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Impaired HPA axis function in diabetes involves adrenal apoptosis and phagocytosis

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Abstract

Purpose

The aim of the present study was to analyze the involvement of oxidative stress and inflammation in the modulation of glucocorticoid production in the adrenal cortex of diabetic rats.

Methods

Male Wistar rats were treated with or without streptozotocin (STZ, an insulinopenic model of diabetes) and either α-lipoic (90 mg/kg ip.), α-tocopherol (200 mg/kg po.) or with STZ and supplemented with insulin (STZ + INS: 2.5U/day) for 4 weeks. Oxidative/nitrosative stress parameters and antioxidant enzymes were determined in adrenocortical tissues. Apoptosis and macrophage activation were evaluated by immunohistochemistry (TUNEL and ED1+). Basal and ACTH-stimulated corticosterone production were assessed by RIA and plasma ACTH levels were determined by an immunometric assay.

Results

Diabetic rats showed a diminished response to exogenous ACTH stimulation along with higher basal corticosterone and lower plasma ACTH levels. In the adrenal cortex we determined an increase in the levels of lipoperoxides, S-nitrosothiols, nitric oxide synthase activity and nitro-tyrosine modified proteins while catalase activity and heme oxygenase-1 expression levels were also elevated. Antioxidant treatments were effective in the prevention of these effects, and in the increase in the number of apoptotic and phagocytic (ED1+) cells detected in diabetic rats. No changes were observed in the STZ + INS group.

Conclusions

Generation of oxidative/nitrosative stress in the adrenal cortex of diabetic rats leads to the induction of apoptosis and the activation of adrenocortical macrophages and is associated with an elevated basal corticosteronemia and the loss of the functional capacity of the gland.

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References

  1. J.L. Rains, S.K. Jain, Oxidative stress, insulin signaling, and diabetes. Free Radic. Biol. Med. 50(5), 567–575 (2011)

    Article  PubMed  CAS  Google Scholar 

  2. D.A. Greene, M.J. Stevens, I. Obrosova, E.L. Feldman, Glucose-induced oxidative stress and programmed cell death in diabetic neuropathy. Eur. J. Pharmacol. 375(1-3), 217–223 (1999)

    Article  PubMed  CAS  Google Scholar 

  3. P. Pacher, I.G. Obrosova, J.G. Mabley, C. Szabo, Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. Curr. Med. Chem. 12(3), 267–275 (2005)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. T. Nishikawa, D. Edelstein, M. Brownlee, The missing link: a single unifying mechanism for diabetic complications. Kidney Int. Suppl. 77, S26–30 (2000)

    Article  PubMed  CAS  Google Scholar 

  5. F. Giacco, M. Brownlee, Oxidative stress and diabetic complications. Circ. Res. 107(9), 1058–1070 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. E. Di Marco, J.C. Jha, A. Sharma, J.L. Wilkinson-Berka, K.A. Jandeleit-Dahm, J.B. de Haan, Are reactive oxygen species still the basis for diabetic complications? Clin. Sci. 129(2), 199–216 (2015)

    Article  PubMed  CAS  Google Scholar 

  7. R. Brito, G. Castillo, J. Gonzalez, N. Valls, R. Rodrigo, Oxidative stress in hypertension: mechanisms and therapeutic opportunities. Exp. Clin. Endocrinol. Diabetes 123(6), 325–335 (2015)

    Article  PubMed  CAS  Google Scholar 

  8. C. Karasu, Glycoxidative stress and cardiovascular complications in experimentally-induced diabetes: effects of antioxidant treatment. Open Cardiovasc. Med. J. 4, 240–256 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. L. Rochette, S. Ghibu, A. Muresan, C. Vergely, Alpha-lipoic acid: molecular mechanisms and therapeutic potential in diabetes. Can. J. Physiol. Pharmacol. 93(12), 1021–1027 (2015)

    Article  PubMed  CAS  Google Scholar 

  10. H. Goldenstein, N.S. Levy, Y.T. Lipener, A.P. Levy, Patient selection and vitamin E treatment in diabetes mellitus. Expert. Rev. Cardiovasc. Ther. 11(3), 319–326 (2013)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. K. Petersen Shay, R.F. Moreau, E.J. Smith, T.M. Hagen, Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity. IUBMB Life 60(6), 362–367 (2008)

    Article  PubMed  CAS  Google Scholar 

  12. H. Moini, L. Packer, N.E. Saris, Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid. Toxicol. Appl. Pharmacol. 182(1), 84–90 (2002)

