We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Research Article

Improved oral nutraceutical-based intervention for the management of obesity: pterostilbene-loaded chitosan nanoparticles

    Lamia A Heikal

    Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, El-Khartoum square, Azarita, Postal code: 21521, Alexandria, Egypt

    ,
    Amal H El-Kamel

    *Author for correspondence: Tel.: +20 100 508 0510;

    E-mail Address: amalelkamel@alexu.edu.eg

    Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, El-Khartoum square, Azarita, Postal code: 21521, Alexandria, Egypt

    ,
    Radwa A Mehanna

    Department of Medical Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Centre of Excellence for Research in Regenerative Medicine and its Applications CERRMA, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    ,
    Hoda M Khalifa

    Department of Histology & Cell Biology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    &
    Passainte S Hassaan

    Department of Medical Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Published Online:https://doi.org/10.2217/nnm-2022-0158

    Aim: To formulate and assess the oral anti-obesity effect of polymeric-based pterostilbene (PS)-loaded nanoparticles. Methods: Pterostilbene–hydroxypropyl β-cyclodextrin inclusion complex loaded in chitosan nanoparticles (PS/HPβCD-NPs) were prepared and characterized in vitro. Cytotoxicity, pharmacokinetics and anti-obesity effects were assessed on Caco-2 cell line and high-fat-diet-induced obesity rat model, respectively. In vivo assessment included histological examination, protein and gene expression of obesity biomarkers in adipose tissues. Results: Safe PS/HPβCD-NPs were successfully prepared with improved bioavailability compared with free PS. PS/HPβCD-NPs showed an improved anti-obesity effect, as supported by histological examination, lipid profile, UCP1 gene expression and protein expression of SIRT1, COX2, IL-6 and leptin. Conclusion: Orally administered PS nanoparticles represent a new and promising anti-obesity strategy owing to the sustainable weight loss and minimal side effects; this may be of great socio-economic impact.

    Plain language summary

    Weight gain or obesity represents a major health risk and leads to diseases including cancer and heart disease. Most anti-obesity medications have significant side effects, and there are notable challenges concerning their availability in the body to produce an effect. Pterostilbene is a herbal drug with beneficial anti-obesity effects. However, it has problems such as poor solubility which restrict its use. The aim of the study was to formulate pterostilbene in a nano-based delivery system and fully characterize its anti-obesity effect when given orally. We evaluated the safety and anti-obesity effects of pterostilbene nanoparticles in cells and in obese rats fed on a high-fat diet. We also looked at how the body absorbs, distributes and gets rid of these nanoparticles. The prepared nanoparticles were nontoxic, with an improved anti-obesity effect; they decreased cholesterol levels and helped in changing white fat (which stores fat) to brown fat (which burns calories). We conclude that the developed pterostilbene nanoparticles, given orally, are a new and promising anti-obesity strategy given their long-lasting effect on weight loss and the minimal side effects. This may be of great economic and societal impact.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest

