Recapsoma®: A Novel Mixture Based on Bergamot, Ipomoea Batatas, Policosanol Extracts and Liposomal Berberine for the Treatment of Hypercholesterolemia
Abstract
:1. Introduction
2. Materials and Methods
2.1. Preparation of Recapsoma® Mixture
2.2. Effect of Berberine and Recapsoma® on PCSK9 and LDL-Receptor (LDLR)
2.2.1. Cell Culture
2.2.2. Detection of the Level of PCSK9 and LDL Receptor (LDLR)
2.3. Determination of the Enzymatic Level of Acyl-CoA-Cholesterol Acyltransferase (ACAT)
2.3.1. Cell Culture
2.3.2. Fluorescence Microscopy
2.4. Determination of Phosphatidic Acid Phosphatase (PAP) Activity in HepG2 Liver Cells
2.5. Analysis of 3-Hydroxy-3-methylglutaryl-CoA Reductase (HMGR)
2.6. Determination of the Formation of Reactive Oxygen Species
2.7. Statistical Analysis
3. Results
3.1. PCSK9 and LDLR Expression in HepG2 Liver Cells
3.2. Enzyme Levels of Acyl-CoA-Cholesterol Acyltransferase (ACAT) in HepG2 Liver Cells
3.3. Phosphatidic Acid Phosphatase (PAP) Activity in HepG2 Liver Cells
3.4. Analysis of 3-Hydroxy-3-methylglutaryl-CoA Reductase (HMGR)
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Roth, G.A.; Abate, D.; Abate, K.H.; Abay, S.M.; Abbafati, C.; Abbasi, N.; Abbastabar, H.; Abd-Allah, F.; Abdela, J.; Abdelalim, A.; et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1736–1788. [Google Scholar] [CrossRef] [Green Version]
- Go, A.S.; Mozaffarian, D.; Roger, V.L.; Benjamin, E.J.; Berry, J.D.; Blaha, M.J.; Dai, S.; Ford, E.S.; Fox, C.S.; Franco, S.; et al. Heart disease and stroke statistics—2014 update: A report from the American Heart Association. Circulation 2014, 129, e28–e292. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kannel, W.B.; Dawber, T.R.; Kagan, A.; Revotskie, N.; Stokes, J., III. Factors of risk in the development of coronary heart disease—six-year follow-up experience: The Framingham Study. Ann. Intern. Med. 1961, 55, 33–50. [Google Scholar] [CrossRef] [PubMed]
- Stamler, J.; Wentworth, D.; Neaton, J.D. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986, 256, 2823–2828. [Google Scholar] [CrossRef] [PubMed]
- Keys, A.; Mienotti, A.; Karvonen, M.J.; Aravanis, C.; Blackburn, H.; Buzina, R.; Djordjevic, B.S.; Dontas, A.S.; Fidanza, F.; Keys, M.H.; et al. The Diet and 15-Year Death Rate in the Seven Countries Study. Am. J. Epidemiol. 1986, 124, 903–915. [Google Scholar] [CrossRef] [PubMed]
- Chait, A.; Eckel, R.H. Lipids, Lipoproteins, and Cardiovascular Disease: Clinical Pharmacology Now and in the Future. J. Clin. Endocrinol. Metab. 2016, 101, 804–814. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gordon, T.; Castelli, W.P.; Hjortland, M.C.; Kannel, W.B.; Dawber, T.R. High density lipoprotein as a protective factor against coronary heart disease: The Framingham Study. Am. J. Med. 1977, 62, 707–714. [Google Scholar] [CrossRef]
- Kannel, W.B.; Castelli, W.P.; Gordon, T. Cholesterol in the prediction of atherosclerotic disease: New perspectives based on the Framingham study. Ann. Intern. Med. 1979, 90, 85–91. [Google Scholar] [CrossRef]
- Catapano, A.L.; Graham, I.; De Backer, G.; Wiklund, O.; Chapman, M.J.; Drexel, H.; Hoes, A.W.; Jennings, C.S.; Landmesser, U.; Pedersen, T.R.; et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur. Heart J. 2016, 37, 2999–3058. [Google Scholar] [CrossRef] [Green Version]
