e036663.
3. Calzadilla Bertot L, Adams LA. The natural course of nonalcoholic fatty liver disease. Int J Mol Sci 2016;17.
4. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med 2018;24:908–22.
5. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356-62.
6. McCracken E, Monaghan M, Sreenivasan S. Pathophysiology of the metabolic syndrome. Clin Dermatol 2018;36:14-20.
7. Grundy SM. Metabolic syndrome update. Trends Cardiovasc Med 2016;26:364-73.
8. Rinella ME, Sanyal AJ. Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol 2016;13:196-205.
9. Tziomalos K, Athyros VG, Paschos P, Karagiannis A. Nonalcoholic fatty liver disease and statins. Metabolism 2015;64:1215-23.
10. Mantovani A, Dalbeni A. Treatments for NAFLD: State of Art. Int J Mol Sci 2021;22:2350.
11. Nascimbeni F, Pellegrini E, Lugari S, Mondelli A, Bursi S, Onfiani G, et al. Statins and nonalcoholic fatty liver disease in the era of precision medicine: more friends than foes. Atherosclerosis 2019;284:66-74.
12. Grundy SM. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov 2006;5:295-309.
13. Jiao B, Wang B, Liu B, Zhao J, Zhang Y. Potential impact of ezetimibe on patients with NAFLD/NASH: a meta-analysis of randomized controlled trials. Front Endocrinol 2024;15:1468476.
14. Yang H, Suh DH, Jung ES, Lee Y, Liu KH, Do IG, et al. Ezetimibe modulates hepatic phospholipid metabolism to alleviate fat accumulation. Front Pharmacol 2024;15:1406493.
15. Chang F, Jaber LA, Berlie HD, O’Connell MB. Evolution of peroxisome proliferator-activated receptor agonists. Ann Pharmacother 2007;41:973-83.
16. Hong F, Pan S, Guo Y, Xu P, Zhai Y. PPARs as nuclear receptors for nutrient and energy metabolism. Molecules 2019;24 14:2545.
17. Kintz P, Ameline A, Gheddar L, Raul JS. Testing for GW501516 in human hair using LC/MS–MS and confirmation by LC/HRMS. Drug Test Anal 2020;12:980-6.
18. Wahli W, Michalik L. PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab 2012;23:351-63.
19. Zahran WE, Salah El-Dien KA, Kamel PG, El-Sawaby AS. Efficacy of TNF and IL-10 analysis in the follow-up of NAFLD progression. Indian J Clin Biochem 2013;28:141-6.
20. Yin J, Zhang H, Ye J. Traditional Chinese medicine in treatment of metabolic syndrome. Endocr Metab Immune Disord Drug Targets 2008;8:99-111.
21. Feng L, Luo H, Xu Z, Yang Z, Du G, Zhang Y, et al. Bavachinin as a natural pan-PPAR agonist shows synergistic effects with synthetic agonists. Diabetologia 2016;59:1276-86.
22. Mahdi C, Citrawati P, Hendrawan VF. The effect of rice bran on triglyceride levels and histopathologic aorta in rats. IOP Conf Ser Mater Sci Eng 2020.
23. Khosraviani S, Emami A, Keshavarz Hedayati S, Keshavarz Shahbaz S, Aali E, Naderi Y. Synergistic glucose-lowering effects of metformin and bavachinin on diabetic rats. Iran J Toxicol 2023;17:79-86.
24. Barsante MM, Roffê E, Yokoro CM, Tafuri WL, Souza DG, Pinho V, et al. Anti-inflammatory and analgesic effects of atorvastatin in arthritis. Eur J Pharmacol 2005;516:282-9.
25. Trocha M, Merwid-Ląd A, Chlebda E, Sozański T, Pieśniewska M, et al. Influence of ezetimibe on oxidative stress parameters in rat liver ischemia/reperfusion. Arch Med Sci 2014;10:817-24.
26. Majtnerová P, Roušar T. An overview of apoptosis assays detecting DNA fragmentation. Mol Biol Rep 2018;45:1469-78.
27. Povsic M, Wong OY, Perry R, Bottomley J. Epidemiology and disease burden of NASH. Adv Ther 2019;36:1574-94.
28. Attar BM, Van Thiel DH. Current concepts and management approaches in nonalcoholic fatty liver disease. Sci World J 2013;2013.
29. Parra-Vargas M, Rodriguez-Echevarria R, Jimenez-Chillaron JC. Nutritional approaches for NAFLD management. Nutrients 2020;12:3860.
30. Wu Y, Min L, Xu Y, Liu H, Zhou N, Hua Z, et al. Evaluation of salt-processed psoraleae fructus-induced hepatotoxicity. J Ethnopharmacol 2022;288:114955.
