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The effect of methylethylpiridinol addition to the therapy on the level of pigment epithelium-derived factor and oxidative status in patients with diabetic nephropathy: randomized controlled open-label clinical study

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Abstract

Purpose

The diabetic nephropathy is associated with oxidative stress and increases in pigment epithelium-derived factor (PEDF) level in the patient’s blood. For the first time, authors investigated the effect of methylethylpiridinol addition to the therapy on oxidative status and pigment epithelium-derived factor concentrations, and examined the relationship between these indicators and clinical markers of pathology development.

Methods

Study design: open label randomized controlled trial study. Authors assessed the effect of methylethylpiridinol addition to the therapy vs basic treatment on antioxidant and NADPH-generating enzymes activity, glutathione’s concentration and free radical-induced oxidation’s intensity using a spectrophotometric method and iron-induced biochemiluminescence. The pigment epithelium-derived factor concentration in the serum was measured by enzyme-linked immunosorbent assay.

Results

Patients receiving combination therapy with methylethylpiridinol showed a more substantial increase in activity of glutathione peroxidase (Δ = 0.04 ± 0.11, p = 0.002), glutathione transferase (Δ = 0.12 ± 0.08, p < 0.001) and the concentration of reduced glutathione (Δ = 0.30 ± 0.17, p = 0.039). In addition, there was a significant decrease in PEDF level (Δ = -6.4 ± 5.4, p = 0.004). Correlation analysis showed a negative link between Δ postprandial glucose and Δ NADP-isocitrate dehydrogenase (-0.39, p = 0.033), Δ reduced glutathione and Δ postprandial glucose (-0.372, p = 0.043), Δ glutathione transferase and Δ PEDF (-0.37, p = 0.044).

Conclusions

The methylethylpiridinol addition to the therapy had a more potent stimulating effect on the patients’ oxidative status in comparison with standard treatment, and reliably decreased pigment epithelium-derived factor level in patients’ serum. The observed differences seem to be associated with the antioxidant activity of methylethylpiridinol which contributing to the mitigation of oxidative stress reducing at diabetes mellitus.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Gnudi L, Coward RJM, Long DA. Diabetic Nephropathy: Perspective on Novel Molecular Mechanisms. Trends Endocrinol Metab. 2016;27:820–30.

    Article  CAS  Google Scholar 

  2. Miranda-Díaz AG, Pazarín-Villaseñor L, Yanowsky-Escatell FG, Andrade-Sierra J. Oxidative Stress in Diabetic Nephropathy with Early Chronic Kidney Disease. J Diabetes Res. 2016;2016:7047238.

    Article  Google Scholar 

  3. Bansal S, Siddarth M, Chawla D, Banerjee BD, Madhu SV, Tripathi AK. Advanced glycation end products enhance reactive oxygen and nitrogen species generation in neutrophils in vitro. Mol Cell Biochem. 2012;361:289–96.

    Article  CAS  Google Scholar 

  4. Lushchak VI. Glutathione homeostasis and functions: potential targets for medical interventions. J AminoAcids. 2012;2012:736837.

    Google Scholar 

  5. Kotova JuA, Zuikova AA, Pashkov AN, Strahova NV, Krasnorutskaya ON. Relationship between indices of oxidative stress, endothelial dysfunction and chaperone activity and the severity of coronary atherosclerosis. International Journal of Biomedicine. 2018;8:182–185.

  6. Martos-Maldonado MC, Casas-Solvas JM, Vargas-Berenguel A, García-Fuentes L. Electrochemical detection of glutathione-S-transferase: an important enzyme in the cell protective mechanism against oxidative stress. Methods Mol Biol. 2015;1208:123–38.

    Article  CAS  Google Scholar 

  7. Nóbrega-Pereira S, Fernandez-Marcos PJ, Brioche T, Gomez-Cabrera MC, Salvador-Pascual A, Flores JM, et al. G6PD protects from oxidative damage and improves health span in mice. Nat Commun. 2016;7:10894.