    References

    • 1. Afshin A, Forouzanfar MH, Reitsma MB et al. Health effects of overweight and obesity in 195 countries over 25 years. N. Engl. J. Med 377(1), 13–27 (2017).
    • 2. Albuquerque D, Nóbrega C, Manco L, Padez C. The contribution of genetics and environment to obesity. Br. Med. Bull. 123(1), 159–173 (2017).
    • 3. Chait A, Den Hartigh LJ. Adipose tissue distribution, inflammation and its metabolic consequences, including diabetes and cardiovascular disease. Front. Cardiovasc. Med. 7, 22 (2020).
    • 4. Baker JS, Supriya R, Dutheil F, Gao Y. Obesity: treatments, conceptualizations, and future directions for a growing problem. Biology (Basel) 11(2), 160 (2022).
    • 5. Pan MH, Wu JC, Ho CT, Lai CS. Antiobesity molecular mechanisms of action: resveratrol and pterostilbene. Biofactors 44(1), 50–60 (2018). • This reference is very helpful in understanding the mechanism of action of the (PS) as anti-obesity drug
    • 6. Moonen MPB, Nascimento EBM, Van Marken Lichtenbelt WD. Human brown adipose tissue: underestimated target in metabolic disease? Biochim. Biophys. Acta Mol. Cell. Biol. Lipids 1864(1), 104–112 (2019).
    • 7. Montanari T, Pošćić N, Colitti M. Factors involved in white-to-brown adipose tissue conversion and in thermogenesis: a review. Obes. Rev. 18(5), 495–513 (2017).
    • 8. Ghosh S, Manchala S, Raghunath M, Sharma G, Singh AK, Sinha JK. Role of phytomolecules in the treatment of obesity: targets, mechanisms and limitations. Curr. Top. Med. Chem. 21(10), 863–877 (2021).
    • 9. De Araújo FF, De Paulo Farias D, Neri-Numa IA, Pastore GM. Polyphenols and their applications: an approach in food chemistry and innovation potential. Food Chem. 338, 127535 (2021).
    • 10. Chan EWC, Wong CW, Tan YH, Foo JPY, Wong SK, Chan HT. Resveratrol and pterostilbene: a comparative overview of their chemistry, biosynthesis, plant sources and pharmacological properties. J. Appl. Pharm. Sci. 9(7), 124–129 (2019).
    • 11. Biasutto L, Mattarei A, Azzolini M et al. Resveratrol derivatives as a pharmacological tool: resveratrol derivatives. Ann. NY Acad. Sci. 1403(1), 27–37 (2017).
    • 12. Etxeberria U, Hijona E, Aguirre L et al. Pterostilbene-induced changes in gut microbiota composition in relation to obesity. Mol. Nutr. Food Res. 61(1), doi:10.1002/mnfr.201500906 (2017) (Epub ahead of print).
    • 13. Moustafa EM, Rashed ER, Rashed RR. Pterostilbene inhibits dyslipidemia-induced activation of progenitor adipose gene under high-fat diet and radiation stressor. Natural Product Communications 16(3), doi:10.1177/1934578X211001267 (2021) (Epub ahead of print).
    • 14. Nagao K, Jinnouchi T, Kai S, Yanagita T. Pterostilbene, a dimethylated analog of resveratrol, promotes energy metabolism in obese rats. J. Nutr. Biochem. 43, 151–155 (2017).
    • 15. Milton-Laskíbar I, Gómez-Zorita S, Arias N et al. Effects of resveratrol and its derivative pterostilbene on brown adipose tissue thermogenic activation and on white adipose tissue browning process. J. Physiol. Biochem. 76(2), 269–278 (2020). • This is very helpful in understanding the mechanism of action of PS as anti-obesity drug
    • 16. Wen W, Lowe G, Roberts CM et al. Pterostilbene, a natural phenolic compound, synergizes the antineoplastic effects of megestrol acetate in endometrial cancer. Sci. Rep. 7(1), 12754 (2017).