31. Kolodziejczyk AA, Zheng D, Shibolet O, Elinav E. Role of microbiome in NAFLD and NASH. EMBO Mol Med 2019;11.
32. Mocciaro G, Allison M, Jenkins B, Azzu V, Huang-Doran I, et al. Reduced PUFA transport in NAFLD. Mol Metab 2023;73:101728.
33. Guo Z, Li P, Wang C, Kang Q, Tu C, Jiang B, et al. Constituents contributing to hepatotoxicity via mitochondrial dysfunction. Front Pharmacol 2021;12:682823.
34. Wang S, Wang M, Wang M, Tian Y, Sun X, Sun G, et al. Bavachinin induces oxidative damage via p38/JNK MAPK. Toxins 2018;10:154.
35. Chen CH, Hwang TL, Chen LC, Chang TH, Wei CS, Chen JJ. Isoflavones and anti-inflammatory constituents from Psoralea corylifolia. Phytochemistry 2017;143:186-93.
36. Haraguchi H, Inoue J, Tamura Y, Mizutani K. Antioxidative components of Psoralea corylifolia. Phytother Res 2002;16:539-44.
37. Dong X, Zhu Y, Wang S, Luo Y, Lu S, Nan F, et al. Bavachinin inhibits cholesterol synthesis via AKT/mTOR/SREBP-2. Int Immunopharmacol 2020;88:106865.
38. Seo E, Oh YS, Jun HS. Psoralea corylifolia seed extract attenuates NAFLD. Nutrients 2016;8:83.
39. Lee SW, Yun BR, Kim MH, Park CS, Lee WS, Oh HM, et al. Phenolics inhibit STAT3 activation. Planta Med 2012;78:903-6.
40. Chen X, Shen Y, Liang Q, Flavell R, Hong Z, Yin Z, et al. Effects of bavachinin on T-cell differentiation. Int Immunopharmacol 2014;19:399-404.
41. Kim DH, Li H, Han YE, Jeong JH, Lee HJ, Ryu JH. Prenylated chalcones inhibit iNOS expression. Molecules 2018;23.
42. Lee MH, Kim JY, Ryu JH. Prenylflavones inhibit nitric oxide synthase. Biol Pharm Bull 2005;28:2253-7.
43. Nepal M, Choi HJ, Choi BY, Kim SL, Ryu JH, Kim DH, et al. Anti-tumor activity of bavachinin. Eur J Pharmacol 2012;691:28-37.
44. Wang J, Jiang Z, Ji J, Li Y, Chen M, Wang Y, et al. Hepatotoxicity and cholestasis induced by Fructus Psoraleae. J Ethnopharmacol 2012;144:73-81.
45. Liu B, Liu X, Ning Q, Zhong R, Xia Z, Li J, et al. Toxicity and anti-osteoporosis effect of Psoraleae flavonoids. J Funct Foods 2020;75:104262.
46. Torres-Peña JD, Martín-Piedra L, Fuentes-Jiménez F. Statins in NASH. Front Cardiovasc Med 2021;8:777131.
47. Nakade Y, Murotani K, Inoue T, Kobayashi Y, Yamamoto T, Ishii N, et al. Ezetimibe for NAFLD: meta-analysis. Hepatol Res 2017;47:1417-28.
48. Li X, Li M. Cholesterol metabolism targets and natural product interventions in MASLD. Pharmaceuticals 2024;17:1073.
49. Park HS, Jang JE, Ko MS, Woo SH, Kim BJ, Kim HS, et al. Statins increase FA oxidation and prevent NASH. Diabetes Metab J 2016;40:376-85.
50. Samy W, Hassanian MA. Paraoxonase-1 activity in NAFLD and effect of atorvastatin. Arab J Gastroenterol 2011;12:80-5.
51. Kimura Y, Hyogo H, Yamagishi SI, Takeuchi M, Ishitobi T, Nabeshima Y, et al. Atorvastatin decreases AGEs in NASH. J Gastroenterol 2010;45:750-7.
52. Yoshida M. Role of NPC1L1 in hepatic metabolism: contribution of ezetimibe. Curr Vasc Pharmacol 2011;9:121-3.
53. Yoneda M, Fujita K, Nozaki Y, Endo H, Takahashi H, Hosono K, et al. Efficacy of ezetimibe in NASH: open-label pilot study. Hepatol Res 2010;40:566-73.
| Files | ||
| Issue | Vol 63 No 5 (2025) | |
| Section | Original Articles | |
| Keywords | ||
| Bavachinin Nonalcoholic fatty liver disease (NAFLD) Peroxisome proliferator-activated | ||
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How to Cite
1.
Hosseini SA, Naderi Y, Mirilavasani S, van Osch F, Samimi R, Abdolvahabi Z, Piri H. Synergistic Effects of Bavachinin in Combination With Either Ezetimibe or Atorvastatin on Liver Biomarkers: A Randomized Controlled Trial in Hyperlipidemic Rats With NAFLD. Acta Med Iran. 2025;63(5):267-277.
