How are the anti-sugar and antioxidant effects of Verbascum glycosides reflected?

For more information please contact: Joanna.jia@wecistanche.com

CLICK HERE TO PART 1

Discussion

Herbal medicines provide a valuable source of new antidiabetic therapies that could be safe and cost-effective [26]. Acteoside [(2R,3R,4R,5R,6R)-6-[2-(3,4-dihydroxyphenyl)ethoxy]- 5-hydroxy-2-(hydroxymethyl)-4-[(2S,3R,4R,5R,6S)- 3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-3-yl] (E)-3-(3,4-dihydroxyphenyl)prop-2-enoate) was isolated

from many medicinal plants and is becoming of interest because of its wide range of pharmacological actions [27]. Acteoside utilized in this work was isolated from Jacaranda mimosifolia D. leaves grown in Egypt. Hereby, we explored the antidiabetic effect of acteoside in a rat model of diabetes-induced by STZ-NA. This animal model of Type 2 diabetes is considered a well-accepted experimental model that allows for preclinical examination of potential new antidiabetic agents [28]. In this work, pioglitazone was used for comparison. Pioglitazone belongs to the thiazolidinediones (TZDs) group of drugs that are used in the treatment of Type 2 diabetes. TZDs act as insulin sensitizers through activation of peroxisome proliferator-activated receptor-gamma (PPARγ) receptors. Activation of these nuclear receptors affects glucose and lipid metabolism [29]. Results of the current work demonstrated significant antidiabetic and antioxidant effects of acteoside that were comparable to that of pioglitazone. Acteoside or pioglitazone treatment for 3 weeks caused a significant decrease in serum glucose and HbA1c as compared to their levels in control diabetic rats. This was associated with a beneficial effect on body weight in contrast to the weight loss demonstrated in the diabetic untreated group. Pioglitazone restored the reductions in rats’ body weight caused by STZ-induced diabetes. This effect is reported by other studies and could be attributed to an increase in insulin sensitivity which is a part of pioglitazone pharmacological actions [30]. However, in some reports, the drug was found to increase body weight due to increased appetite, lipogenesis, and fluid retention [31]. These different results in the literature could be related to the diabetes model used and the duration of the study. Improvement of body weight caused by acteoside could be related to its ability to reduce hyperglycemia. Other studies reported that acteoside reduces weight due to inhibition of pancreatic lipase [32] as well as improving levels of postprandial glucose in response to a load of starch in mice [14].

Cistanche deserticola has many effects, click here to know more

Our study demonstrated an antihyperglycemic effect of acteoside in STZ-NA-induced diabetes. Hyperglycemia increases the liability of proteins to glycation resulting in changes in their structure and function. Non-enzymatic glycation of globin fraction of hemoglobin produces HbA1c which is used for reliable monitoring of glycemic control in diabetes [33]. In agreement with the previous reports using the STZ-NA model of diabetes; in this investigation, HBA1c was higher in the diabetic model group compared to the control vehicle group [34], [35]. Treatment with either pioglitazone or acteoside improved glycemic control over the study period as indicated by blood glucose and HbA1c levels in the treated groups. Pioglitazone