    • 17. Gómez-Zorita S, Trepiana J, Fernández-Quintela A, González M, Portillo MP. Resveratrol and pterostilbene, two analogue phenolic compounds, affect aquaglyceroporin expression in a different manner in adipose tissue. Int. J. Mol. Sci. 19(9), 2654 (2018).
    • 18. Gomez-Zorita S, Belles C, Briot A, Fernández-Quintela A, Portillo MP, Carpéné C. Pterostilbene inhibits lipogenic activity similar to resveratrol or caffeine but differently modulates lipolysis in adipocytes. Phytother. Res. 31(8), 1273–1282 (2017).
    • 19. Matshetshe KI, Parani S, Manki SM, Oluwafemi OS. Preparation, characterization and in vitro release study of β-cyclodextrin/chitosan nanoparticles loaded Cinnamomum zeylanicum essential oil. Int. J. Biol. Macromol. 118(Pt A), 676–682 (2018).
    • 20. Bagheri R, Ariaii P, Motamedzadegan A. Characterization, antioxidant and antibacterial activities of chitosan nanoparticles loaded with nettle essential oil. J. Food Meas. Charact. 15, 1395–1402 (2021).
    • 21. Alizadeh N, Malakzadeh S. Antioxidant, antibacterial and anti-cancer activities of β-and γ-CDs/curcumin loaded in chitosan nanoparticles. Int. J. Biol. Macromol. 147, 778–791 (2020).
    • 22. Ding W-Y, Zheng S-D, Qin Y et al. Chitosan grafted with β-cyclodextrin: synthesis, characterization, antimicrobial activity, and role as absorbefacient and solubilizer. Front. Chem. 6, 657 (.2019).
    • 23. Shahid N, Erum A, Zaman M et al. Synthesis and evaluation of chitosan based controlled release nanoparticles for the delivery of ticagrelor. Des. Monomers Polym. 25(1), 55–63 (2022).
    • 24. Houben T, Yadati T, De Kruijf R et al. Pro-inflammatory implications of 2-hydroxypropyl-β-cyclodextrin treatment. Front. Immunol. 12, 716357 (.2021).
    • 25. Scantlebery AML, Ochodnicky P, Kors L et al. β-Cyclodextrin counteracts obesity in western diet-fed mice but elicits a nephrotoxic effect. Sci. Rep. 9(1), 17633–17633 (2019).
    • 26. Hu Q, Fu X, Su Y et al. Enhanced oral bioavailability of koumine by complexation with hydroxypropyl-β-cyclodextrin: preparation, optimization, ex vivo and in vivo characterization. Drug Deliv. 28(1), 2415–2426 (2021). • This reference has been useful in the preparation and characterization of the inclusion complex
    • 27. Lacerda D, Bianchi S, Pinós W et al. Effect of pterostilbene complexed with cyclodextrin on rat liver: potential reduction of oxidative damage and modulation redox-sensitive proteins. Med. Chem. Res. 27, 2265–2278 (2018).
    • 28. Mohamed HI, El-Kamel AH, Hammad GO, Heikal LA. Design of targeted flurbiprofen biomimetic nanoparticles for management of arthritis: in vitro and in vivo appraisal. Pharmaceutics 14(1), 140 (2022).
    • 29. Zhou H, Qian H. Preparation and characterization of pH-sensitive nanoparticles of budesonide for the treatment of ulcerative colitis. Drug Des. Devel. Ther. 12, 2601–2609 (2018).
    • 30. El-Habashy SE, Eltaher HM, Gaballah A, Zaki EI, Mehanna RA, El-Kamel AH. Hybrid bioactive hydroxyapatite/polycaprolactone nanoparticles for enhanced osteogenesis. Mater. Sci. Eng. C Mater. Biol. Appl. 119, 111599 (2021).
    • 31. Radwan SE-S, El-Moslemany RM, Mehanna RA, Thabet EH, Abdelfattah E-ZA, El-Kamel A. Chitosan-coated bovine serum albumin nanoparticles for topical tetrandrine delivery in glaucoma: in vitro and in vivo assessment. Drug Deliv. 29(1), 1150–1163 (2022).
    • 32. Liu Q, Chen J, Qin Y, Jiang B, Zhang T. Encapsulation of pterostilbene in nanoemulsions: influence of lipid composition on physical stability, in vitro digestion, bioaccessibility, and Caco-2 cell monolayer permeability. Food Funct. 10(10), 6604–6614 (2019).