    Article  PubMed  CAS  Google Scholar 

  13. M. Whiteman, H. Tritschler, B. Halliwell, Protection against peroxynitrite-dependent tyrosine nitration and alpha 1-antiproteinase inactivation by oxidized and reduced lipoic acid. FEBS Lett. 379(1), 74–76 (1996)

    Article  PubMed  CAS  Google Scholar 

  14. L. Packer, E.H. Witt, H.J. Tritschler, alpha-Lipoic acid as a biological antioxidant. Free Radic. Biol. Med. 19(2), 227–250 (1995)

    Article  PubMed  CAS  Google Scholar 

  15. V.E. Kagan, A. Shvedova, E. Serbinova, S. Khan, C. Swanson, R. Powell, L. Packer, Dihydrolipoic acid—a universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals. Biochem. Pharmacol. 44(8), 1637–1649 (1992)

    Article  PubMed  CAS  Google Scholar 

  16. S. Golbidi, M. Badran, I. Laher, Diabetes and alpha lipoic acid. Front. Pharmacol. 2, 69 (2011)

    Article  PubMed  PubMed Central  Google Scholar 

  17. T. Tankova, D. Koev, L. Dakovska, Alpha-lipoic acid in the treatment of autonomic diabetic neuropathy (controlled, randomized, open-label study). Rom. J. Intern. Med. 42(2), 457–464 (2004)

    PubMed  CAS  Google Scholar 

  18. T. Varkonyi, A. Korei, Z. Putz, T. Martos, K. Keresztes, C. Lengyel, S. Nyiraty, A. Stirban, G. Jermendy, P. Kempler, Advances in the management of diabetic neuropathy. Minerva Med. 108(5), 419–437 (2017)

    PubMed  Google Scholar 

  19. D. Ziegler, A. Ametov, A. Barinov, P.J. Dyck, I. Gurieva, P.A. Low, U. Munzel, N. Yakhno, I. Raz, M. Novosadova, J. Maus, R. Samigullin, Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 29(11), 2365–2370 (2006)

    Article  PubMed  CAS  Google Scholar 

  20. J.W. Chang, E.K. Lee, T.H. Kim, W.K. Min, S. Chun, K.U. Lee, S.B. Kim, J.S. Park, Effects of alpha-lipoic acid on the plasma levels of asymmetric dimethylarginine in diabetic end-stage renal disease patients on hemodialysis: a pilot study. Am. J. Nephrol. 27(1), 70–74 (2007)

    Article  PubMed  CAS  Google Scholar 

  21. M. Morcos, V. Borcea, B. Isermann, S. Gehrke, T. Ehret, M. Henkels, S. Schiekofer, M. Hofmann, J. Amiral, H. Tritschler, R. Ziegler, P. Wahl, P.P. Nawroth, Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study. Diabetes Res. Clin. Pract. 52(3), 175–183 (2001)

    Article  PubMed  CAS  Google Scholar 

  22. S.K. Hegazy, O.A. Tolba, T.M. Mostafa, M.A. Eid, D.R. El-Afify, Alpha-lipoic acid improves subclinical left ventricular dysfunction in asymptomatic patients with type 1 diabetes. Rev. Diabet. Stud. 10(1), 58–67 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  23. G.W. Burton, K.U. Ingold, Vitamin E as an in vitro and in vivo antioxidant. Ann. N. Y. Acad. Sci. 570, 7–22 (1989)

    Article  PubMed  CAS  Google Scholar 

  24. P.G. Khatami, A. Soleimani, N. Sharifi, E. Aghadavod, Z. Asemi, The effects of high-dose vitamin E supplementation on biomarkers of kidney injury, inflammation, and oxidative stress in patients with diabetic nephropathy: a randomized, double-blind, placebo-controlled trial. J. Clin. Lipidol. 10(4), 922–929 (2016)

    Article  PubMed  Google Scholar 

  25. S. Gupta, T.K. Sharma, G.G. Kaushik, V.P. Shekhawat, Vitamin E supplementation may ameliorate oxidative stress in type 1 diabetes mellitus patients. Clin. Lab. 57(5-6), 379–386 (2011)

    PubMed  CAS  Google Scholar 

  26. C. Giannini, F. Lombardo, F. Curro, M. Pomilio, T. Bucciarelli, F. Chiarelli, A. Mohn, Effects of high-dose vitamin E supplementation on oxidative stress and microalbuminuria in young adult patients with childhood onset type 1 diabetes mellitus. Diabetes Metab. Res. Rev. 23(7), 539–546 (2007)

