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Antioxidant effects of β-carotene, but not of retinol and vitamin E, in orbital fibroblasts from patients with Graves’ orbitopathy (GO)

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Abstract

Background

Oxidative stress is involved in the pathogenesis of Graves’ orbitopathy (GO) and several antioxidant agents, namely, selenium, quercetin, enalapril, vitamin C, N-acetyl-l-cysteine, and melatonin, have been shown to reduce oxidative stress and its consequences in primary culture of orbital fibroblasts. In addition, selenium is effective for the treatment of mild GO. Here, we investigated the action of three additional antioxidants in orbital fibroblasts, namely, retinol, β-carotene, and vitamin E.

Methods

Primary cultures of orbital fibroblasts were established from GO patients and control subjects. To induce oxidative stress, cells were treated with H2O2, after which glutathione disulfide (GSSG) (a parameter of oxidative stress), cell proliferation, hyaluronic acid, TNFα, IFNγ, and IL1β were measured.

Results

H2O2-dependent oxidative stress (augmented GSSG) was associated with increased cell proliferation and cytokine release. All the three antioxidant substances reduced GSSG in both GO and control fibroblasts. β-carotene reduced proliferation in GO, but not in control fibroblasts. IL1β was reduced by all three substances. Retinol reduced IFNγ in GO and control fibroblasts.

Conclusions

Our study supports an antioxidant role of retinol, β-carotene, and vitamin E in orbital fibroblasts from patients with GO and provides a basis for a possible clinical use these substances.

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References

  1. Piantanida E, Tanda ML, Lai A, Sassi L, Bartalena L (2013) Prevalence and natural history of Graves’ orbitopathy in the XXI century. J Endocrinol Invest 36:444–449

    PubMed  CAS  Google Scholar 

  2. Leo M, Menconi F, Rocchi R, Latrofa F, Sisti E, Profilo MA, Mazzi B, Albano E, Nardi M, Vitti P, Marcocci C, Marinò M (2015) Role of the underlying thyroid disease on the phenotype of Graves’ orbitopathy in a tertiary referral center. Thyroid 25:347–351

    Article  PubMed  Google Scholar 

  3. Bahn RS (2010) Graves’ ophthalmopathy. N Engl J Med 362:726–738

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Menconi F, Leo M, Vitti P, Marcocci C, Marinò M (2015) Total thyroid ablation in Graves’ orbitopathy. J Endocrinol Invest 38:809–815

    Article  PubMed  CAS  Google Scholar 

  5. Leo M, Sabini E, Ionni I, Sframeli A, Mazzi B, Menconi F, Molinaro E, Bianchi F, Brozzi F, Santini P, Elisei R, Nardi M, Vitti P, Marcocci C, Marinò M (2017) Use of low-dose radioiodine ablation for Graves’ orbitopathy: results of a pilot, perspective study in a small series of patients. J Endocrinol Invest. https://doi.org/10.1007/s40618-017-0754-3 (in press)

    Article  PubMed  Google Scholar 

  6. Leo M, Bartalena L, Rotondo Dottore G, Piantanida E, Premoli P, Ionni I, Di Cera M, Masiello E, Sassi L, Tanda ML, Latrofa F, Vitti P, Marcocci C, Marinò M (2017) Effects of selenium on short-term control of hyperthyroidism due to Graves’ disease treated with methimazole: results of a randomized clinical trial. J Endocrinol Invest 40:281–287

    Article  PubMed  CAS  Google Scholar 

  7. Rotondo Dottore G, Leo M, Casini G, Latrofa F, Cestari L, Sellari-Franceschini S, Nardi M, Vitti P, Marcocci C, Marinò M (2017) Antioxidant actions of selenium in orbital fibroblasts: a basis for the effects of selenium in Graves’ orbitopathy. Thyroid 27:271–278

    Article  PubMed  CAS  Google Scholar 

  8. Lisi S, Botta R, Lemmi M, Sellari-Franceschini S, Altea MA, Sisti E, Casini G, Nardi M, Marcocci C, Pinchera A, Marinò M (2011) Quercetin decreases proliferation of orbital fibroblasts and their release of hyaluronic acid. J Endocrinol Invest 34:521–527

    PubMed  CAS  Google Scholar 

  9. Botta R, Lisi S, Marcocci C, Sellari-Franceschini S, Rocchi R, Latrofa F, Menconi F, Altea MA, Leo M, Sisti E, Casini G, Nardi M, Pinchera A, Vitti P, Marinò M (2013) Enalapril reduces proliferation and hyaluronic acid release in orbital fibroblasts. Thyroid 23:92–96