    • 33. Annapurna M, Bukkapatnam V, Teja G. Development of a validated stability indicating liquid chromatographic method for the determination of pterostilbene. Ind. J. Pharm. Edu. Res. 52, S63–S70 (2018).
    • 34. Ahmed I, Leach DN, Wohlmuth H, De Voss JJ, Blanchfield JT. Caco-2 cell permeability of flavonoids and saponins from Gynostemma pentaphyllum: the immortal herb. ACS Omega 5(34), 21561–21569 (2020).
    • 35. Jain R. Comparative pharmacokinetics of synthetic and natural pterostilbene. Hamdan Med. J. 12(4), 242–243 (2019).
    • 36. Ashour AA, Ramadan AA, Abdelmonsif DA, El-Kamel AH. Enhanced oral bioavailability of tanshinone IIA using lipid nanocapsules: formulation, in vitro appraisal and pharmacokinetics. Int. J. Pharm. 586, 119598 (2020).
    • 37. Levin BE, Dunn-Meynell AA. Defense of body weight depends on dietary composition and palatability in rats with diet-induced obesity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282(1), R46–54 (2002).
    • 38. Wang D, Guo H, Yang H, Wang D, Gao P, Wei W. Pterostilbene, an active constituent of blueberries, suppresses proliferation potential of human cholangiocarcinoma via enhancing the autophagic flux. Front. Pharmacol. 10, 1238 (2019).
    • 39. Aguirre L, Milton-Laskibar I, Hijona E, Bujanda L, Rimando AM, Portillo MP. Effects of pterostilbene in brown adipose tissue from obese rats. J. Physiol. Biochem. 73(3), 457–464 (2016).
    • 40. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4), 402–408 (2001).
    • 41. Liu Q, Chen J, Qin Y, Jiang B, Zhang T. Zein/fucoidan-based composite nanoparticles for the encapsulation of pterostilbene: preparation, characterization, physicochemical stability, and formation mechanism. Int. J. Biol. Macromol. 158, 461–470 (2020).
    • 42. Zou Y, Wang X, Bi D et al. Pterostilbene nanoparticles with small particle size show excellent anti-breast cancer activity in vitro and in vivo. Nanotechnology 32(32), doi:10.1088/1361-6528/abfdec (2021).
    • 43. Zhao X, Shi A, Ma Q et al. Nanoparticles prepared from pterostilbene reduce blood glucose and improve diabetes complications. J. Nanobiotechnology 19(1), 191 (2021).
    • 44. La Spina M, Galletta E, Azzolini M et al. Browning effects of a chronic pterostilbene supplementation in mice fed a high-fat diet. Int. J. Mol. Sci. 20(21), 5377 (2019).
    • 45. Tang D, Wang Y, Kang W, Zhou J, Dong R, Feng Q. Chitosan attenuates obesity by modifying the intestinal microbiota and increasing serum leptin levels in mice. J. Funct. Foods 64, 103659 (2020).
    • 46. Alvi Z, Akhtar M, Syed SK et al. Enhancedoral bioavailability of epalrestat SBE(7)-β-CD complex loaded chitosan nanoparticles: preparation, characterization and in vivo pharmacokinetic evaluation. Int. J. Nanomedicine 16, 8353–8373 (2021). • This reference was used as our reference in preparation of NPs loaded with the inclusion complex
    • 47. Yu SC, Chen TC, Hou YT, Wan L, Tsai FJ, Tsai Y. β-Sitosterol-2-hydroxypropyl-β-cyclodextrin inclusion complex: characterization and inhibitory effect on adipogenesis in 3T3-L1 pre-adipocytes. Steroids 140, 196–201 (2018).
    • 48. Sabourian P, Yazdani G, Ashraf SS et al. Effect of physico-chemical properties of nanoparticles on their intracellular uptake. Int. J. Mol. Sci. 21(21), 8019 (2020).
