Regulation of carbohydrate metabolism and insulin secretion in diabetic rats following treatment with Hypericum perforatum L. hairy root aqueous methanol extract

Authors

  • Elena Rafailovska Department of Experimental Physiology and Biochemistry, Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University in Skopje, Skopje, N. Macedonia
  • Oliver Tusevski Laboratory of Plant Cell and Tissue Culture, Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University in Skopje, Skopje, N. Macedonia
  • Sonja Gadzovska- Simic Laboratory of Plant Cell and Tissue Culture, Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University in Skopje, Skopje, N. Macedonia
  • Sasho Panov Department of Molecular Biology and Genetics, Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University in Skopje, Skopje, N. Macedonia
  • Jasmina Petreska Stanoeva Institute of Chemistry, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University in Skopje, Skopje, N. Macedonia
  • Suzana Dinevska – Kjovkarovska Department of Experimental Physiology and Biochemistry, Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University in Skopje, Skopje, N. Macedonia
  • Biljana Miova Department of Experimental Physiology and Biochemistry, Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University in Skopje, Skopje, N. Macedonia

DOI:

https://doi.org/10.20450/mjcce.2024.2849

Keywords:

Hypericum perforatum L.,, carbohydrate metabolism, AMPK, PKCε, diabetic rats, hairy roots

Abstract

Hairy root (HR) cultures of Hypericum perforatum L. have shown promise in controlling hyperglycemia, regulating blood lipid and enzyme profiles, and improving metabolic function in vivo. These benefits are mainly attributed to the phenolic acids, flavonoids, and xanthones present in HR extracts. However, the specific mechanism underlying these effects remains unclear. This study was performed to elucidate the biochemical and molecular mechanisms driving HR the antihyperglycemic and antidiabetic effects of HR extracts.

HR extract (200 mg/kg body weight) was administered daily for 14 days to healthy rats and rats with streptozotocin-induced diabetes, with glibenclamide serving as a positive control. The phenolic composition of the HR extracts was confirmed through high-performance liquid chromatography/diode array detection/electrospray ionization mass spectrometry (HPLC/DAD/ESI-MSn ) analysis.

The results showed that HR extract treatment increased the plasma insulin level and pancreatic poly (adenosine diphosphate-ribose) polymerase (PARP) activity in diabetic rats, thus normalizing blood glucose levels. Additionally, it reduced the activity of gluconeogenic enzymes, increased the activity of glycolytic enzymes, and normalized the glycogen content in the liver. HR extract-treated rats also exhibited increased hepatic adenosine monophosphate-activated protein kinase (AMPK) mRNA expression and a decreased protein kinase Cε (PKCε) concentration.

In conclusion, HR extract demonstrated insulinotropic effects and effectively regulated hepatic carbohydrate metabolism in diabetic rats by modulating AMPK expression and the PKCε concentration. These findings suggest the potential use of HR extract as an herbal medicine for diabetes treatment and a source of antidiabetic drug development.

References

(1) Standards of medical care in diabetes — 2013, Diabetes Care 2012, 36. DOI:10.2337/dc13-s011

(2) Zhao, C.; Yang, C.; Wai, S. T.; Zhang, Y.; Portillo, M. P.; Paoli, P., et al., Regulation of glucose metabolism by bioactive phytochemicals for the management of type 2 diabetes mellitus, Crit. Rev. Food Sci. Nutr. 2018, 59, 830–847. DOI:10.1080/10408398.2018.1501658

(3) Gutierrez-Valdes, N.; Häkkinen, S. T.; Lemasson, C.; Guillet, M.; Oksman-Caldentey, K.-M.; Ritala, A., et al., Hairy root cultures — a versatile tool with multiple appli-cations, Front. Plant Sci. 2020, 11.

DOI:10.3389/fpls.2020.00033

(4) Georgiev, M. I.; Pavlov, A. I.; Bley, T., Hairy root type plant in vitro systems as sources of bioactive substances, Appl. Microbiol. Biotechnol. 2007, 74, 1175–1185. DOI:10.1007/s00253-007-0856-5

(5) Nahrstedt, A.; Butterweck, V., Lessons learned from herbal medicinal products: The example of St. John’s Wort, J. Nat. Prod. 2010, 73, 1015–1021.

