Exploration of phytochemicals and antihyperlipidemic effect of crateva religiosa bark: in vivo mechanistic approach for management of hyperlipidaemia
DOI:
https://doi.org/10.1590/s2175-97902026e24772Keywords:
Cholesterol diet, HMG-CoA reductase, Oxidative stress, Hypercholesterolemia, PPARγ, CCAAT/EBPαAbstract
The work investigated the presence of phytochemicals and antihyperlipidemic potential of the ethanolic extract of Crateva religiosa (CRETE). The extraction yield was found to be highest with ethanol (15.81% w/w), followed by ethyl acetate (11.98% w/w) and very poor in hexane (3.05% w/w), using as solvents of variable polarity. Quantitative phytochemical analysis revealed that CRETE consists of higher total phenolic content (81.19 µg/mg equivalent to gallic acid) and flavonoid contents (49.0 µg/mg quercetin equivalents) compared to the ethyl acetate extract. GC–MS analysis confirmed the presence of stigmasterol, gamma-sitosterol and lupeol as phytochemicals. In vivo studies demonstrated that 400 mg/kg of CRETE reduced the levels of triglycerides (155.9 ± 1.51 mg/dl), total cholesterol (234.27 ± 1.91 mg/dl) and low-density lipoprotein cholesterol (66.27 ± 2.07 mg/dl), while increased the level of high-density lipoprotein cholesterol (133.48 ± 3.72 mg/dl). Atherogenic indices were also improved significantly. CRETE restored hepatic architecture and reduced adipocyte size. CRETE also exhibited strong antioxidant effects by lowering malondialdehyde (MDA) levels and enhancing glutathione (GSH), superoxide dismutase (SOD) and catalase activities. Mechanistically, in comparison to control groups, CRETE inhibited HMG-CoA reductase activity (p < 0.0001) and up-regulated PPARγ (p < 0.01) and CCAAT/EBPα (p
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Adamu BA, Emiru YK, Sintayehu B, Araya EM, Periasamy G, Gebrelibanos Hiben M. In vivo Hepatoprotective and in vitro Radical Scavenging Activities of Extracts of Rumex abyssinicus Jacq. Rhizome. J Exp Pharmacol. 2020;12:221-231.
Andreadou I, Schulz R, Badimon L, Adameova A, Kleinbongard P, Lecour S, et al. Hyperlipidaemia and cardio-protection: Animal models for translational studies. Br J Pharmacol. 2020;177:5287-5311.
Andrich DE, Ou Y, Melbouci L, Leduc-Gaudet JP, Auclair N, Mercier J, et al. Altered Lipid Metabolism Impairs Skeletal Muscle Force in Young Rats Submitted to a Short-Term High-Fat Diet. Front Physiol. 2018;9:1327.
Andrus SB, Fillios LC, Mann GV, Stare FJ. Experimental production of gross atherosclerosis in the rat. J Exp Med. 1956;104:539-54.
Ashafa AO, Orekoya LO, Yakubu MT. Toxicity profile of ethanolic extract of Azadirachta indica stem bark in male Wistar rats. Asian Pac J Trop Biomed. 2012;2:811-7.
Barnstable CJ, Zhang M, Tombran-Tink, J. Uncoupling Proteins as Therapeutic Targets for Neurodegenerative Diseases. Int J Mol Sci. 2022;23:5672.
Basu D, Huggins LA, Scerbo D, Obunike J, Mullick AE, Rothenberg PL, et al. Mechanism of Increased LDL (Low-Density Lipoprotein) and Decreased Triglycerides with SGLT2 (Sodium-Glucose Cotransporter 2) Inhibition. Arterioscler ThrombVasc Biol. 2018;38:2207-2216.
Bhardwaj S, Bhattacharjee J, Bhatnagar MK, Tyagi S. Atherogenic Index of Plasma, Castelli Risk Index and Atherogenic Coefficient- New Parameters In Assessing Cardiovascular Risk, Int J Pharm Biol. 2013;3:359-364.
Blainski A, Lopes GC, De Mello JC. Application and analysis of the folin ciocalteu method for the determination of the total phenolic content from Limonium brasiliense L. Molecules. 2013;18:6852-65.