    • 49. Wang F, Yu W, Popescu C et al. Cholecalciferol complexation with hydroxypropyl-β-cyclodextrin (HPBCD) and its molecular dynamics simulation. Pharm. Dev. Technol. 27(4), 389–398 (2022).
    • 50. Catenacci L, Sorrenti M, Bonferoni MC, Vicatos A, Caira M. Inclusion of pterostilbene in natural cyclodextrins: complex preparation and solid-state characterization. The 1st International Electronic Conference on Pharmaceutics doi:10.3390/IECP2020-08713 (2020). • This reference is an important reference for the preparation of inclusion complex with HPBCD
    • 51. Lacerda D, Ortiz V, Türck P et al. Stilbenoid pterostilbene complexed with cyclodextrin preserves left ventricular function after myocardial infarction in rats: possible involvement of thiol proteins and modulation of phosphorylated GSK-3β. Free Radic. Res. 52(9), 988–999 (2018).
    • 52. Tzeng W-S, Teng W-L, Huang P-H, Lin T-C, Yen F-L, Shiue Y-L. Pterostilbene nanoparticles downregulate hypoxia-inducible factors in hepatoma cells under hypoxic conditions. Int. J. Nanomedicine 16, 867–879 (2021).
    • 53. Liu T, Wan X, Luo Z et al. A donepezil/cyclodextrin complexation orodispersible film: effect of cyclodextrin on taste-masking based on dynamic process and in vivo drug absorption. Asian J. Pharm. Sci. 14(2), 183–192 (2019).
    • 54. Fenyvesi F, Nguyen P, Haimhoffer Á et al. Cyclodextrin complexation improves the solubility and Caco-2 permeability of chrysin. Materials 13, 3618 (2020).
    • 55. Bensouiki S, Belaib F, Sindt M et al. Synthesis of cyclodextrins-metronidazole inclusion complexes and incorporation of metronidazole-2-hydroxypropyl-β-cyclodextrin inclusion complex in chitosan nanoparticles. J. Mol. Struct. 1247, 131298 (2021).
    • 56. Sharma M, Sharma R, Jain DK, Saraf A. Enhancement of oral bioavailability of poorly water soluble carvedilol by chitosan nanoparticles: optimization and pharmacokinetic study. Int. J. Biol. Macromol. 135, 246–260 (2019).
    • 57. Tang P, Sun Q, Zhao L et al. Mesalazine/hydroxypropyl-β-cyclodextrin/chitosan nanoparticles with sustained release and enhanced anti-inflammation activity. Carbohydr. Polym. 198, 418–425 (2018).
    • 58. Kavaz D, Kirac F, Kirac M, Vaseashta A. Low Rreleasing mitomycin C molecule encapsulated with chitosan nanoparticles for intravesical installation. J. Biomater. Nanobiotechnol. 8, 203–219 (2017).
    • 59. Zhao L, Tang B, Tang P et al. Chitosan/sulfobutylether-β-cyclodextrin nanoparticles for ibrutinib delivery: a potential nanoformulation of novel kinase inhibitor. J. Pharm. Sci. 109(2), 1136–1144 (2019).
    • 60. Yan X, Huang Z, Wu Y et al. Sequential loading of inclusion complex/nanoparticles improves the gastric retention of Vladimiriae radix essential oil to promote the protection of acute gastric mucosal injury. Int. J. Pharm. 610, 121234 (2021).
    • 61. Jhaveri J, Raichura Z, Khan T, Omri A, Momin M. Chitosan nanoparticles-insight into properties, functionalization and applications in drug delivery and theranostics. Molecules 26(2), 272 (2021).
    • 62. Herdiana Y, Wathoni N, Shamsuddin S, Muchtaridi M. Drug release study of the chitosan-based nanoparticles. Heliyon 8(1), e08674 (2022).
    • 63. Mohammed MA, Syeda JTM, Wasan KM, Wasan EK. An overview of chitosan nanoparticles and its application in non-parenteral drug delivery. Pharmaceutics 9(4), 53 (2017).