as a PPAR γ agonist improves fasting blood glucose and HA1c through increased insulin sensitivity in liver, muscle, and adipose tissue; effects were repeatedly reported both in experimental and in human diabetes [36], [37]. There was a comparable effect of acteoside on glycemic control in this study. This could be mediated through acteoside ability to scavenge free radicals produced by STZ with the improvement of beta-cell function and insulin levels or through improving target organ response to insulin. Acteoside successfully prevented in vitro production of advanced glycation end products (AGE) [12]. These products were found to induce resistance to insulin action in adipocytes, muscles, and hepatocytes [38]. In addition, high levels of AGE produced in chronic hyperglycemia bind to cell membrane receptors to increase free radicals through activating NADPH oxidase [39]. Taking these studies into consideration, acteoside could have exerted its beneficial effect in diabetic rats, at least partly, through improving insulin resistance. The findings of this study showed that 3 weeks of treatment with pioglitazone or acteoside exerted a significant amelioration of total cholesterol and triglyceride (TG) levels, hepatic lipid peroxidation, and GSH. Moreover, it prevented the histopathological changes in liver architecture associated with STZ-NA diabetes. Reactive oxygen species production is augmented in diabetes and prolonged oxidative burden plays a part in the development of long-term diabetes-related complications. Antidiabetic agents offering antioxidant action could be effective in preventing or at least delaying, and progression of diabetes complications [40]. Pioglitazone antioxidant capacity is well documented in STZ models of diabetes and in various tissues including the liver [36], [41]. Structure-activity studies of acteoside revealed that the hydroxyphenyl ethyl and caffeoyl moieties of the compound are thought to be responsible for its antioxidant effects [27]. In the current experiment, to examine the antioxidant activity of acteoside in comparison to pioglitazone, hepatic MDA contents – an indicator of lipid peroxidation – and GSH liver contents were estimated. In addition, in vitro study using DPPH assay was employed to assess acteoside free radical scavenging activity. Acteoside showed antioxidant activity in vitro and was able to reduce MDA levels and restore GSH in livers of diabetic rats. Consistent with these results, previous studies reported the ability of acteoside to cause a significant reduction in lipid peroxidation and reversal of hepatic GSH depletion induced by carbon tetrachloride [8]. In a different study by Peerzada et al. [10], acteoside was able to protect rat liver cells against diethylnitrosamine-induced carcinogenesis by preventing DNA damage and cell apoptosis. The effect was further elucidated through nucleoside's ability to scavenge reactive oxygen species produced by diethylnitrosamine. Furthermore, in a prior study, acteoside protected pulmonary endothelial cells against oxidative stress induced by hydroxyl radicals. In this mentioned study, acteoside also demonstrated the

acteoside in cistanche can anti-aging

ability to scavenge DPPH radicals in a dose-dependent manner [42]. Studies investigating the antioxidant property of various phenylethanoids especially acteoside have demonstrated that these compounds protect cells due to their direct antioxidant and scavenging activity of free radicals. Other reports further explained the antioxidant effect of acteoside at subcellular levels. Acteoside upregulates the endogenous antioxidantdefensive systems [43]. This effect of acteoside could be exerted at the level of post-transitional modification or at gene transcription of redox enzymes. In vitro and in vivo neuroprotective effects of acteoside were found to occur through activation of Nrf2, a transcription factor for genes encoding antioxidant and stress-responsive proteins [9], [44]. The liver is one of the major organs affected by impaired insulin levels or action. In diabetes, there is the activation of glycogenolysis leading to higher hepatic production of glucose. Furthermore, insulin resistance through changes in lipid metabolism and provision of inflammatory milieu contribute to the development of liver fatty changes. High levels of free fatty acids in insulin resistance can exert a direct toxic effect on hepatocytes and increase pro-inflammatory cytokines release contributing to hepatocellular changes seen in diabetes [45]. In our experiment, diabetic rats demonstrated higher levels of total cholesterol and triglycerides than the levels found in control non-diabetic rats. After 3 weeks of daily administration of acteoside or pioglitazone, the levels of total cholesterol and triglycerides were improved in the diabetic group compared to their counterpart levels in diabetic untreated rats. In addition, histopathological examination of livers from diabetic rats showed histopathological changes that were significantly ameliorated by treatment with either pioglitazone or acteoside. This pioglitazone effect is in line with the previous reports. Pioglitazone ameliorated increases in total cholesterol and TG in STZ-induced diabetes; an effect that was accompanied by upregulation of hepatic PPARγ [46]. Regarding the improvement in cholesterol and TG levels after treatment with acteoside, it could be explained by its antidiabetic effect which was sustained throughout the study period as indicated by lower levels of HBA1c in treated rats. However, the literature provides evidence linking acteoside to PPAR-alpha (PPAR-α). PPAR-α is expressed in high amounts in the liver, muscles, heart, and kidney, and acts chiefly to control genes concerned with lipids and lipoproteins metabolism. In the liver, this transcription factor controls the genes of proteins and enzymes regulating β-oxidation of fatty acids and lipid transport [47]. In a report by Esposito et al. [48], PPAR-α was linked to the anti-inflammatory effect of acteoside in an experimental inflammatory bowel disease model of PPAR-α knock-out mice. Moreover, in a recent review of natural products with potential anti-dyslipidemic effect through targeting PPAR-α, acteoside was considered as one of these products [49]. However, more studies are needed to prove this mechanism of acteoside action.