- Banach, M.; Rizzo, M.; Toth, P.P.; Farnier, M.; Davidson, M.H.; Al-Rasadi, K.; Aronow, W.S.; Athyros, V.; Djuric, D.M.; Ezhov, M.V.; et al. Statin intolerance—An attempt at a unified definition. Position paper from an International Lipid Expert Panel. Expert Opin. Drug Saf. 2015, 14, 935–955. [Google Scholar] [CrossRef]
- Stoclet, J.-C.; Chataigneau, T.; Ndiaye, M.; Oak, M.-H.; El Bedoui, J.; Chataigneau, M.; Schini-Kerth, V.B. Vascular protection by dietary polyphenols. Eur. J. Pharmacol. 2004, 500, 299–313. [Google Scholar] [CrossRef] [PubMed]
- Shahidi, F. Nutraceuticals and functional foods in health promotion and disease prevention. In Proceedings of the III WOCMAP Congress on Medicinal and Aromatic Plants, Chiang Mai, Thailand, 3–7 February 2002; Volume 6, pp. 13–24. [Google Scholar]
- Huang, Y.; Tocmo, R.; Nauman, M.C.; Haughan, M.A.; Johnson, J.J. Defining the Cholesterol Lowering Mechanism of Bergamot (Citrus bergamia) Extract in HepG2 and Caco-2 Cells. Nutrients 2021, 13, 3156. [Google Scholar] [CrossRef] [PubMed]
- Musolino, V.; Gliozzi, M.; Scarano, F.; Bosco, F.; Scicchitano, M.; Nucera, S.; Carresi, C.; Ruga, S.; Zito, M.C.; Maiuolo, J.; et al. Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease. Sci. Rep. 2020, 10, 2565. [Google Scholar] [CrossRef] [PubMed]
- Musolino, V.; Gliozzi, M.; Nucera, S.; Carresi, C.; Maiuolo, J.; Mollace, R.; Paone, S.; Bosco, F.; Scarano, F.; Scicchitano, M.; et al. The effect of bergamot polyphenolic fraction on lipid transfer protein system and vascular oxidative stress in a rat model of hyperlipemia. Lipids Health Dis. 2019, 18, 115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Toth, P.P.; Patti, A.M.; Nikolic, D.; Giglio, R.V.; Castellino, G.; Biancucci, T.; Geraci, F.; David, S.; Montalto, G.; Rizvi, A.; et al. Bergamot Reduces Plasma Lipids, Atherogenic Small Dense LDL, and Subclinical Atherosclerosis in Subjects with Moderate Hypercholesterolemia: A 6 Months Prospective Study. Front. Pharmacol. 2016, 6, 299. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dong, B.; Li, H.; Singh, A.B.; Cao, A.; Liu, J. Inhibition of PCSK9 Transcription by Berberine Involves Down-regulation of Hepatic HNF1α Protein Expression through the Ubiquitin-Proteasome Degradation Pathway. J. Biol. Chem. 2015, 290, 4047–4058. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, W.; Miao, Y.-Q.; Fan, D.-J.; Yang, S.-S.; Lin, X.; Meng, L.-K.; Tang, X. Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats. AAPS PharmSciTech 2011, 12, 705–711. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, X.; Qiu, F.; Jiang, J.; Gao, C.; Tan, Y. Intestinal absorption mechanisms of berberine, palmatine, jateorhizine, and coptisine: Involvement of P-glycoprotein. Xenobiotica 2011, 41, 290–296. [Google Scholar] [CrossRef] [PubMed]
- Duong, T.; Isomäki, A.; Paaver, U.; Laidmäe, I.; Tõnisoo, A.; Yen, T.; Kogermann, K.; Raal, A.; Heinämäki, J.; Pham, T.-M. Nanoformulation and Evaluation of Oral Berberine-Loaded Liposomes. Molecules 2021, 26, 2591. [Google Scholar] [CrossRef]
