SpringerLink
Log in

Alpha-mangostin decreased cellular senescence in human umbilical vein endothelial cells

  • Research article
  • Published:
DARU Journal of Pharmaceutical Sciences Aims and scope Submit manuscript

Abstract

Background

The hyperglycemic condition in diabetes induces cellular senescence in vascular endothelial cells and causes cardiovascular complications. Alpha-mangostin is a xanthone found in Garcinia mangostana, and has shown protective effects in metabolic syndrome.

Objective

In this study, the anti-senescence effects of alpha-mangostin in the hyperglycemic condition are investigated.

Methods

HUVECs were incubated with high glucose for 6 days and co-treated by metformin or alpha-mangostin. After 6 days, cell viability, reactive oxygen species, the percentage of senescent cells, secretory interleukin-6, and the expression of SIRT1, AMPK, p53 and p21 were measured.

Results

High glucose (60 mM) significantly decreased cellular viability and increased reactive oxygen species and cellular senescence through the reduction of senescence-associated β-galactosidase activity. Moreover, high glucose increased the protein levels of p53, acetyl-p53 and p21. The protein levels of SIRT1 and total AMPK were decreased by high glucose. High glucose increased the secretion of IL-6. Alpha-mangostin (1.25 μM) and metformin (50 μM) reversed the toxic effects of high glucose in HUVECs.

Conclusion

These results show that alpha-mangostin, similar to metformin, has anti-senescence effects in high-glucose conditions, which is probably due to its antioxidant activity through the SIRT1 pathway. Alpha-mangostin has previously shown anti-inflammatory effects and metabolic status improvement in animal and clinical studies. Therefore, this natural agent can be considered as a supplement to prevent vascular complications caused by high glucose in patients with diabetes.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

Similar content being viewed by others

Abbreviations

AGEs:

Advanced glycation end products

Akt:

Protein kinase B

alpha-MG:

Alpha-mangostin

AMPK:

5’-AMP-activated protein kinase

eNOS:

Endothelial nitric oxide synthase

FOXO1:

Forkhead box O1

FoxO3a:

Forkhead box O3

HG:

High glucose

HO-1:

Heme oxygenase 1

HUVECs:

Human umbilical vein endothelial cells

IL-6:

Interleukin-6

JNK:

c-Jun N-terminal kinases

LPS:

Lipopolysaccharides

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NO:

Nitric oxide

Nrf2:

Nuclear factor erythroid 2-related factor 2

p38-MAPK:

P38 mitogen-activated protein kinases

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PI3K:

Phosphatidylinositol-4,5-bisphosphate 3-kinase

PPAR:

Peroxisome proliferator-activated receptor

ROS:

Reactive oxygen species

SASP:

Senescence-associated secretory phenotype

SA-β-GAL:

Senescence-associated beta galactosidase

SIRT1:

Sirtuin 1

TNF-α:

Tumor necrosis factor alpha

References

  1. Cade WT. Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ther. 2008;88(11):1322–35. https://doi.org/10.2522/ptj.20080008.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Stolar M. Glycemic control and complications in type 2 diabetes mellitus. Am J Med. 2010;123(3 Suppl):S3–11. https://doi.org/10.1016/j.amjmed.2009.12.004.

    Article  CAS  PubMed  Google Scholar 

  3. Burton DGA, Faragher RGA. Obesity and type-2 diabetes as inducers of premature cellular senescence and ageing. Biogerontology. 2018;19(6):447–59. https://doi.org/10.1007/s10522-018-9763-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Goligorsky MS. Vascular endothelium in diabetes. American journal of physiology Renal physiology. 2017;312(2):F266–f75. https://doi.org/10.1152/ajprenal.00473.2016.

    Article  CAS  PubMed  Google Scholar 

  5. Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H. Trends in oxidative aging theories. Free Radic Biol Med. 2007;43(4):477–503.