acteoside in cistanche can boost the immune system

Conclusion

The evidence from this study suggests that acteoside has antidiabetic and antioxidant effects. In addition, it offered advantages in the control of Type 2 diabetes induced by STZ-NA in rats through ameliorating body weight changes, cholesterol, and TG levels. The antioxidant effects were evidenced by reducing lipid peroxidation, DDPH activity, and elevating GSH content as well as ameliorating hepatic histopathological alterations of diabetes. However, more in-depth experimental studies of the detailed mechanisms behind these beneficial effects are warranted.

Acknowledgment

The authors are grateful to Prof. Adel Baker, Professor of Pathology, Faculty of Veterinary Medicine, Cairo University, for his assistance in conducting the histopathological examination.

acteoside in cistanche can enhance memory

References

1. Zheng Y, Ley SH, Hu FB. Global etiology and epidemiology of Type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88-98. https://doi.org/10.1038/ Nuendo.2017.151 PMid:29219149 2. Krentz AJ, Clough G, Byrne CD. Interactions between microvascular and macrovascular disease in diabetes: Pathophysiology and therapeutic implications. Diabetes Obes Metab. 2007;9(6):781-91. https://doi. org/10.1111/j.1463-1326.2007.00670.x PMid:17924862 3. Chaudhury A, Dufour C, Reddy Dendi VS, Kraleti S, Chada A, Ravilla R, et al. Clinical Review of antidiabetic drugs: Implications for Type 2 diabetes mellitus management. Front Endocrinol (Lausanne). 2017;8:6. https://doi.org/10.3389/ Vendo.2017.00006 PMid:28167928 4. Mohammed A, Ibrahim MA, Islam MS. African medicinal plants with antidiabetic potentials: A review. Planta Med. A - Basic Sciences Pharmacology 132 https://www.id-press.eu/mjms/index 2014;80(5):354-77. https://doi.org/10.1055/s-0033-1360335 PMid:24535720 5. Fatma AM, Mohamed SM. A novel phenylethanoid dimer and flavonoids from Jacaranda mimosifolia. Für Naturforschung. 2007;62:1213. https://doi.org/10.1515/znb-2007-0918 6. Potapovich AI, Kostyuk VA, Kostyuk TV, de Luca C, Korkina LG. Effects of pre-and post-treatment with plant polyphenols on human keratinocyte responses to solar UV. Inflamm Res. 2013;62(8):773-80. https://doi.org/10.1007/s00011-013-0634-z PMid:23689555 7. Seo ES, Oh BK, Pak JH, Yim SH, Gurunathan S, Kim YP, et al. Acteoside improves survival in cecal ligation and punctureinduced septic mice via blocking of high mobility group box 1 release. Mol Cells. 2013;35(4):348-54. https://doi.org/10.1007/ s10059-013-0021-1 PMid:23563799 8. Lee KJ, Woo ER, Choi CY, Shin DW, Lee DG, You HJ, et al. Protective effect of acteoside on carbon tetrachloride-induced hepatotoxicity. Life Sci. 2004;74(8):1051-64. https://doi. org/10.1016/j.lfs.2003.07.020 PMid:14672760 9. Kostyuk VA, Potapovich AI, Suhan TO, de Luca C, Korkina LG. Antioxidant and signal modulation properties of plant polyphenols in controlling vascular inflammation. Eur J Pharmacol. 