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Volumn 55, Issue 6, 2009, Pages 451-459

Evaluation of the effect of acetyl L-carnitine on experimental cisplatin nephrotoxicity

Author keywords

Acetyl L carnitine; Apoptosis; Cisplatin; Nephrotoxicity; Ultrastructure

Indexed keywords

CASPASE 3; CASPASE 8; CASPASE 9; CISPLATIN; CISPLATIN EBEWE; CREATININE; LEVACECARNINE; UNCLASSIFIED DRUG;

EID: 71249140647     PISSN: 00093157     EISSN: None     Source Type: Journal    
DOI: 10.1159/000240020     Document Type: Article
Times cited : (42)

References (51)
  • 1
    • 34547100275 scopus 로고    scopus 로고
    • The resurgence of platinum based cancer chemotherapy
    • Kelland L: The resurgence of platinum based cancer chemotherapy. Nat Rev Cancer 2007; 7: 573-584.
    • (2007) Nat Rev Cancer , vol.7 , pp. 573-584
    • Kelland, L.1
  • 2
    • 18244379333 scopus 로고    scopus 로고
    • Cellular processing of platinum anticancer drugs
    • Wang D, Lippard SJ: Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 2005; 4: 307-320.
    • (2005) Nat Rev Drug Discov , vol.4 , pp. 307-320
    • Wang, D.1    Lippard, S.J.2
  • 3
    • 33846404174 scopus 로고    scopus 로고
    • Molecular mechanisms of resistance and toxicity associated with platinating agents
    • Rabik CA, Dolan ME: Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 2007; 33: 9-23.
    • (2007) Cancer Treat Rev , vol.33 , pp. 9-23
    • Rabik, C.A.1    Dolan, M.E.2
  • 4
    • 0345256652 scopus 로고    scopus 로고
    • Cisplatin: Mode of cytotoxic action and molecular basis of resistance
    • Siddik ZH: Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003; 22: 7265-7279.
    • (2003) Oncogene , vol.22 , pp. 7265-7279
    • Siddik, Z.H.1
  • 5
    • 22244478065 scopus 로고    scopus 로고
    • Severe neurotoxicity, ototoxicity and nephrotoxicity following highdose cisplatin and amifostine
    • Sastry J, Kellie SJ: Severe neurotoxicity, ototoxicity and nephrotoxicity following highdose cisplatin and amifostine. Pediatr Hematol Oncol 2005; 22: 441-445.
    • (2005) Pediatr Hematol Oncol , vol.22 , pp. 441-445
    • Sastry, J.1    Kellie, S.J.2
  • 7
    • 2142694056 scopus 로고    scopus 로고
    • Cisplatin and platinum drugs at the molecular level
    • Boulikas T, Vougiouka M: Cisplatin and platinum drugs at the molecular level. Oncol Rep 2003; 10: 1663-1682.
    • (2003) Oncol Rep , vol.10 , pp. 1663-1682
    • Boulikas, T.1    Vougiouka, M.2
  • 8
    • 36048968131 scopus 로고    scopus 로고
    • High-dose platinum combination therapy in pretreated patients with disseminated melanoma
    • Hofmann MA, Gabriel V, Milling A, Kiecker F, Sterry W, Trefzer U: High-dose platinum combination therapy in pretreated patients with disseminated melanoma. Chemotherapy 2007; 53: 422-428.
    • (2007) Chemotherapy , vol.53 , pp. 422-428
    • Hofmann, M.A.1    Gabriel, V.2    Milling, A.3    Kiecker, F.4    Sterry, W.5    Trefzer, U.6
  • 10
    • 42149187768 scopus 로고    scopus 로고
    • Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies
    • Pabla N, Dong Z: Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 2008; 73: 994-1007.
    • (2008) Kidney Int , vol.73 , pp. 994-1007
    • Pabla, N.1    Dong, Z.2
  • 11
    • 15444367037 scopus 로고    scopus 로고
    • L-carnitine
    • Monograph
    • Monograph. L-carnitine. Altern Med Rev 2005; 10: 42-50.
    • (2005) Altern Med Rev , vol.10 , pp. 42-50
  • 12
    • 30544442097 scopus 로고    scopus 로고
    • Acetylcarnitine and cellular stress response: Roles in nutritional redox homeostasis and regulation of longevity genes
    • Calabrese V, Giuffrida Stella AM, Calvani M, Butterfield DA: Acetylcarnitine and cellular stress response: roles in nutritional redox homeostasis and regulation of longevity genes. J Nutr Biochem 2006; 17: 73-88.