    Article  CAS  Google Scholar 

  6. Harman D. Aging: overview. Ann N Y Acad Sci. 2001;928(1):1–21.

    Article  CAS  Google Scholar 

  7. Shin DH, Lee SJ, Kim JS, Ryu JH, Kim JS. Synergistic effect of immunoliposomal gemcitabine and bevacizumab in glioblastoma stem cell-targeted therapy. J Biomed Nanotechnol. 2015;11(11):1989–2002.

    Article  CAS  Google Scholar 

  8. Signer RAJ, Morrison SJ. Mechanisms that regulate stem cell aging and life span. Cell Stem Cell. 2013;12(2):152–65. https://doi.org/10.1016/j.stem.2013.01.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science (New York, NY). 2004;303(5666):2011–5. https://doi.org/10.1126/science.1094637.

  10. Arunachalam G, Samuel SM, Marei I, Ding H, Triggle CR. Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1. Br J Pharmacol. 2014;171(2):523–35. https://doi.org/10.1111/bph.12496.

    Article  CAS  PubMed  Google Scholar 

  11. Bumrungpert A, Kalpravidh RW, Chitchumroonchokchai C, Chuang CC, West T, Kennedy A, et al. Xanthones from mangosteen prevent lipopolysaccharide-mediated inflammation and insulin resistance in primary cultures of human adipocytes. J Nutr. 2009;139(6):1185–91. https://doi.org/10.3945/jn.109.106617.

    Article  CAS  PubMed  Google Scholar 

  12. Jariyapongskul A, Areebambud C, Suksamrarn S, Mekseepralard C. Alpha-mangostin attenuation of hyperglycemia-induced ocular hypoperfusion and blood retinal barrier leakage in the early stage of type 2 diabetes rats. Biomed Res Int. 2015;2015:785826. https://doi.org/10.1155/2015/785826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Choi Y. al. e. α-Mangostin regulates hepatic Steatosis and obesity through SirT1-AMPK and PPARγ pathways in high-fat diet-induced obese mice. J Agric Food Chem. 2015;63:8399–406.

    Article  CAS  Google Scholar 

  14. Chae HS, Kim YM, Bae JK, Sorchhann S, Yim S, Han L, et al. Mangosteen extract attenuates the metabolic disorders of high-fat-fed mice by activating AMPK. J Med Food. 2016;19(2):148–54. https://doi.org/10.1089/jmf.2015.3496.

    Article  PubMed  Google Scholar 

  15. Taher M, Tg Zakaria TM, Susanti D, Zakaria ZA. Hypoglycaemic activity of ethanolic extract of Garcinia mangostana Linn in normoglycaemic and streptozotocin-induced diabetic rats. BMC complementary and alternative medicine 2016;16:135. https://doi.org/10.1186/s12906-016-1118-9.

  16. Zhang E, Guo Q, Gao H, Xu R, Teng S, Wu Y. Metformin and resveratrol inhibited high glucose-induced metabolic memory of endothelial senescence through SIRT1/p300/p53/p21 pathway. PLoS One. 2015;10(12):e0143814. https://doi.org/10.1371/journal.pone.0143814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rameshrad M, Imenshahidi M, Razavi BM, Iranshahi M, Hosseinzadeh H. Bisphenol a vascular toxicity: protective effect of Vitis vinifera (grape) seed extract and resveratrol. Phytotherapy research : PTR. 2018. https://doi.org/10.1002/ptr.6175.

  18. Wang H, Joseph JA. Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic Biol Med. 1999;27(5–6):612–6.

    Article  CAS  Google Scholar 

  19. Tong YF, Liu Y, Hu ZX, Li ZC. A a. Protocatechuic aldehyde inhibits TNF-alpha-induced fibronectin expression in human umbilical vein endothelial cells via a c-Jun N-terminal kinase dependent pathway. Experimental and therapeutic medicine. 2016;11(1):277–82. https://doi.org/10.3892/etm.2015.2896.