2011;658(2-3):248-56. https://doi.org/10.1016/j. ejphar.2011.02.022 PMid:21371465 10. Peerzada KJ, Faridi AH, Sharma L, Bhardwaj SC, Satti NK, Shashi B, et al. Acteoside-mediates chemoprevention of experimental liver carcinogenesis through STAT-3 regulated oxidative stress and apoptosis. Environ Toxicol. 2016;31(7):782- 98. https://doi.org/10.1002/tox.22089 PMid:26990576 11. Yuan J, Ren J, Wang Y, He X, Zhao Y. Acteoside binds to caspase-3 and exerts neuroprotection in the rotenone rat model of Parkinson's disease. PLoS One. 2016;11(9):e0162696. https://doi.org/10.1371/journal.pone.0162696 PMid:27632381 12. Liu YH, Lu YL, Han CH, Hou WC. Inhibitory activities of acteoside, isoacteoside, and its structural constituents against protein glycation in vitro. Bot Stud. 2013;54(1):6. https://doi. org/10.1186/1999-3110-54-6 PMid:28510849 13. Xiong WT, Gu L, Wang C, Sun HX, Liu X. Anti-hyperglycemic and hypolipidemic effects of Cistanche tubulosa in Type 2 diabetic DB/DB mice. J Ethnopharmacol. 2013;150(3):935-45. https://doi.org/10.1016/j.jep.2013.09.027 PMid:24095831 14. Morikawa T, Ninomiya K, Imamura M, Akaki J, Fujikura S, Pan Y, et al. Acylated phenylethanoid glycosides, echinacoside and acteoside from Cistanche tubulosa, improve glucose tolerance in mice. J Nat Med. 2014;68(3):561-6. https://doi.org/10.1007/ s11418-014-0837-9 PMid:24748124 15. El-Mary SA, Abdallah HM, El-Shenawy SM, El-Khatib AS, El-Shabrawy OA, Kenawy SA. Anti-depressant effect of hesperidin in diabetic rats. Can J Physiol Pharmacol. 2014;92(11):945-52. https://doi.org/10.1139/cjpp-2014-0281 PMid:253580 20 16. Kröger H, Dietrich A, Ohde M, Lange R, Ehrlich W, Kurpisz M. Protection from acetaminophen-induced liver damage by the synergistic action of low doses of the poly(ADP-ribose) polymerase-inhibitor nicotinamide and the antioxidant N-acetylcysteine or the amino acid L-methionine. Gen Pharmacol. 1997;28(2):257-63. https://doi.org/10.1016/ s0306-3623(96)00181-4 PMid:9013204 17. Liu S, Zhang J, Li W, Zhang T, Hu D. Acteoside reduces testosterone by inhibiting cAMP, p450scc, and StAR in rat Leydig cells. Mol Cell Toxicol. 2015;11:11-7. https://doi.org/10.1007/ s13273-015-0002-x 18. Vidal R, Valdizán EM, Most any R, Pazos A, Castro E. Longterm treatment with fluoxetine induces desensitization of 5-HT4 receptor-dependent signaling and functionality in rat brain. J Neurochem. 2009;110(3):1120-7. https://doi. org/10.1111/j.1471-4159.2009.06210.x PMid:19522734 19. Trinder P. Determination of blood glucose using 4-amino phenazone as oxygen acceptor. J Clin Pathol. 1969;22(2):246. https://doi.org/10.1136/jcp.22.2.246-b PMid:5776563 20. Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem. 1982;28(10):2077-80. https://doi. org/10.1093/clincher/28.10.2077 PMid:6812986 21. Satoh K. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta. 1978;90(1):37-43. https://doi. org/10.1016/0009-8981(78)90081-5 PMid:719890 22. Beutler E, Duron O, Kelly BM. An improved method for the determination of blood glutathione. J Lab Clin Med. 1963;61:882-8. PMid:13967893 23. Peiwu L, Hopia A, Jari S, Yrjönen T, Vuorela H. TLC Method for Evaluation of Free Radical Scavenging Activity of Rapeseed Meal by Video Scanning Technology. In: Proceedings of the 10th International Rapeseed Congress; 1999. 