    Article  PubMed  CAS  Google Scholar 

  27. E.M. Repetto, R. Sanchez, J. Cipelli, F. Astort, C.M. Calejman, G.G. Piroli, P. Arias, C.B. Cymeryng, Dysregulation of corticosterone secretion in streptozotocin-diabetic rats: modulatory role of the adrenocortical nitrergic system. Endocrinology 151(1), 203–210 (2010)

    Article  PubMed  CAS  Google Scholar 

  28. D.D. Wink, S. Kim, E. Coffin, J. Cook, Y. Vodovotz, D. Chistodoulou, D. Jourd’heuil, M. Grisham, Detection of S-nitrosothiols by fluorometric and colorimetric methods. Methods Enzymol. 301, 201–211 (1999). https://doi.org/10.1016/S0076-6879(99)01083-6

    Article  PubMed  CAS  Google Scholar 

  29. Y. Pomeraniec, N. Grion, L. Gadda, V. Pannunzio, E.J. Podesta, C.B. Cymeryng, Adrenocorticotropin induces heme oxygenase-1 expression in adrenal cells. J. Endocrinol. 180(1), 113–124 (2004)

    Article  PubMed  CAS  Google Scholar 

  30. H. Aebi. Catalase. Methods of Enzymatic Analysis. H. Bermeyer (ed.) Verlag Chemie, Wenheim), 1982) 271–282

    Google Scholar 

  31. M.E. Mercau, F. Astort, E.F. Giordanino, C. Martinez Calejman, R. Sanchez, L. Caldareri, E.M. Repetto, O.A. Coso, C.B. Cymeryng, Involvement of PI3K/Akt and p38 MAPK in the induction of COX-2 expression by bacterial lipopolysaccharide in murine adrenocortical cells. Mol. Cell. Endocrinol. 384(1-2), 43–51 (2013)

    Article  CAS  Google Scholar 

  32. S.A. Motzer, V. Hertig, Stress, stress response, and health. Nurs. Clin. N. Am. 39(1), 1–17 (2004)

    Article  Google Scholar 

  33. T.H. Puar, N.M. Stikkelbroeck, L.C. Smans, P.M. Zelissen, A.R. Hermus, Adrenal crisis: still a deadly event in the 21st century. Am. J. Med. 129(3), 339 e331–339 (2016)

    Article  Google Scholar 

  34. P.K. Singh, D. Baxi, S. Banerjee, A.V. Ramachandran, Therapy with methanolic extract of Pterocarpus marsupium Roxb and Ocimum sanctum Linn reverses dyslipidemia and oxidative stress in alloxan induced type I diabetic rat model. Exp. Toxicol. Pathol. 64(5), 441–448 (2010)

    Article  PubMed  CAS  Google Scholar 

  35. I.G. Danilova, T.S. Bulavintceva, I.F. Gette, S.Y. Medvedeva, V.V. Emelyanov, M.T. Abidov, Partial recovery from alloxan-induced diabetes by sodium phthalhydrazide in rats. Biomed. Pharmacother. 95, 103–110 (2017)

    Article  PubMed  CAS  Google Scholar 

  36. O. Chan, K. Inouye, M. Vranic, S.G. Matthews, Hyperactivation of the hypothalamo-pituitary-adrenocortical axis in streptozotocin-diabetes is associated with reduced stress responsiveness and decreased pituitary and adrenal sensitivity. Endocrinology 143(5), 1761–1768 (2002)

    Article  PubMed  CAS  Google Scholar 

  37. K. Simunkova, R. Hampl, M. Hill, L. Kriz, P. Hrda, D. Janickova-Zdarska, V. Zamrazil, J. Vrbikova, K. Vondra, Adrenocortical function in young adults with diabetes mellitus type 1. J. Steroid Biochem. Mol. Biol. 122(1-3), 35–41 (2010)

    Article  PubMed  CAS  Google Scholar 

  38. X. Gaete, G. Iniguez, J. Linares, A. Avila, V. Mericq, Cortisol hyporesponsiveness to the low dose ACTH test is a frequent finding in a pediatric population with type 1 diabetes mellitus. Pediatr. Diabetes 14(6), 429–434 (2010)

    Article  CAS  Google Scholar 

  39. A.N. Sharma, J. Wigham, J.D. Veldhuis, Corticotropic axis drive of overnight cortisol secretion is suppressed in adolescents and young adults with type 1 diabetes mellitus. Pediatr. Diabetes 15(6), 444–452 (2014)