Bruckert E. New advances in lipid-modifying therapies for reducing cardiovascular risk. Cardiology. 2002;97(2):59-66.
Busiello RA, Savarese S, Lombardi A. Mitochondrial uncoupling proteins and energy metabolism. Front Physiol. 2015;6:36.
Castrejon-Tellez V, Rodriguez-Perez JM, Perez-Torres I, Perez-Hernandez N, Cruz-Lagunas A, Guarner-Lans V, et al. The Effect of Resveratrol and Quercetin Treatment on PPAR Mediated Uncoupling Protein (UCP-) 1, 2, and 3 Expression in Visceral White Adipose Tissue from Metabolic Syndrome Rats. Int J Mol Sci. 2016;17:1069.
Clark BA, Alloosh M, Wenzel JW, Sturek M, Kostrominova TY. Effect of diet-induced obesity and metabolic syndrome on skeletal muscles of Ossabaw miniature swine. Am J Physiol Endocrinol Metab. 2011;300:e848-57.
Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci. 2013;9:191-200.
Debril MB, Renaud JP, Fajas L, Auwerx J. The pleiotropic functions of peroxisome proliferator-activated receptor gamma. J Mol Med (Berl). 2001;79:30-47.
Dhingra D, Lamba D, Kumar R, Nath P, Gauttam S. Antihyperlipidemic Activity of Aloe succotrina in Rats: Possibly Mediated by Inhibition of HMG-CoA Reductase. ISRN Pharmacol. 2014;2014:243575.
Elmowafy M, Ibrahim HM, Ahmed MA, Shalaby K, Salama A, Hefesha H. Atorvastatin-loaded nanostructured lipid carriers (NLCs): strategy to overcome oral delivery drawbacks. Drug Deliv. 2017; 24: 932-941.
Fajas L, Debril MB, Auwerx J. Peroxisome proliferator-activated receptor-gamma: from adipogenesis to carcinogenesis. J Mol Endocrinol. 2001;27:1-9.
Fang L, Guo F, Zhou L, Stahl R, Grams J. The cell size and distribution of adipocytes from subcutaneous and visceral fat is associated with type 2 diabetes mellitus in humans. Adipocyte. 2015;4:273-9.
Fava F, Lovegrove JA, Gitau R, Jackson KG, Tuohy KM. The gut microbiota and lipid metabolism: implications for human health and coronary heart disease. Curr Med Chem. 2006;13:3005-21.
Gamucci O, Lisi S, Scabia G, Marchi M, Piaggi P, Duranti E, et al. Haptoglobin deficiency determines changes in adipocyte size and adipogenesis. Adipocyte. 2012;1:142-183.
Ghezzi AC, Cambri LT, Botezelli JD, Ribeiro C, Dalia RA, de Mello MA. Metabolic syndrome markers in wistar rats of different ages. DiabetolMetabSyndr. 2012;4:16.
Giustarini D, Fanti P, Matteucci E, Rossi R. Micro-method for the determination of glutathione in human blood. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;964:191-4.
Gregory M, Divya B, Mary RA, Viji MM, Kalaichelvan VK, Palanivel V. Anti-ulcer activity of Ficus religiosa leaf ethanolic extract. Asian Pac J Trop Biomed. 2013;3:554-6.
Guo L, Li X, Tang QQ. Transcriptional regulation of adipocyte differentiation: a central role for CCAAT/enhancer-binding protein (C/EBP) β. J Biol Chem. 2015;290:755-61.
Hardie DG. AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels. Annu Rev Nutr. 2014;34:31-55.
Huesca-Gomez C, Torres-Paz YE, Fuentevilla-Alvarez G, Gonzalez-Moyotl NJ, Ramirez-Marroquin ES, Vasquez-Jimenez X, et al. Expressions of mRNA and encoded proteins of mitochondrial uncoupling protein genes (UCP1, UCP2, and UCP3) in epicardial and mediastinal adipose tissue and associations with coronary artery disease. Arch Endocrinol Metab. 2023;67:214-223.