    • (2006) J Nutr Biochem , vol.17 , pp. 73-88
    • Calabrese, V.1    Giuffrida Stella, A.M.2    Calvani, M.3    Butterfield, D.A.4
  • 13
    • 0021024932 scopus 로고
    • Carnitine-metabolism and functions
    • Bremer J: Carnitine-metabolism and functions. Physiol Rev 1983; 63: 1420-1480.
    • (1983) Physiol Rev , vol.63 , pp. 1420-1480
    • Bremer, J.1
  • 14
    • 0034769470 scopus 로고    scopus 로고
    • Carnitine as a free radical scavenger in aging
    • Arockia Rani PJ, Panneerselvam C: Carnitine as a free radical scavenger in aging. Exp Gerontol 2001; 36: 1713-1726.
    • (2001) Exp Gerontol , vol.36 , pp. 1713-1726
    • Arockia Rani, P.J.1    Panneerselvam, C.2
  • 15
    • 0035103186 scopus 로고    scopus 로고
    • Carnitine protects mitochondria and removes toxic acyls from xenobiotics
    • Arrigoni-Martelli E, Caso V: Carnitine protects mitochondria and removes toxic acyls from xenobiotics. Drugs Exp Clin Res 2001; 27: 27-49.
    • (2001) Drugs Exp Clin Res , vol.27 , pp. 27-49
    • Arrigoni-Martelli, E.1    Caso, V.2
  • 16
    • 0035976362 scopus 로고    scopus 로고
    • Neuroprotective role of L -carnitine in the 3-nitropropionic acid induced neurotoxicity
    • Binienda ZK, Ali SF: Neuroprotective role of L -carnitine in the 3-nitropropionic acid induced neurotoxicity. Toxicol Lett 2001; 125: 67-73.
    • (2001) Toxicol Lett , vol.125 , pp. 67-73
    • Binienda, Z.K.1    Ali, S.F.2
  • 17
    • 30544455318 scopus 로고    scopus 로고
    • Antioxidant and antiradical activities of L -carnitine
    • Gülçin I: Antioxidant and antiradical activities of L -carnitine. Life Sci 2006; 78: 803-811.
    • (2006) Life Sci , vol.78 , pp. 803-811
    • Gülçin, I.1
  • 18
    • 28844438030 scopus 로고    scopus 로고
    • Antioxidant effect of L -carnitine and its short chain esters: Relevance for the protection from oxidative stress related cardiovascular damage
    • Calò LA, Pagnin E, Davis PA, et al: Antioxidant effect of L -carnitine and its short chain esters: relevance for the protection from oxidative stress related cardiovascular damage. Int J Cardiol 2006; 107: 54-60.
    • (2006) Int J Cardiol , vol.107 , pp. 54-60
    • Calò, L.A.1    Pagnin, E.2    Davis, P.A.3
  • 19
    • 37849189638 scopus 로고    scopus 로고
    • Protective effect of acetyl- L -carnitine against oxidative stress induced by antiretroviral drugs
    • Ferraresi R, Troiano L, Roat E, et al: Protective effect of acetyl- L -carnitine against oxidative stress induced by antiretroviral drugs. FEBS Lett 2006; 580: 6612-6616.
    • (2006) FEBS Lett , vol.580 , pp. 6612-6616
    • Ferraresi, R.1    Troiano, L.2    Roat, E.3
  • 20
    • 34547841506 scopus 로고    scopus 로고
    • Acetyl- L -carnitine ameliorates hypobaric hypoxic impairment and spatial memory deficits in rats
    • Barhwal K, Singh SB, Hota SK, Jayalakshmi K, Ilavazhagan G: Acetyl- L -carnitine ameliorates hypobaric hypoxic impairment and spatial memory deficits in rats. Eur J Pharmacol 2007; 570: 97-107.
    • (2007) Eur J Pharmacol , vol.570 , pp. 97-107
    • Barhwal, K.1    Singh, S.B.2    Hota, S.K.3    Jayalakshmi, K.4    Ilavazhagan, G.5
  • 21
    • 34547994382 scopus 로고    scopus 로고
    • Protective effect of acetyl- L -carnitine on the apoptotic pathway of peripheral neuropathy
    • Di Cesare Mannelli L, Ghelardini C, Calvani M, et al: Protective effect of acetyl- L -carnitine on the apoptotic pathway of peripheral neuropathy. Eur J Neurosci 2007; 26: 820-827.
    • (2007) Eur J Neurosci , vol.26 , pp. 820-827
    • Di Cesare Mannelli, L.1    Ghelardini, C.2    Calvani, M.3
  • 22
    • 63049089317 scopus 로고    scopus 로고