    Article  PubMed  CAS  Google Scholar 

  40. S. Azhar, L. Cao, E. Reaven, Alteration of the adrenal antioxidant defense system during aging in rats. J. Clin. Invest. 96(3), 1414–1424 (1995)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. P. Patak, H.S. Willenberg, S.R. Bornstein, Vitamin C is an important cofactor for both adrenal cortex and adrenal medulla. Endocr. Res. 30(4), 871–875 (2004)

    Article  PubMed  CAS  Google Scholar 

  42. J. Zhen, H. Lu, X.Q. Wang, N.D. Vaziri, X.J. Zhou, Upregulation of endothelial and inducible nitric oxide synthase expression by reactive oxygen species. Am. J. Hypertens. 21(1), 28–34 (2008)

    Article  PubMed  CAS  Google Scholar 

  43. J.H. Jang, J.N. Chun, S. Godo, G. Wu, H. Shimokawa, C.Z. Jin, J.H. Jeon, S.J. Kim, Z.H. Jin, Y.H. Zhang, ROS and endothelial nitric oxide synthase (eNOS)-dependent trafficking of angiotensin II type 2 receptor begets neuronal NOS in cardiac myocytes. Basic Res. Cardiol. 110(3), 21 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. N.D. Vaziri, Y. Ding, Z. Ni, Compensatory up-regulation of nitric-oxide synthase isoforms in lead-induced hypertension; reversal by a superoxide dismutase-mimetic drug. J. Pharmacol. Exp. Ther. 298(2), 679–685 (2001)

    PubMed  CAS  Google Scholar 

  45. G.M. Buga, J.M. Griscavage, N.E. Rogers, L.J. Ignarro, Negative feedback regulation of endothelial cell function by nitric oxide. Circ. Res. 73(5), 808–812 (1993)

    Article  PubMed  CAS  Google Scholar 

  46. Y. Du, C.M. Miller, T.S. Kern, Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radic. Biol. Med. 35(11), 1491–1499 (2003)

    Article  PubMed  CAS  Google Scholar 

  47. R.A. Kowluru, R.L. Engerman, T.S. Kern, Diabetes-induced metabolic abnormalities in myocardium: effect of antioxidant therapy. Free Radic. Res. 32(1), 67–74 (2000)

    Article  PubMed  CAS  Google Scholar 

  48. D. Koya, K. Hayashi, M. Kitada, A. Kashiwagi, R. Kikkawa, M. Haneda, Effects of antioxidants in diabetes-induced oxidative stress in the glomeruli of diabetic rats. J. Am. Soc. Nephrol. 14(8Suppl 3), S250–253 (2003)

    Article  PubMed  CAS  Google Scholar 

  49. V.M. Altan, The pharmacology of diabetic complications. Curr. Med. Chem. 10(15), 1317–1327 (2003)

    Article  PubMed  CAS  Google Scholar 

  50. M.A. Haidara, D.P. Mikhailidis, M.A. Rateb, Z.A. Ahmed, H.Z. Yassin, I.M. Ibrahim, L.A. Rashed, Evaluation of the effect of oxidative stress and vitamin E supplementation on renal function in rats with streptozotocin-induced Type 1 diabetes. J. Diabetes Complicat. 23(2), 130–136 (2009)

    Article  PubMed  Google Scholar 

  51. S. Alireza, N. Leila, S. Siamak, K.A. Mohammad-Hasan, I. Behrouz, Effects of vitamin E on pathological changes induced by diabetes in rat lungs. Respir. Physiol. Neurobiol. 185(3), 593–599 (2013)

    Article  PubMed  CAS  Google Scholar 

  52. M.B. Gomes, C.A. Negrato, Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol. Metab. Syndr. 6(1), 80 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. G. Nascimento Gomes, F.T. Barbosa, R.F. Radaeli, M.F. Cavanal, M. Mello Aires, F. Zaladek Gil, Effect of D-alpha-tocopherol on tubular nephron acidification by rats with induced diabetes mellitus. Braz. J. Med. Biol. Res. 38(7), 1043–1051 (2005)

    Article  PubMed  CAS  Google Scholar 

  54. D. Comin, L. Gazarini, J.N. Zanoni, H. Milani, R.M. de Oliveira, Vitamin E improves learning performance and changes the expression of nitric oxide-producing neurons in the brains of diabetic rats. Behav. Brain. Res. 210(1), 38–45 (2010)