- Duong, T.T.; Yen, T.T.H.; Nguyen, L.T.; Nguyen, T.D.; Pham, H.T.; Raal, A.; Heinämäki, J. Berberine-loaded liposomes for oral delivery: Preparation, physicochemical characterization and in-vivo evaluation in an endogenous hyperlipidemic animal model. Int. J. Pharm. 2022, 616, 121525. [Google Scholar] [CrossRef]
- Charman, W.; Stella, V. Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules. Int. J. Pharm. 1986, 34, 175–178. [Google Scholar] [CrossRef]
- Ntchapda, F.; Tchatchouang, F.C.; Miaffo, D.; Maidadi, B.; Vecchio, L.; Talla, R.E.; Bonabe, C.; Etet, P.F.S.; Dimo, T. Hypolipidemic and anti-atherosclerogenic effects of aqueous extract of Ipomoea batatas leaves in diet-induced hypercholesterolemic rats. J. Integr. Med. 2021, 19, 243–250. [Google Scholar] [CrossRef] [PubMed]
- Lockyer, S.; Rowland, I.; Spencer, J.P.E.; Yaqoob, P.; Stonehouse, W. Impact of phenolic-rich olive leaf extract on blood pressure, plasma lipids and inflammatory markers: A randomised controlled trial. Eur. J. Nutr. 2017, 56, 1421–1432. [Google Scholar] [CrossRef] [Green Version]
- Hadrich, F.; Mahmoudi, A.; Bouallagui, Z.; Feki, I.; Isoda, H.; Feve, B.; Sayadi, S. Evaluation of hypocholesterolemic effect of oleuropein in cholesterol-fed rats. Chem.-Biol. Interact. 2016, 252, 54–60. [Google Scholar] [CrossRef] [Green Version]
- Oliaro-Bosso, S.; Gaudino, E.C.; Mantegna, S.; Giraudo, E.; Meda, C.; Viola, F.; Cravotto, G. Regulation of HMGCoA Reductase Activity by Policosanol and Octacosadienol, a New Synthetic Analogue of Octacosanol. Lipids 2009, 44, 907–916. [Google Scholar] [CrossRef] [Green Version]
- Meydani, M. Vitamin E and Atherosclerosis: Beyond Prevention of LDL oxidation. J. Nutr. 2001, 131, 366S–368S. [Google Scholar] [CrossRef] [PubMed]
- Princen, H.M.; van Duyvenvoorde, W.; Buytenhek, R.; van der Laarse, A.; van Poppel, G.; Leuven, J.A.G.; van Hinsbergh, V.W. Supplementation with Low Doses of Vitamin E Protects LDL From Lipid Peroxidation in Men and Women. Arterioscler. Thromb. Vasc. Biol. 1995, 15, 325–333. [Google Scholar] [CrossRef]
- Cameron, J.; Ranheim, T.; Kulseth, M.A.; Leren, T.P.; Berge, K.E. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis 2008, 201, 266–273. [Google Scholar] [CrossRef]
- Sui, G.-G.; Xiao, H.-B.; Lu, X.-Y.; Sun, Z.-L. Naringin activates AMPK resulting in altered expression of SREBPs, PCSK9, and LDLR to reduce body weight in obese C57BL/6J mice. J. Agric. Food Chem. 2018, 66, 8983–8990. [Google Scholar] [CrossRef]
- McNutt, M.C.; Kwon, H.J.; Chen, C.; Chen, J.R.; Horton, J.D.; Lagace, T.A. Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J. Biol. Chem. 2009, 284, 10561–10570. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fan, J.; Rone, M.B.; Papadopoulos, V. Translocator Protein 2 Is Involved in Cholesterol Redistribution during Erythropoiesis. J. Biol. Chem. 2009, 284, 30484–30497. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lada, A.T.; Davis, M.; Kent, C.; Chapman, J.; Tomoda, H.; Omura, S.; Rudel, L.L. Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell-based fluorescence assay: Individual ACAT uniqueness. Lipid Res. 2004, 45, 378–386. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, Y.; Yi, X.; Ghanam, K.; Zhang, S.; Zhao, T.; Zhu, X. Berberine decreases cholesterol levels in rats through multiple mechanisms, including inhibition of cholesterol absorption. Metabolism 2014, 63, 1167–1177. [Google Scholar] [CrossRef] [PubMed]