    Article  PubMed  CAS  Google Scholar 

  10. Rotondo Dottore G, Ionni I, Menconi F, Casini G, Sellari-Franceschini S, Nardi M, Vitti P, Marcocci C, Marinò M (2017) Action of three bioavailable antioxidants in orbital fibroblasts from patients with Graves’ orbitopathy (GO): a new frontier for GO treatment? J Endocrinol Invest. https://doi.org/10.1007/s40618-017-0718-7 (in press)

    Article  PubMed  Google Scholar 

  11. Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, Altea MA, Nardi M, Pitz S, Boboridis K, Sivelli P, von Arx G, Mourits MP, Baldeschi L, Bencivelli W, Wiersinga W (2011) Selenium and the course of mild Graves’ orbitopathy. N Engl J Med 364:1920–1931

    Article  PubMed  CAS  Google Scholar 

  12. Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM, European Group on Graves’ Orbitopathy (EUGOGO) (2016) The 2016 European Thyroid Association/European Group on Graves’ orbitopathy guidelines for the management of Graves’ orbitopathy. Eur Thyroid J 5:9–26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Bartalena L, Veronesi G, Krassas GE, Wiersinga WM, Marcocci C, Marinò M, Salvi M, Daumerie C, Bournaud C, Stahl M, Sassi L, Azzolini C, Boboridis KG, Mourits MP, Soeters MR, Baldeschi L, Nardi M, Currò N, Boschi A, Bernard M, von Arx G, Perros P, Kahaly GJ, European Group on Graves’ Orbitopathy (EUGOGO) (2017) Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves’ orbitopathy? J Endocrinol Invest 40:547–553

    Article  PubMed  CAS  Google Scholar 

  14. Sisti E, Menconi F, Leo M, Profilo MA, Mautone T, Mazzi B, Rocchi R, Latrofa F, Nardi M, Vitti P, Marcocci C, Marinò M (2015) Long-term outcome of Graves’ orbitopathy following high-dose intravenous glucocorticoids and orbital radiotherapy. J Endocrinol Invest 38:661–668

    Article  PubMed  CAS  Google Scholar 

  15. Sisti E, Coco B, Menconi F, Leo M, Rocchi R, Latrofa F, Profilo MA, Mazzi B, Albano E, Vitti P, Marcocci C, Brunetto M, Marinò M (2015) Intravenous glucocorticoid therapy for Graves’ ophthalmopathy and acute liver damage: an epidemiological study. Eur J Endocrinol 172:269–276

    Article  PubMed  CAS  Google Scholar 

  16. Sisti E, Coco B, Menconi F, Leo M, Rocchi R, Latrofa F, Profilo MA, Mazzi B, Vitti P, Marcocci C, Brunetto M, Marinò M (2015) Age and dose are major risk factors for liver damage associated with intravenous glucocorticoid pulse therapy for Graves’ orbitopathy. Thyroid 25:846–850

    Article  PubMed  CAS  Google Scholar 

  17. Sabini E, Sisti E, Coco B, Leo M, Ionni I, Menconi F, Profilo MA, Mazzi B, Rocchi R, Latrofa F, Vitti P, Brunetto M, Marcocci C, Marinò M (2016) Statins are not a risk factor for liver damage associated with intravenous glucocorticoid pulse therapy for Graves’ orbitopathy. J Endocrinol Invest 39:1323–1327

    Article  PubMed  CAS  Google Scholar 

  18. Menconi F, Profilo MA, Leo M, Sisti E, Altea MA, Rocchi R, Latrofa F, Nardi M, Vitti P, Marcocci C, Marinò M (2014) Spontaneous improvement of untreated mild Graves’ ophthalmopathy: Rundle’s curve revisited. Thyroid 24:60–66

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Anagnostis P, Boboridis K, Adamidou F, Kita M (2017) Natural course of mild Graves’ orbitopathy: is it a chronic remitting or a transient disease? J Endocrinol Invest 40:257–261

    Article  PubMed  CAS  Google Scholar 

  20. Tsai CC, Wu SB, Kao SC, Kau HC, Lee FL, Wei YH (2013) The protective effect of antioxidants on orbital fibroblasts from patients with Graves’ ophthalmopathy in response to oxidative stress. Mol Vis 19:927–934

    PubMed  PubMed Central  CAS  Google Scholar 

  21. Burch HB, Lahiri S, Bahn RS, Barnes S (1997) Superoxide radical production stimulates retroocular fibroblast proliferation in Graves’ ophthalmopathy. Exp Eye Res 65:311–316

    Article  PubMed  CAS  Google Scholar 

  22. Heufelder AE, Wenzel BE, Bahn RS (1992) Methimazole and propylthiouracil inhibit the oxygen free radical-induced expression of a 72 kilodalton heat shock protein in Graves’ retroocular fibroblasts. J Clin Endocrinol Metab 74:737–742