24. Govindarajan R, Rastogi S, Vijayakumar M, Shirwaikar A, Rawat AK, Mehrotra S, et al. Studies on the antioxidant activities of Desmodium gangeticum. Biol Pharm Bull. 2003;26(10):1424-7. https://doi.org/10.1248/bpb.26.1424 PMid:14519948 25. Bancroft JD, Gamble M. Theory and Practice of Histological Techniques. 6th ed. Edinburgh: Churchill Livingstone; 2008. 26. Tiwari P. Recent trends in therapeutic approaches for diabetes management: A comprehensive update. J Diabetes Res. 2015;2015:340838. PMid:26273667 27. Alipieva K, Korkina L, Orhan IE, Georgiev MI. Verbascoside is a review of its occurrence, (bio)synthesis, and pharmacological significance. Biotechnol Adv. 2014;32(6):1065-76. https://doi. org/10.1016/j.biotechadv.2014.07.001 PMid:25048704 28. Szkudelski T. Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med (Maywood). 2012;237(5):481-90. https://doi.org/10.1258/ EBM.2012.011372 PMid:22619373 29. Soccio RE, Chen ER, Lazar MA. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab. 2014;20(4):573-91. https://doi.org/10.1016/j.cmet.2014.08.005 PMid:25242225 30. Staels B. Metformin and pioglitazone: Effectively treating insulin resistance. Curr Med Res Opin. 2006;22(Suppl 2): S27-37. PMid:16914073 31. Lehrke M, Lazar MA. The many faces of PPARgamma. Cell. 2005;123(6):993-9. PMid:16360030El-Marasy et al. Antidiabetic and Antioxidant Effects of Acteoside in STZ–NA Diabetes in Rats Open Access Maced J Med Sci. 2020 Apr 10; 8(A):125-133. 133 32. Han LK, Kimura Y, Kawashima M, Takaku T, Taniyama T, Hayashi T, et al. Anti-obesity effects in rodents of dietary tea saponin, a lipase inhibitor. Int J Obes Relat Metab Disord. 2001;25(10):1459-64. https://doi.org/10.1038/sj.ijo.0801747 PMid:11673766 33. Monnier L, Colette C. Target for glycemic control: Concentrating on glucose. Diabetes Care 2009;32(Suppl 2): S199-204. HTTPS:// doi.org/10.2337/dc09-s310 PMid:19875552 34. Dhananjayan I, Kathiroli S, Subramani S, Veerasamy V. Ameliorating effect of betanin, a natural chromoalkaloid by modulating hepatic carbohydrate metabolic enzyme activities and glycogen content in streptozotocin nicotinamide induced experimental rats. Biomed Pharmacother. 2017;88:1069-79. https://doi.org/10.1016/j.biopha.2017.01.146 PMid:28192880 35. Muruganathan U, Srinivasan S, Vinothkumar V. Antidiabetogenic efficiency of menthol, improves glucose homeostasis and attenuates pancreatic β-cell apoptosis in streptozotocinnicotinamide induced experimental rats through ameliorating glucose metabolic enzymes. Biomed Pharmacother. 2017;92:229-39. https://doi.org/10.1016/j.biopha.2017.05.068 PMid:28549291 36. Chaudhry J, Ghosh NN, Roy K, Chandra R. Antihyperglycemic effect of a new thiazolidinedione analog and its role in ameliorating oxidative stress in alloxan-induced diabetic rats. Life Sci. 2007;80(12):1135-42. https://doi.org/10.1016/j. life.2006.12.004 PMid:17234217 37. Filipova E, Uzunova K, Kalinov K, Vekov T. Effects of pioglitazone therapy on blood parameters, weight and BMI: A meta-analysis. Diabetol Metab Syndr. 