- Charman, W.; Stella, V. Effects of lipid class and lipid vehicle volume on the intestinal lymphatic transport of DDT. Int. J. Pharm. 1986, 33, 165–172. [Google Scholar] [CrossRef]
- Heidarian, E.; Rafieian-Kopaei, M.; Khoshdel, A.; Bakhshesh, M. Metabolic effects of berberine on liver phosphatidate phosphohydrolase in rats fed on high lipogenic diet: An additional mechanism for the hypolipidemic effects of berberine. Asian Pac. J. Trop. Biomed. 2014, 4, S429–S435. [Google Scholar] [CrossRef] [Green Version]
- Nam, D.-E.; Yun, J.-M.; Kim, D.; Kim, O.-K. Policosanol Attenuates Cholesterol Synthesis via AMPK Activation in Hypercholesterolemic Rats. J. Med. Food 2019, 22, 1110–1117. [Google Scholar] [CrossRef]
- Leopoldini, M.; Malaj, N.; Toscano, M.; Sindona, G.; Russo, N. On the inhibitor effects of bergamot juice flavonoids binding to the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) enzyme. J. Agric. Food Chem. 2010, 58, 10768–10773. [Google Scholar] [CrossRef]
- Parker, R.A.; Pearce, B.C.; Clark, R.W.; Gordon, D.A.; Wright, J.J. Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J. Biol. Chem. 1993, 268, 11230–11238. [Google Scholar] [CrossRef]
- Santini, A.; Tenore, G.C.; Novellino, E. Nutraceuticals: A paradigm of proactive medicine. Eur. J. Pharm. Sci. 2017, 96, 53–61. [Google Scholar] [CrossRef]
- Kumar, S.; Pandey, A.K. Chemistry and Biological Activities of Flavonoids: An Overview. Sci. World J. 2013, 2013, 162750. [Google Scholar] [CrossRef] [Green Version]
- Ashrafizadeh, M.; Fekri, H.S.; Ahmadi, Z.; Farkhondeh, T.; Samarghandian, S. Therapeutic and biological activities of berberine: The involvement of Nrf2 signaling pathway. J. Cell. Biochem. 2019, 121, 1575–1585. [Google Scholar] [CrossRef] [PubMed]
Ingredient | Amount (mg) |
---|---|
Bergamot extract | 300 |
Liposomal berberine | 200 |
Ipomea batatas extract | 100 |
Oleuropein | 25 |
Vitamin E | 15 |
Policosanol extract | 11.1 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Amante, C.; Esposito, T.; Luccheo, G.; Luccheo, L.; Russo, P.; Del Gaudio, P. Recapsoma®: A Novel Mixture Based on Bergamot, Ipomoea Batatas, Policosanol Extracts and Liposomal Berberine for the Treatment of Hypercholesterolemia. Life 2022, 12, 1162. https://doi.org/10.3390/life12081162
Amante C, Esposito T, Luccheo G, Luccheo L, Russo P, Del Gaudio P. Recapsoma®: A Novel Mixture Based on Bergamot, Ipomoea Batatas, Policosanol Extracts and Liposomal Berberine for the Treatment of Hypercholesterolemia. Life. 2022; 12(8):1162. https://doi.org/10.3390/life12081162
Chicago/Turabian StyleAmante, Chiara, Tiziana Esposito, Gianni Luccheo, Luigi Luccheo, Paola Russo, and Pasquale Del Gaudio. 2022. "Recapsoma®: A Novel Mixture Based on Bergamot, Ipomoea Batatas, Policosanol Extracts and Liposomal Berberine for the Treatment of Hypercholesterolemia" Life 12, no. 8: 1162. https://doi.org/10.3390/life12081162