    Article  PubMed  CAS  Google Scholar 

  23. Lu R, Wang P, Wartofsky L, Sutton BD, Zweier JL, Bahn RS, Garrity J, Burman KD (1999) Oxygen free radicals in interleukin-1beta-induced glycosaminoglycan production by retro-ocular fibroblasts from normal subjects and Graves’ ophthalmopathy patients. Thyroid 9:297–303

    Article  PubMed  CAS  Google Scholar 

  24. Esposito D, Rotondi M, Accardo G, Vallone G, Conzo G, Docimo G, Selvaggi F, Cappelli C, Chiovato L, Giugliano D, Pasquali D (2017) Influence of short-term selenium supplementation on the natural course of Hashimoto’s thyroiditis: clinical results of a blinded placebo-controlled randomized prospective trial. J Endocrinol Invest 40:83–89

    Article  PubMed  CAS  Google Scholar 

  25. Bartalena L, Chiovato L, Vitti P (2016) Management of hyperthyroidism due to Graves’ disease: frequently asked questions and answers (if any). J Endocrinol Invest 39:1105–1114

    Article  PubMed  CAS  Google Scholar 

  26. Ruggeri RM, Vicchio TM, Cristani M, Certo R, Caccamo D, Alibrandi A, Giovinazzo S, Saija A, Campennì A, Trimarchi F, Gangemi S (2016) Oxidative stress and advanced glycation end products in Hashimoto’s thyroiditis. Thyroid 26:504–511

    Article  PubMed  CAS  Google Scholar 

  27. Erdman JW, Bierer TL, Gugger ET (1993) Absorption and transport of carotenoids. Ann N Y Acad Sci 691:76–85

    Article  PubMed  CAS  Google Scholar 

  28. Napoli JL, Race KR (1988) Biogenesis of retinoic acid from b-carotene. Differences between metabolism of b-carotene andretinal. J Biol Chem 263:17372–117377

    PubMed  CAS  Google Scholar 

  29. Blumhoff R, Green MH, Berg T, Norum KR (1990) Transport and storage of vitamin A. Science 250:399–404

    Article  Google Scholar 

  30. Tesoriere L, Ciaccio M, Bongiorno A, Riccio A, Pintaudi AM, Livrea MA (1993) Antioxidant activity of all-trans-retinol in homogeneous solution and in phophastidylcholine liposomes. Arch Biochem Biophys 307:217–223

    Article  PubMed  CAS  Google Scholar 

  31. Petiz LL, Kunzler A, Bortolin RC, Gasparotto J, Matté C, Moreira JCF, Gelain DP (2017) Role of vitamin A oral supplementation on oxidative stress and inflammatory response in the liver of trained rat. Appl Physiol Nutr Metab 42:1192–1200

    Article  PubMed  CAS  Google Scholar 

  32. Iskakova M, Karbyshev M, Piskunov A, Rochette-Egly C (2015) Nuclear and extranuclear effects of vitamin A. Can J Physiol Pharmacol 93:1065–1075. https://doi.org/10.1139/cjpp-2014-0522 (epub 2015 Apr 28)

    Article  PubMed  CAS  Google Scholar 

  33. Olson JA (1989) Provitamin A function of carotenoids: the conversion of b-carotene into vitamin A. J Nutr 119:105–108

    Article  PubMed  CAS  Google Scholar 

  34. Parker RS (1989) Carotenoids in human blood and tissues. J Nutr 119:101–104

    Article  PubMed  CAS  Google Scholar 

  35. Krinsky NI (1989) Antioxidant functions of carotenoids. Free Radic Biol Med 7:617–635

    Article  PubMed  CAS  Google Scholar 

  36. Marinó M, Andrews D, Brown D, McCluskey RT (2001) Transcytosis of retinol-binding protein across renal proximal tubule cells after megalin (gp 330)-mediated endocytosis. J Am Soc Nephrol 12:637–648

    PubMed  Google Scholar 

  37. Wefers H, Sies H (1988) The protection of ascorbate and glutathione against microsomal lipid peroxidation is dependent on vitamin E. Eur J Biochem 174:353–357

    Article  PubMed  CAS  Google Scholar 

  38. Traber MG, Atkinson J (2007) Vitamin E, antioxidant and nothing more. Free Radic Biol Med 43:4–15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Boscoboinik D, Szewczyk A, Hensey C, Azzi A (1991) Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C. J Biol Chem 266:6188–6194

    PubMed  CAS  Google Scholar 

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Correspondence to M. Marinò.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Rotondo Dottore, G., Ionni, I., Menconi, F. et al. Antioxidant effects of β-carotene, but not of retinol and vitamin E, in orbital fibroblasts from patients with Graves’ orbitopathy (GO). J Endocrinol Invest 41, 815–820 (2018). https://doi.org/10.1007/s40618-017-0809-5

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