    Article  PubMed  CAS  Google Scholar 

  55. I. Obrosova, X. Cao, D.A. Greene, M.J. Stevens, Diabetes-induced changes in lens antioxidant status, glucose utilization and energy metabolism: effect of DL-alpha-lipoic acid. Diabetologia 41(12), 1442–1450 (1998)

    Article  PubMed  CAS  Google Scholar 

  56. A.C. Maritim, R.A. Sanders, J.B. Watkins, 3rd: effects of alpha-lipoic acid on biomarkers of oxidative stress in streptozotocin-induced diabetic rats. J. Nutr. Biochem. 14(5), 288–294 (2003)

    Article  PubMed  CAS  Google Scholar 

  57. C. Hurdag, I. Uyaner, E. Gurel, A. Utkusavas, P. Atukeren, C. Demirci, The effect of alpha-lipoic acid on NOS dispersion in the lung of streptozotocin-induced diabetic rats. J. Diabetes Complicat. 22(1), 56–61 (2008)

    Article  PubMed  Google Scholar 

  58. S. Xu, C. Chen, W.X. Wang, S.R. Huang, J. Yu, X.Y. Chen, IIA phospholipase A2 in pancreatitis-associated adrenal injury in acute necrotizing pancreatitis. Pathol. Res. Pract. 206(2), 73–82 (2010).

    Article  PubMed  CAS  Google Scholar 

  59. J. Yu, S. Xu, W.X. Wang, W.H. Deng, H. Jin, X.Y. Chen, C. Chen, H.T. Sun, Changes of inflammation and apoptosis in adrenal gland after experimental injury in rats with acute necrotizing pancreatitis. Inflammation 35(1), 11–22 (2012)

    Article  PubMed  CAS  Google Scholar 

  60. J. Yu, T. Zuo, W. Deng, Q. Shi, P. Ma, C. Chen, L. Zhao, K. Zhao, W. Wang, Poly(ADP-ribose) polymerase inhibition suppresses inflammation and promotes recovery from adrenal injury in a rat model of acute necrotizing pancreatitis. Bmc. Gastroenterol. 16(1), 81 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. A. Kupsco, D. Schlenk, Oxidative stress, unfolded protein response, and apoptosis in developmental toxicity. Int. Rev. Cell. Mol. Biol. 317, 1–66 (2011)

    Google Scholar 

  62. C.J. Norbury, I.D. Hickson, Cellular responses to DNA damage. Annu. Rev. Pharmacol. Toxicol. 41, 367–401 (2001)

    Article  PubMed  CAS  Google Scholar 

  63. R. Saraswathi, S.N. Devaraj, Oxidative stress in skeletal muscle impairs mitochondrial function in alloxan induced diabetic rats: role of alpha lipoic acid. Biomed. Prev. Nutr. 3(3), 213–219 (2013). https://doi.org/10.1016/j.bionut.2012.08.006

    Article  Google Scholar 

  64. Y. Yang, W. Wang, Y. Liu, T. Guo, P. Chen, K. Ma, C. Zhou, Alpha-lipoic acid inhibits high glucose-induced apoptosis in HIT-T15 cells. Dev. Growth Differ. 54(5), 557–565 (2012)

    Article  PubMed  CAS  Google Scholar 

  65. J. Shin, S.J. Yang, Y. Lim, Gamma-tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice. Exp. Biol. Med. 242(5), 505–515 (2017)

    Article  CAS  Google Scholar 

  66. H. Almeida, J. Ferreira, D. Neves, Macrophages of the adrenal cortex: a morphological study of the effects of aging and dexamethasone administration. Ann. N. Y. Acad. Sci. 1019, 135–140 (2004)

    Article  PubMed  CAS  Google Scholar 

  67. S. McIlmoil, J. Strickland, A.M. Judd, Interleukin 6 increases the in vitro expression of key proteins associated with steroidogenesis in the bovine adrenal zona fasciculata. Domest. Anim. Endocrinol. 55, 11–24 (2016)

    Article  PubMed  CAS  Google Scholar 

  68. A.V. Turnbull, C.L. Rivier, Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol. Rev. 79(1), 1–71 (1999)

    Article  PubMed  CAS  Google Scholar 

  69. S.R. Bornstein, H. Rutkowski, I. Vrezas, Cytokines and steroidogenesis. Mol. Cell. Endocrinol. 215(1-2), 135–141 (2004)