    Article  CAS  PubMed  Google Scholar 

  20. Tousian Shandiz H, Razavi BM, Hosseinzadeh H. Review of Garcinia mangostana and its xanthones in metabolic syndrome and related complications. Phytother Res. 2017;31(8):1173–82. https://doi.org/10.1002/ptr.5862.

    Article  CAS  PubMed  Google Scholar 

  21. Detaille D, Guigas B, Chauvin C, Batandier C, Fontaine E, Wiernsperger N, et al. Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes. 2005;54(7):2179–87.

    Article  CAS  Google Scholar 

  22. Ding A-J, Zheng S-Q, Huang X-B, **ng T-K, Wu G-S, Sun H-Y, et al. Current perspective in the discovery of anti-aging agents from natural products. Natural products and bioprospecting. 2017;7(5):335–404. https://doi.org/10.1007/s13659-017-0135-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jittiporn K. Moongkarndi p, samer j, suvitayavat w. protective effect of α-Mangostin on high glucose induced endothelial cell apoptosis. Walailak J Sci & Tech. 2017;15(8):579–87.

    Google Scholar 

  24. Kitada M, Ogura Y, Koya D. The protective role of Sirt1 in vascular tissue: its relationship to vascular aging and atherosclerosis. Aging. 2016;8(10):2290–307. https://doi.org/10.18632/aging.101068.

  25. Olmos Y, Sánchez-Gómez FJ, Wild B, García-Quintans N, Cabezudo S, Lamas S, et al. SirT1 regulation of antioxidant genes is dependent on the formation of a FoxO3a/PGC-1α complex. Antioxid Redox Signal. 2013;19(13):1507–21. https://doi.org/10.1089/ars.2012.4713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. D'Onofrio N, Servillo L, Balestrieri ML. SIRT1 and SIRT6 signaling pathways in cardiovascular disease protection. Antioxid Redox Signal. 2018;28(8):711–32. https://doi.org/10.1089/ars.2017.7178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Huo J, Xu Z, Hosoe K, Kubo H, Miyahara H, Dai J, et al. Coenzyme Q10 prevents senescence and dysfunction caused by oxidative stress in vascular endothelial cells. Oxidative Med Cell Longev. 2018;2018:3181759. https://doi.org/10.1155/2018/3181759.

    Article  CAS  Google Scholar 

  28. Olivieri F, Lazzarini R, Babini L, Prattichizzo F, Rippo MR, Tiano L, et al. Anti-inflammatory effect of ubiquinol-10 on young and senescent endothelial cells via miR-146a modulation. Free Radic Biol Med. 2013;63:410–20. https://doi.org/10.1016/j.freeradbiomed.2013.05.033.

    Article  CAS  PubMed  Google Scholar 

  29. Mohan S, Syam S, Abdelwahab SI, Thangavel N. An anti-inflammatory molecular mechanism of action of alpha-mangostin, the major xanthone from the pericarp of Garcinia mangostana: an in silico, in vitro and in vivo approach. Food Funct. 2018;9(7):3860–71. https://doi.org/10.1039/c8fo00439k.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was financially supported by Mashhad University of Medical Sciences (Grant No. 327 941389).

Author information

Authors and Affiliations

  1. Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Hourieh Tousian, Bibi Marjan Razavi & Hossein Hosseinzadeh

  2. Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Bibi Marjan Razavi

  3. Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Hossein Hosseinzadeh

Authors
  1. Hourieh Tousian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bibi Marjan Razavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hossein Hosseinzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hossein Hosseinzadeh.

Ethics declarations

Conflict of interest

All authors state that there are no actual or potential conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tousian, H., Razavi, B.M. & Hosseinzadeh, H. Alpha-mangostin decreased cellular senescence in human umbilical vein endothelial cells. DARU J Pharm Sci 28, 45–55 (2020). https://doi.org/10.1007/s40199-019-00305-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40199-019-00305-z

Keywords

Search

Navigation