    Article  Google Scholar 

  8. Medvedeva LV, Popova TN, Artyukhov VG, Matasova LV, Pinheiro de Carvalho MAA. Intensity of free radical processes and regulation of cytoplasmic NADP-isocitrate dehydrogenase in rat cardiomyocytes under normal and ischemic conditions. Biochemistry (Moscow). 2002;67:696–705.

  9. Cheung CYY, Lee CH, Tang CS. Genetic Regulation of Pigment Epithelium-Derived Factor (PEDF): An Exome-Chip Association Analysis in Chinese Subjects With Type 2 Diabetes. Diabetes. 2019;68:198–206.

    Article  CAS  Google Scholar 

  10. Voelker J, Berg PH, Sheetz M, Duffin K, Shen T, Moser B, Greene T, Blumenthal SS, Rychlik I, Yagil Y, Zaoui P, Lewis JB. Anti-TGF-β1 Antibody Therapy in Patients with Diabetic Nephropathy. J Am Soc Nephrol. 2017;28:953–62.

    Article  CAS  Google Scholar 

  11. Volchegorskii IA, Miroshnichenko IY, Rassokhina LM, Faizullin RM, Pryakhina KE. Anxiolytic and antidepressant effects of emoxipine, reamberin and mexidol in experimental diabetes mellitus. ZhNevrolPsikhiatrIm S SKorsakova. 2017;117:52–7.

    CAS  Google Scholar 

  12. Julious SA. Tutorial in biostatistics. Sample sizes for clinical trials with Normal data. Statist. Med. 2004;23: 1921–1986.

  13. Piskarev IM, Trofimova SV, Ivanova IP, Burkhina OE. Investigation of the level of free-radical processes in substrates and biological samples using induced chemiluminescence. Biophysics. 2015;60:400–8.

    Article  CAS  Google Scholar 

  14. Ellman GL. Tissue sulfhydryl groups Arch BiochemBiophys. 1959;82:70–7.

    CAS  Google Scholar 

  15. Sifuentes-Franco S, Padilla-Tejeda DE, Carrillo-Ibarra S, Miranda-Díaz AG. Oxidative Stress, Apoptosis, and Mitochondrial Function in Diabetic Nephropathy. Int J Endocrinol. 2018;2018:1875870.

    Article  Google Scholar 

  16. Peresypkina A, Pazhinsky A, Pokrovskii M, Beskhmelnitsyna E, Pobeda A, Korokin M. Correction of Experimental Retinal Ischemia by l-Isomer of Ethylmethylhydroxypyridine Malate. Antioxidants (Basel). 2019;8:E34.

    Article  Google Scholar 

  17. Scherbinina SP, Levina AA, Lisovskaya IL, Ataullakhanov FI. Effect of exogenous antioxidants on erythrocyte redox status and hepcidin content in disorders of iron metabolism regulation. Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry. 2012;6:338–342.

  18. Loznikova SG, Sukhodola AA, ShcharbinaNYu, Shcharbin DG. The effects of magnesium, acetylsalicylic acid, and emoxypine on platelet aggregation. Biophysics. 2015;59:900–903.

  19. He X, Cheng R, Benyajati S, Ma JX. PEDF and its roles in physiological and pathological conditions: implication in diabetic and hypoxia-induced angiogenic diseases. Clin Sci (Lond). 2015;128:805–23.

    Article  Google Scholar 

  20. Ishibashi Y, Matsui T, Taira J, Higashimoto Y, Yamagishi S. Protective Role of PEDF-Derived Synthetic Peptide Against Experimental Diabetic Nephropathy. HormMetab Res. 2016;48:613–9.

    CAS  Google Scholar 

  21. Rubin A, Salzberg AC, Imamura Y, Grivitishvilli A, Tombran-Tink J. Identification of novel targets of diabetic nephropathy and PEDF peptide treatment using RNA-seq. BMC Genomics. 2016;17:936.

    Article  Google Scholar 

  22. He Y, Leung KW, Ren Y, Pei J, Ge J, Tombran-Tink J. PEDF improves mitochondrial function in RPE cells during oxidative stress. Invest Ophthalmol Vis Sci. 2014;55:6742–55.