DOI:10.1021/np1000329

(6) Tusevski, O.; Stanoeva, J.; Stefova, M.; Kungulovski, D.; Pancevska, N.; Sekulovski, N., et al., Hairy roots of Hy-pericum perforatum L.: a promising system for xanthone Production, Open Life Sci. 2013, 8, 1010–1022. DOI:10.2478/s11535-013-0224-7

(7) Tusevski, O.; Vinterhalter, B.; Krstić Milošević, D.; Soković, M.; Ćirić, A.; Vinterhalter, D., et al., Production of phenolic compounds, antioxidant and antimicrobial ac-tivities in hairy root and shoot cultures of Hypericum per-foratum L., Plant Cell Tissue Organ Cult. 2016, 128, 589–605. DOI:10.1007/s11240-016-1136-9

(8) Chen, S.-P.; Lin, S.-R.; Chen, T.-H.; Ng, H.-S.; Yim, H.-S.; Leong, M.K., et al. Mangosteen xanthone γ-mangostin exerts lowering blood glucose effect with potentiating in-sulin sensitivity through the mediation of AMPK/PPARγ, Biomed. Pharmacother. 2021, 144, 112333. DOI:10.1016/j.biopha.2021.112333

(9) El-Seedi, H. R.; Ibrahim, H. M. S.; Yosri, N.; Ibrahim, M. A.; Hegazy, M.-E. F.; Setzer, W. N., et al., Naturally occurring xanthones; biological activities, chemical pro-files and in silico drug discovery, Curr. Med. Chem. 2024, 31(1), 62–101. DOI:10.2174/0929867330666230221111941

(10) Tusevski, O.; Todorovska, M.; Petreska Stanoeva, J.; Stefova, M.; Gadzovska Simic, S., In vitro and in silico insights on the biological activities, phenolic compounds composition of Hypericum perforatum l. hairy root cul-tures, Phyton. 2023, 92, 921–941.

DOI:10.32604/phyton.2023.024995

(11) Rafailovska, E.; Tushevski, O.; Gadzovska-Simic, S.; Dinevska-Kjovkarovska, S.; Miova, B., Hypericum per-foratum L. hairy root extracts – regulation of glycemic, metabolic, serum enzyme and lipid profile in STZ - in-duced diabetic rats, Maced. Vet. Rev. 2022, 45, 5–15. DOI:10.2478/macvetrev-2021-0027

(12) Jiang, S.; Young, J.; Wang, K.; Qian, Y.; Cai, L., Diabet-ic induced alterations in hepatic glucose and lipid metabo-lism: The role of type 1 and type 2 diabetes mellitus (re-view), Mol. Med. Rep. 2020, 22, 603–611. DOI:10.3892/mmr.2020.11175

(13) Steinberg, G. R.; Carling, D., AMP-activated protein kinase: The current landscape for drug development, Nat. Rev. Drug Discov. 2019, 18, 527–551.

DOI:10.1038/s41573-019-0019-2.

(14) Gassaway, B. M.; Petersen, M. C.; Surovtseva, Y. V.; Barber, K. W.; Sheetz, J. B.; Aerni, H. R., et al., PKCΕ contributes to lipid-induced insulin resistance through cross talk with p70s6K and through previously unknown regulators of insulin signaling, PNAS 2018, 115. DOI:10.1073/pnas.1804379115

(15) Sellamuthu, P. S.; Muniappan, B. P.; Perumal, S. M.; Kandasamy, M., Antihyperglycemic effect of Mangiferin in streptozotocin induced diabetic rats, J. Health Sci. 2009, 55, 206–214. DOI:10.1248/jhs.55.206

(16) Gerazova-Efremova, K.; Dinevska-Kjovkarovska, S.; Miova, B., Heat-shock protein 70–mediated heat precon-ditioning attenuates hepatic carbohydrate and oxidative disturbances in rats with type 1 diabetes, Can. J. Diabe-tes. 2019, 43, 345–353.