Iqbal D, Khan MS, Khan A, Khan MS, Ahmad S, Srivastava AK, et al. In vitro screening for β-hydroxy-β-methylglutaryl-CoA reductase inhibitory and antioxidant activity of sequentially extracted fractions of Ficus palmate Forsk. Biomed Res Int. 2014;2014:762620.
Islam SU, Ahmed MB, Ahsan H, Lee YS. Recent Molecular Mechanisms and Beneficial Effects of Phytochemicals and Plant-Based Whole Foods in Reducing LDL-C and Preventing Cardiovascular Disease. Antioxidants (Basel). 2021;10:784.
Jezek P, Jaburek M, Porter RK. Uncoupling mechanism and redox regulation of mitochondrial uncoupling protein 1 (UCP1). Biochim Biophys Acta Bioenerg. 2019;1860:259-269.
John J, Nampoothiri M, Kumar N, Mudgal J, Nampurath GK, Chamallamudi MR. Sesamol, a lipid lowering agent, ameliorates aluminium chloride induced behavioral and biochemical alterations in rats. Pharmacogn Mag. 2015;11:327-36.
Khandelwal KR. Practical Pharmacognosy. 9th Edition, Delhi: Nirali Prakashan; 2002. 149-153.
Kim JA, Montagnani M, Chandrasekran S, Quon MJ. Role of lipotoxicity in endothelial dysfunction. Heart Fail Clin. 2012;8:589-607.
Krause BR, Newton RS. Lipid-lowering activity of atorvastatin and lovastatin in rodent species: triglyceride-lowering in rats correlates with efficacy in LDL animal models. Atherosclerosis. 1995;117:237-44.
Kumar DG, Deepa P, Rathi MA, Meenakshi P, Gopalakrishnan VK. Modulatory effects of Crataeva nurvala bark against testosterone and N-methyl-N-nitrosourea-induced oxidative damage in prostate of male albino rats. Pharmacogn Mag. 2012;8:285-91.
Kumar V, Sharma P, Bairagya HR, Sharma S, Singh TP, Tiku PK. Inhibition of human 3-hydroxy-3-methylglutaryl CoA reductase by peptides leading to cholesterol homeostasis through SREBP2 pathway in HepG2 cells. Biochim Biophys Acta Proteins Proteom. 2019;1867:604-615.
Kupfer D, Munsell T. A colorimetric method for the quantitative determination of reduced pyridine nucleotides (NADPH and NADH). Anal Biochem. 1968;25:10–16.
Lee JE, Schmidt H, Lai B, Ge K. Transcriptional and Epigenomic Regulation of Adipogenesis. Mol Cell Biol. 2019;39:e00601-18.
Loh K, Tam S, Murray-Segal L, Huynh K, Meikle PJ, Scott JW, et al. Inhibition of Adenosine Monophosphate-Activated Protein Kinase-3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Signaling Leads to Hypercholesterolemia and Promotes Hepatic Steatosis and Insulin Resistance. Hepatol Commun. 2018;3:84-98.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265-75.
Mahmoodi MR, Najafipour H. Associations between serum vitamin D3, atherogenic indices of plasma and cardiometabolic biomarkers among patients with diabetes in the KERCADR study. BMC Endocr Disord. 2022;22:126.
Meharie BG, Amare GG, Belayneh YM. Evaluation of Hepatoprotective Activity of the Crude Extract and Solvent Fractions of Clutiaabys sinica (Euphorbiaceae) Leaf Against CCl4-Induced Hepatotoxicity in Mice. J ExpPharmacol. 2020;12:137-150.
Mengesha T, Gnanasekaran N, Mehare T. Hepatoprotective effect of silymarin on fructose induced nonalcoholic fatty liver disease in male albino wistar rats. BMC Complement Med Ther. 2021;21:104.
Meriga B, Ganjayi MS, Parim BN. Phytocompounds as Potential Agents to Treat Obesity-Cardiovascular Ailments. Cardiovasc Hematol Agents Med Chem. 2017;30.
Nadkami KM. Indian Materia Medica. Bombay: Popular Prakashan; 2017. 388.
Niki E, Yoshida Y, Saito Y, Noguchi N. Lipid peroxidation: mechanisms, inhibition, and biological effects. Biochem Biophys Res Commun. 2005;338(1):668-76.