    • Neuroprotective effects of acetyl- L - Carnitine on neuropathic pain and apoptosis: A role for the nicotinic receptor
    • Di Cesare Mannelli L, Ghelardini C, Calvani M, et al: Neuroprotective effects of acetyl- L - carnitine on neuropathic pain and apoptosis: a role for the nicotinic receptor. J Neurosci Res 2009; 87: 200-207.
    • (2009) J Neurosci Res , vol.87 , pp. 200-207
    • Di Cesare Mannelli, L.1    Ghelardini, C.2    Calvani, M.3
  • 23
    • 52049105602 scopus 로고    scopus 로고
    • Acetyl- L -carnitine suppresses apoptosis of thioredoxin 2-deficient DT40 cells
    • Zhu X, Sato EF, Wang Y, Nakamura H, Yodoi J, Inoue M: Acetyl- L -carnitine suppresses apoptosis of thioredoxin 2-deficient DT40 cells. Arch Biochem Biophys 2008; 478: 154-160.
    • (2008) Arch Biochem Biophys , vol.478 , pp. 154-160
    • Zhu, X.1    Sato, E.F.2    Wang, Y.3    Nakamura, H.4    Yodoi, J.5    Inoue, M.6
  • 24
    • 41149160642 scopus 로고    scopus 로고
    • Combined treatment with L -carnitine and a pan-caspase inhibitor effectively reverses amiodarone-induced injury in cultured human lung epithelial cells
    • Yano T, Itoh Y, Yamada M, Eqashira N, Oishi R: Combined treatment with L -carnitine and a pan-caspase inhibitor effectively reverses amiodarone-induced injury in cultured human lung epithelial cells. Apoptosis 2008; 13: 543-552.
    • (2008) Apoptosis , vol.13 , pp. 543-552
    • Yano, T.1    Itoh, Y.2    Yamada, M.3    Eqashira, N.4    Oishi, R.5
  • 25
    • 0033922436 scopus 로고    scopus 로고
    • Anti-apoptotic effect of acetyl- L -carnitine and L -carnitine in primary cultured neurons
    • Ishii T, Shimpo Y, Matsuoka Y, Kinoshita K: Anti-apoptotic effect of acetyl- L -carnitine and L -carnitine in primary cultured neurons. Jpn J Pharmacol 2000; 83: 119-124.
    • (2000) Jpn J Pharmacol , vol.83 , pp. 119-124
    • Ishii, T.1    Shimpo, Y.2    Matsuoka, Y.3    Kinoshita, K.4
  • 27
    • 0036715482 scopus 로고    scopus 로고
    • L -Carnitine inhibits cisplatininduced injury of the kidney and small intestine
    • Chang B, Nishikawa M, Sato E, Utsumi K, Inoue M, et al: L -Carnitine inhibits cisplatininduced injury of the kidney and small intestine. Arch Biochem Biophys 2002; 405: 55-64.
    • (2002) Arch Biochem Biophys , vol.405 , pp. 55-64
    • Chang, B.1    Nishikawa, M.2    Sato, E.3    Utsumi, K.4    Inoue, M.5
  • 28
    • 35548953105 scopus 로고    scopus 로고
    • Reversal of cisplatin-induced carnitine deficiency and energy starvation by propionyl- L -Carnitine in rat kidney tissues
    • Aleisa AM, Al-Majed AA, Al-Yahya AA, et al: Reversal of cisplatin-induced carnitine deficiency and energy starvation by propionyl- L -carnitine in rat kidney tissues. Clin Exp Pharmacol Physiol 2007; 34: 1252-1259.
    • (2007) Clin Exp Pharmacol Physiol , vol.34 , pp. 1252-1259
    • Aleisa, A.M.1    Al-Majed, A.A.2    Al-Yahya, A.A.3
  • 29
    • 35348908316 scopus 로고    scopus 로고
    • Ultrastructural changes in the kidney of rats with acute exposure to cadmium and effects of exogenous metallothionein
    • Kukner A, Colakoglu N, Kara H, Oner H, Ozogul C, Ozan E: Ultrastructural changes in the kidney of rats with acute exposure to cadmium and effects of exogenous metallothionein. Biol Trace Elem Res 2007; 119: 137-146.
    • (2007) Biol Trace Elem Res , vol.119 , pp. 137-146
    • Kukner, A.1    Colakoglu, N.2    Kara, H.3    Oner, H.4    Ozogul, C.5    Ozan, E.6
  • 30
    • 35348837275 scopus 로고    scopus 로고
    • The protective effects of trimetazidine on testicular ischemia and reperfusion injury in rats
    • Pekcetin C, Ergur BU, Kiray M, et al: The protective effects of trimetazidine on testicular ischemia and reperfusion injury in rats. Pediatr Surg Int 2007; 23: 1113-1118.