2017;9:90. https://doi. org/10.1186/s13098-017-0290-5 PMid:29163673 38. Ottum MS, Mistry AM. Advanced glycation end-products: Modifiable environmental factors profoundly mediate insulin resistance. J Clin Biochem Nutr. 2015;57(1):1-2. https://doi. org/10.3164/job.15-3 PMid:26236094 39. Calcutt NA, Cooper ME, Kern TS, Schmidt AM. Therapies for hyperglycemia-induced diabetic complications: From animal models to clinical trials. Nat Rev Drug Discov. 2009;8(5):417-29. https://doi.org/10.1038/nrd2476 PMid:19404313 40. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058-70. https://doi. org/10.1161/circresaha.110.223545 PMid:21030723 41. Zaitone SA, Barakat BM, Bilasy SE, Fawzy MS, Abdelaziz EZ, Farag NE. Protective effect of Boswellia acids versus pioglitazone in a rat model of diet-induced non-alcoholic fatty liver disease: Influence on insulin resistance and energy expenditure. Naunyn Schmiedebergs Arch Pharmacol. 2015;388(6):587-600. HTTPS:// doi.org/10.1007/s00210-015-1102-9 PMid:25708949 42. Chiou WF, Lin LC, Chen CF. Acteoside protects endothelial cells against free radical-induced oxidative stress. J Pharm Pharmacol. 2004;56(6):743-8. https://doi.org/10.1211/0022357023501 PMid:15231039 43. Sgarbossa A, Dal Bosco M, Press G, Cuzzocrea S, Dal Toso R, Menegazzi M. Phenylpropanoid glycosides from plant cell cultures induce heme oxygenase 1 gene expression in a human keratinocyte cell line by affecting the balance of NRF2 and BACH1 transcription factors. Chem Biol Interact. 2012;199(2):87-95. https://doi.org/10.1016/j.cbi.2012.06.006 PMid:22735309 44. Wang HQ, Xu YX, Zhu CQ. Upregulation of heme oxygenase-1 by acteoside through ERK and PI3 K/Akt pathway confers neuroprotection against beta-amyloid-induced neurotoxicity. Neurotox Res. 2012;21(4):368-78. https://doi.org/10.1007/ s12640-011-9292-5 PMid:22147269 45. Loria P, Lonardo A, Anania F. Liver and diabetes. A vicious circle. Hepatol Res. 2013;43(1):51-64. https://doi. org/10.1111/j.1872-034x.2012.01031.x PMid:23332087 46. Plaidy SM, Hussain MA, El-Kherbetawy MK. Time-dependent therapeutic roles of nitazoxanide on high-fat diet/streptozotocin-induced diabetes in rats: Effects on hepatic peroxisome proliferator-activated receptor-gamma receptors. Can J Physiol Pharmacol. 2018;96(5):485-97. https://doi.org/10.1139/ app-2017-0533 PMid:29244961 47. Staels B, Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes. 2005;54(8):2460-70. https://doi.org/10.2337/diabetes.54.8.2460 PMid:16046315 48. Esposito E, Mazzon E, Paterniti I, Dal Toso R, Press G, Caminiti R, et al. PPAR-alpha contributes to the anti-inflammatory activity of verbascoside in a model of inflammatory bowel disease in mice. PPAR Res. 2010;2010:917312. HTTPS:// doi.org/10.1155/2010/917312 PMid:20671911 49. Rigano D, Sirignano C, Taglialatela-Scafati O. The potential of natural products for targeting PPARα. Acta Pharm Sin B. 2017;7(4):427-38. https://doi.org/10.1016/j.apsb.2017.05.005 PMid:28752027