DOI:10.1016/j.jcjd.2019.01.002

(17) Rafailovska, E.; Tushevski, O.; Shijakova, K.; Simic, S. G.; Kjovkarovska, S. D.; Miova, B. Hypericum perfora-tum L. extract exerts insulinotropic effects and inhibits gluconeogenesis in diabetic rats by regulating AMPK ex-pression and PKCε concentration, J. Ethnopharmacol. 2023, 302, 115899. DOI:10.1016/j.jep.2022.115899

(18) Nahdi, A. M.; John, A.; Raza, H., Elucidation of molecu-lar mechanisms of streptozotocin-induced oxidative stress, apoptosis, and mitochondrial dysfunction in Rin-5f pancreatic β-cells. Oxid. Med. Cell. Longev. 2017, 1–15. DOI:10.1155/2017/7054272

(19) Lee, D.; Choi, P.; Hwang, B. S.; Kim, T.; Kim, Y.; Kim, J.-C., et al., Protective effect of hypoxylonol C and 4,5,4′,5′-tetrahydroxy-1,1′-binaphthyl isolated from An-nulohypoxylon annulatum against streptozotocin-induced damage in INS-1 cells, Bioorg. Chem. 2019, 90, 103053. DOI:10.1016/j.bioorg.2019.103053

(20) Ke, W.; Zhang, Z.; Wang, Z.; Zeng, R.; et al., The role of parps in inflammation — and metabolic — related diseas-es: Molecular mechanisms and beyond, Cells 2019, 8, 1047. DOI:10.3390/cells8091047

(21) Kun, E.; Kirsten, E.; Bauer, P.; Ordahl, C., Quantitative correlation between cellular proliferation and nuclear poly(ADP-ribose) polymerase (PARP-1), Int. J. Mol. Med. 2006. DOI:10.3892/ijmm.17.2.293

(22) Gan, Q.; Lin, C.; Lu, C.; Chang, Y.; Che, Q.; Zhang, G.; et al., Staprexanthones, xanthone-type stimulators of pan-creatic β-cell proliferation from a mangrove endophytic fungus, J. Nat. Prod. 2020, 83, 2996–3003. DOI:10.1021/acs.jnatprod.0c00535

(23) Wang, H.-L.; Li, C.-Y.; Zhang, B.; Liu, Y.-D.; Lu, B.-M.; Shi, Z.; et al. Mangiferin facilitates islet regeneration and β-cell proliferation through upregulation of cell cycle and β-cell regeneration regulators, Int. J. Mol. Sci. 2014, 15, 9016–9035. DOI:10.3390/ijms15059016

(24) Wang, J.; Fang, X.; Ge, L.; Cao, F.; Zhao, L.; Wang, Z.; et al., Antitumor, antioxidant and anti-inflammatory activi-ties of Kaempferol and its corresponding glycosides and the enzymatic preparation of Kaempferol, PLOS ONE 2018, 13. DOI:10.1371/journal.pone.0197563

(25) Chen, S.; Guo, D.; Lei, B.; Bi, J.; Yang, H., Biglycan protects human neuroblastoma cells from nitric oxide-induced death by inhibiting AMPK-mTOR mediated au-tophagy and intracellular ROS level, Biotechnol. Lett. 2020, 42, 657–668. DOI:10.1007/s10529-020-02818-z

(26) Jeon, S.-M., Regulation and function of AMPK in physi-ology and diseases, Exp. Mol. Med. 2016, 48. DOI:10.1038/emm.2016.81

Downloads

Published

2024-05-14 — Updated on 2024-05-19

Versions

How to Cite

Rafailovska, E., Tusevski, O., Gadzovska- Simic, S. ., Panov, S., Petreska Stanoeva, J., Dinevska – Kjovkarovska, S., & Miova, B. (2024). Regulation of carbohydrate metabolism and insulin secretion in diabetic rats following treatment with Hypericum perforatum L. hairy root aqueous methanol extract. Macedonian Journal of Chemistry and Chemical Engineering, 43(1), 75–86. https://doi.org/10.20450/mjcce.2024.2849 (Original work published May 14, 2024)

Issue

Vol. 43 No. 1 (2024): Golden Jubilee

Section

Biochemistry

License

Copyright (c) 2024 Elena Rafailovska, Oliver Tusevski, Sonja Gadzovska- Simic, Sasho Panov, Jasmina Petreska Stanoeva, Suzana Dinevska – Kjovkarovska, Biljana Miova

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

The authors agree to the following licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

  • Adapt — remix, transform, and build upon the material
  • for any purpose, even commercially.
The licensor cannot revoke these freedoms as long as you follow the license terms.

 Under the following terms:

  • Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.

  • NonCommercial — You may not use the material for commercial purposes.

Most read articles by the same author(s)