Nortjie E, Basitere M, Moyo D, Nyamukamba P. Extraction methods, quantitative and qualitative phytochemical screening of medicinal plants for antimicrobial textiles: a review. Plants. 2022;11:2011.
Odukoya JO, Odukoya JO, Mmutlane EM, Ndinteh DT. Ethnopharmacological Study of Medicinal Plants Used for the Treatment of Cardiovascular Diseases and Their Associated Risk Factors in sub-Saharan Africa. Plants (Basel). 2022;11:1387.
OECD Guidelines for the testing of chemicals, revised draft guidelines 423: Acute Oral toxicity- Acute toxic class method, revised document, CPCSEA, Ministry of Social Justice and Empowerment, Govt. of India. 2000.
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction, Anal Biochem. 1979;95:351-358.
Parveen M, Azeem M, Aslam A, Azam M, Siddiqui S, Tabish M, et al. Isolation, Identification, Spectral Studies and X-ray Crystal Structures of Two Compounds from Bixa orellana, DFT Calculations and DNA Binding Studies. Crystals. 2022;12(3):380.
Pedersen TA, Bereshchenko O, Garcia-Silva S, Ermakova O, Kurz E, Mandrup S, et al. Distinct C/EBPalpha motifs regulate lipogenic and gluconeogenic gene expression in vivo. EMBO J. 2007;26:1081-93.
Ross FA, Jensen TE, Hardie DG. Differential regulation by AMP and ADP of AMPK complexes containing different γ subunit isoforms. Biochem J. 2016;473:189-99.
Roy A, Khan A, Ahmad I, Alghamdi S, Rajab BS, Babalghith AO, et al. Flavonoids a Bioactive Compound from Medicinal Plants and Its Therapeutic Applications. Biomed Res Int. 2022;2022:5445291.
Ruotolo G, Howard BV. Dyslipidemia of the metabolic syndrome. Curr Cardiol Rep. 2002;4:494-500.
Sikarwar MS, Patil MB. Antihyperlipidemic activity of Salacia chinensis root extracts in triton-induced and atherogenic diet-induced hyperlipidemic rats. Indian J Pharmacol. 2012;44:88-92.
Sztolsztener K, Bzdęga W, Hodun K, Chabowski A. N-Acetylcysteine Decreases Myocardial Content of Inflammatory Mediators Preventing the Development of Inflammation State and Oxidative Stress in Rats Subjected to a High-Fat Diet. Int J Inflam. 2023;2023:5480199.
Tao C, Sifuentes A, Holland WL. Regulation of glucose and lipid homeostasis by adiponectin: effects on hepatocytes, pancreatic β cells and adipocytes. Best Pract Res Clin Endocrinol Metab. 2014;28:43-58.
Tipple TE, Rogers LK. Methods for the determination of plasma or tissue glutathione levels. Methods Mol Biol. 2012;889:315-24.
Tungmunnithum D, Thongboonyou A, Pholboon A, Yangsabai A. Flavonoids and Other Phenolic Compounds from Medicinal Plants for Pharmaceutical and Medical Aspects: An Overview. Medicines (Basel). 2018;5:93.
Unger RH, Clark GO, Scherer PE, Orci L. Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim Biophys Acta. 2010;1801:209-14.
Varga T, Czimmerer Z, Nagy L. PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta. 2011;1812:1007-22.
Villarroya F, Iglesias R, Giralt M. PPARs in the Control of Uncoupling Proteins Gene Expression. PPAR Res. 2007;2007:74364.
Vogel HG. Drug Discovery and Evaluation: Pharmacological Assays. Second Edition. Springer-Verlag 2002.
Yan Y, Gu X, Xu HE, Melcher K. A Highly Sensitive Non-Radioactive Activity Assay for AMP-Activated Protein Kinase (AMPK). Methods Protoc. 2018;1:3.
Zhou M, Zhu L, Cui X, Feng L, Zhao X, He S, et al. The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of insulin resistance but not of β cell function in a Chinese population with different glucose tolerance status. Lipids Health Dis. 2016;15:104.
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