    Article  CAS  Google Scholar 

  23. Yamagishi S, Nakamura K, Ueda S, Kato S, Imaizumi T. Pigment epithelium-derived factor (PEDF) blocks angiotensin II signaling in endothelial cells via suppression of NADPH oxidase: a novel anti-oxidative mechanism of PEDF. Cell Tissue Res. 2005;320:437–45.

    Article  CAS  Google Scholar 

  24. Yoshida T, Akiba J, Matsui T, Nakamura K, Hisamoto T, Abe M, Ikezono Y, Wada F, Iwamoto H, Nakamura T, Koga H, Yamagishi SI, Torimura T. Pigment Epithelium-Derived Factor (PEDF) Prevents Hepatic Fat Storage, Inflammation, and Fibrosis in Dietary Steatohepatitis of Mice. Dig Dis Sci. 2017;62:1527–36.

    Article  CAS  Google Scholar 

  25. Li XH, Wang HP, Tan J, Wu YD, Yang M, Mao CZ, Gao SF, Li H, Chen H, Cai WB. Loss of pigment epithelium-derived factor leads to ovarian oxidative damage accompanied by diminished ovarian reserve in mice. Life Sci. 2019;216:129–39.

    Article  CAS  Google Scholar 

  26. Hui E, Yeung CY, Lee PC, Woo YC, Fong CH, Chow WS, Xu A, Lam KS. Elevated circulating pigment epithelium-derived factor predicts the progression of diabetic nephropathy in patients with type 2 diabetes. J Clin Endocrinol Metab. 2014;99:E2169-2177.

    Article  CAS  Google Scholar 

  27. Al-Waili N, Al-Waili H, Al-Waili T, Salom K. Natural antioxidants in the treatment and prevention of diabetic nephropathy; a potential approach that warrants clinical trials. Redox Rep. 2017;22:99–118.

    Article  CAS  Google Scholar 

  28. Matsuyama K, Ogata N, Matsuoka M, Shima C, Wada M, Jo N, Matsumura M. Relationship between pigment epithelium-derived factor (PEDF) and renal function in patients with diabetic retinopathy. Mol Vis. 2008;14:992–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Xu Y, Osborne BW, Stanton RC. Diabetes causes inhibition of glucose-6-phosphate dehydrogenase via activation of PKA, which contributes to oxidative stress in rat kidney cortex. Am J Physiol Renal Physiol. 2005;289:F1040-1047.

    Article  CAS  Google Scholar 

  30. Lai YK, Lai NM, Lee SW. Glucose-6-phosphate dehydrogenase deficiency and risk of diabetes: a systematic review and meta-analysis. Ann Hematol. 2017;96:839–45.

    Article  Google Scholar 

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Funding

This study was not supported by any funds.

Conflicts of interest/Competing interests. No conflicts of interest have been declared.

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Authors and Affiliations

  1. Voronezh State Medical University named after N.N. Burdenko, Studencheskaya Street 10, 394036, Voronezh, Russia

    Sergey Sergeevich Popov, Elena Igorevna Anufrieva & Aleksander Nikolaevich Pashkov

  2. Voronezh State University, Universitetskaya sq. 1, 394018, Voronezh, Russia

    Evgenii Dmitrievich Kryl’skii, Konstantin Konstantinovich Shulgin, Aleksey Nikolaevich Verevkin & Tatyana Nikolaevna Popova

Authors
  1. Sergey Sergeevich Popov
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  2. Elena Igorevna Anufrieva
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  3. Evgenii Dmitrievich Kryl’skii
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  5. Aleksey Nikolaevich Verevkin
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  6. Tatyana Nikolaevna Popova
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  7. Aleksander Nikolaevich Pashkov
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Correspondence to Evgenii Dmitrievich Kryl’skii.

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Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The research was approved by the Ethics Committee of the Voronezh State Medical University named after N.N. Burdenko, the extract from the protocol No.4 of September 29, 2016.

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Popov, S.S., Anufrieva, E.I., Kryl’skii, E.D. et al. The effect of methylethylpiridinol addition to the therapy on the level of pigment epithelium-derived factor and oxidative status in patients with diabetic nephropathy: randomized controlled open-label clinical study. J Diabetes Metab Disord 20, 709–717 (2021). https://doi.org/10.1007/s40200-021-00802-6

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