    Article  PubMed  CAS  Google Scholar 

  70. I.V. Tkachenko, T. Jaaskelainen, J. Jaaskelainen, J.J. Palvimo, R. Voutilainen, Interleukins 1alpha and 1beta as regulators of steroidogenesis in human NCI-H295R adrenocortical cells. Steroids 76(10-11), 1103–1115 (2011)

    Article  PubMed  CAS  Google Scholar 

  71. A. Hasanvand, H. Amini-Khoei, M.R. Hadian, A. Abdollahi, S.M. Tavangar, A.R. Dehpour, E. Semiei, S.E. Mehr, Anti-inflammatory effect of AMPK signaling pathway in rat model of diabetic neuropathy. Inflammopharmacology 24(5), 207–219 (2016)

    Article  PubMed  CAS  Google Scholar 

  72. J.F. Navarro-Gonzalez, C. Mora-Fernandez, The role of inflammatory cytokines in diabetic nephropathy. J. Am. Soc. Nephrol. 19(3), 433–442 (2008)

    Article  PubMed  CAS  Google Scholar 

  73. R.A. Kowluru, Q. Zhong, J.M. Santos, M. Thandampallayam, D. Putt, D.L. Gierhart, Beneficial effects of the nutritional supplements on the development of diabetic retinopathy. Nutr. Metab. 11(1), 8 (2014)

    Article  CAS  Google Scholar 

  74. T. Ono, S. Takada, S. Kinugawa, H. Tsutsui, Curcumin ameliorates skeletal muscle atrophy in type 1 diabetic mice by inhibiting protein ubiquitination. Exp. Physiol. 100(9), 1052–1063 (2015)

    Article  PubMed  CAS  Google Scholar 

  75. M.B. Ka, A. Daumas, J. Textoris, J.L. Mege, Phenotypic diversity and emerging new tools to study macrophage activation in bacterial infectious diseases. Front. Immunol. 5, 500 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. A. Nilsson, L. Vesterlund, P.A. Oldenborg, Macrophage expression of LRP1, a receptor for apoptotic cells and unopsonized erythrocytes, can be regulated by glucocorticoids. Biochem. Biophys. Res. Commun. 417(4), 1304–1309 (2012)

    Article  PubMed  CAS  Google Scholar 

  77. J.S. Gilmour, A.E. Coutinho, J.F. Cailhier, T.Y. Man, M. Clay, G. Thomas, H.J. Harris, J.J. Mullins, J.R. Seckl, J.S. Savill, K.E. Chapman, Local amplification of glucocorticoids by 11 beta-hydroxysteroid dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes. J. Immunol. 176(12), 7605–7611 (2006)

    Article  PubMed  CAS  Google Scholar 

  78. M.E. Reyland, R.M. Evans, E.K. White, Lipoproteins regulate expression of the steroidogenic acute regulatory protein (StAR) in mouse adrenocortical cells. J. Biol. Chem. 275(47), 36637–36644 (2000)

    Article  PubMed  CAS  Google Scholar 

  79. G.S. Prasath, S.P. Subramanian, Antihyperlipidemic effect of fisetin, a bioflavonoid of strawberries, studied in streptozotocin-induced diabetic rats. J. Biochem. Mol. Toxicol. 28(10), 442–449 (2014)

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors want to thank Dr. Silvia Sanchez Puch for the invaluable technical support.

Funding

This work was supported by grants from ANPCyT (PICT 2008 N°1034), CONICET (PIP11220120100257) and UBA (UBACYT 20020130100115BA-UBACYT 20020150200065BA).

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Authors and Affiliations

  1. Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina

    Esteban M. Repetto

  2. Facultad de Medicina, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Laboratorio de Endocrinología Molecular (LEM), Universidad de Buenos Aires, Buenos Aires, Argentina

    Esteban M. Repetto, Morena Wiszniewski, Ana L. Bonelli, Carolina V. Vecino, Camila Martinez Calejman & Cora B. Cymeryng

  3. Departamento de Fisiología, Facultad de Medicina, Universidad Nacional de Rosario, Rosario, Argentina

    Pablo Arias

  4. Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

    Cora B. Cymeryng

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  1. Esteban M. Repetto
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Repetto, E.M., Wiszniewski, M., Bonelli, A.L. et al. Impaired HPA axis function in diabetes involves adrenal apoptosis and phagocytosis. Endocrine 63, 602–614 (2019). https://doi.org/10.1007/s12020-018-1755-5

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