    • 64. Souza MPCD, Sábio RM, Ribeiro TDC, Santos AMD, Meneguin AB, Chorilli M. Highlighting the impact of chitosan on the development of gastroretentive drug delivery systems. Int. J. Biol. Macromol. 159, 804–822 (2020).
    • 65. Liu Y, You Y, Lu J, Chen X, Yang Z. Recent advances in synthesis, bioactivity, and pharmacokinetics of pterostilbene, an important analog of resveratrol. Molecules 25(21), 5166 (2020).
    • 66. Yeo SC, Ho PC, Lin HS. Pharmacokinetics of pterostilbene in Sprague–Dawley rats: the impacts of aqueous solubility, fasting, dose escalation, and dosing route on bioavailability. Mol. Nutr. Food Res. 57(6), 1015–1025 (2013).
    • 67. Sánchez AB, Calpena AC, Mallandrich M, Clares B. Validation of an ex vivo permeation method for the intestinal permeability of different BCS drugs and its correlation with Caco-2 in vitro experiments. Pharmaceutics 11(12), 638 (2019).
    • 68. Ibrahim WN, Muizzuddin Bin Mohd Rosli L, Doolaanea AA. Formulation, cellular uptake and cytotoxicity of thymoquinone-loaded PLGA nanoparticles in malignant melanoma cancer cells. Int. J. Nanomedicine 15, 8059–8074 (2020).
    • 69. Terauchi M, Tamura A, Yamaguchi S, Yui N. Enhanced cellular uptake and osteogenic differentiation efficiency of melatonin by inclusion complexation with 2-hydroxypropyl β-cyclodextrin. Int. J. Pharm. 547(1-2), 53–60 (2018).
    • 70. Foroozandeh P, Aziz AA. Insight into cellular uptake and intracellular trafficking of nanoparticles. Nanoscale Res. Lett. 13(1), 339 (2018).
    • 71. Mustafa WW, Moahammed SS, Al-Jewari WM, Abdulrahman HS, Hussain SA. Association of visceral adiposity index, lipid profile, and serum leptin with glucose intolerance risks in Iraqi obese patients: a cross-sectional study. J. Pharm. Bioallied Sci. 12(4), 468–474 (2020).
    • 72. Thadhani V. Resveratrol in management of diabetes and obesity: clinical applications, bioavailability, and nanotherapy. In: Resveratrol: Adding Life to Years, Not Adding Years to Life. Badria FA (Ed.). IntechOpen, London (2019).
    • 73. Hussein A, Fareed F. Biochemical effect of resveratrol on lipids profile and hepatic oxidative stress in experimentally induced obesity in female rats. Benha Vet. Med. J. 32, 67–74 (2017).
    • 74. Jorge AS, Jorge GC, Paraíso AF et al. Brown and white adipose tissue expression of IL6, UCP1 and SIRT1 are associated with alterations in clinical, metabolic and anthropometric parameters in obese humans. Exp. Clin. Endocrinol. Diabetes 125(3), 163–170 (2017). • This reference helped in identifying different obesity biomarkers needed to be evaluated in the study
    • 75. Obradovic M, Sudar-Milovanovic E, Soskic S et al. Leptin and obesity: role and clinical implication. Front. Endocrinol. 12, 585887 (2021).
    • 76. Banhos Danneskiold-Samsøe N, Sonne SB, Larsen JM et al. Overexpression of cyclooxygenase-2 in adipocytes reduces fat accumulation in inguinal white adipose tissue and hepatic steatosis in high-fat fed mice. Sci. Rep. 9(1), 8979 (2019).
    • 77. Escalona-Garrido C, Vázquez P, Mera P et al. Moderate SIRT1 overexpression protects against brown adipose tissue inflammation. Mol. Metab. 42, 101097 (2020).
    • 78. Wang S, Pan MH, Hung WL, Tung YC, Ho CT. From white to beige adipocytes: therapeutic potential of dietary molecules against obesity and their molecular mechanisms. Food Funct. 10(3), 1263–1279 (2019).
    • 79. Kroon T, Harms M, Maurer S et al. PPARγ and PPARα synergize to induce robust browning of white fat in vivo. Mol. Metab. 36, 100964 (2020).