    • (2007) Pediatr Surg Int , vol.23 , pp. 1113-1118
    • Pekcetin, C.1    Ergur, B.U.2    Kiray, M.3
  • 31
    • 0141702103 scopus 로고    scopus 로고
    • TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure
    • Ramesh G, Reeves WB: TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure. Am J Physiol Renal Physiol 2003; 285:F610-F618.
    • (2003) Am J Physiol Renal Physiol , vol.285
    • Ramesh, G.1    Reeves, W.B.2
  • 32
    • 0036738517 scopus 로고    scopus 로고
    • TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity
    • Ramesh G, Reeves WB: TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 2002; 110: 835-842.
    • (2002) J Clin Invest , vol.110 , pp. 835-842
    • Ramesh, G.1    Reeves, W.B.2
  • 33
    • 4644324913 scopus 로고    scopus 로고
    • Inflammatory cytokines in acute renal failure
    • Ramesh G, Reeves WB: Inflammatory cytokines in acute renal failure. Kidney Int Suppl 2004; 91:S56-S61.
    • (2004) Kidney Int Suppl , vol.91
    • Ramesh, G.1    Reeves, W.B.2
  • 34
    • 54249163313 scopus 로고    scopus 로고
    • The role of inflammatory markers in the cardioprotective effect of L -carnitine in L -NAMEinduced hypertension
    • Miguel-Carrasco JL, Mate A, Monserrat MT, Arias JL, Aramburu O, Vazquez CM: The role of inflammatory markers in the cardioprotective effect of L -carnitine in L -NAMEinduced hypertension. Am J Hypertens 2008; 21: 1231-1237.
    • (2008) Am J Hypertens , vol.21 , pp. 1231-1237
    • Miguel-Carrasco, J.L.1    Mate, A.2    Monserrat, M.T.3    Arias, J.L.4    Aramburu, O.5    Vazquez, C.M.6
  • 35
    • 34748921578 scopus 로고    scopus 로고
    • Protective effects of L -carnitine and alphalipoic acid in rats with adjuvant arthritis
    • Tastekin N, Aydogdu N, Dokmeci D, et al: Protective effects of L -carnitine and alphalipoic acid in rats with adjuvant arthritis. Pharmacol Res 2007; 5: 303-310.
    • (2007) Pharmacol Res , vol.5 , pp. 303-310
    • Tastekin, N.1    Aydogdu, N.2    Dokmeci, D.3
  • 36
    • 11844262893 scopus 로고    scopus 로고
    • L - Carnitine infusions may suppress serum Creactive protein and improve nutritional status in maintenance hemodialysis patients
    • Savica V, Santoro D, Mazzaglia G, et al: L - carnitine infusions may suppress serum Creactive protein and improve nutritional status in maintenance hemodialysis patients. J Ren Nutr 2005; 15: 225-230.
    • (2005) J Ren Nutr , vol.15 , pp. 225-230
    • Savica, V.1    Santoro, D.2    Mazzaglia, G.3
  • 37
    • 56049117823 scopus 로고    scopus 로고
    • Carnitine deficiency aggravates carboplatin nephropathy through deterioration of energy status, oxidant/anti-oxidant balance, and inflammatory endocoids
    • Arafa HM: Carnitine deficiency aggravates carboplatin nephropathy through deterioration of energy status, oxidant/anti-oxidant balance, and inflammatory endocoids. Toxicology 2008; 254: 51-60.
    • (2008) Toxicology , vol.254 , pp. 51-60
    • Arafa, H.M.1
  • 38
    • 12244271446 scopus 로고    scopus 로고
    • Protective effect of procaine hydrochloride on cisplatin-induced alterations in rat kidney
    • Fenoglio C, Boicelli CA, Ottone M, Addario C, Chiari P, Viale M: Protective effect of procaine hydrochloride on cisplatin-induced alterations in rat kidney. Anticancer Drugs 2002; 13: 1043-1054.
    • (2002) Anticancer Drugs , vol.13 , pp. 1043-1054
    • Fenoglio, C.1    Boicelli, C.A.2    Ottone, M.3    Addario, C.4    Chiari, P.5    Viale, M.6
  • 39
    • 0036866125 scopus 로고    scopus 로고
    • Nephrotoxicity of combined treatment with cisplatin and gentamicin in the guinea pig: Glomerular injury findings
    • Kohn S, Fradis M, Ben-David J, Zidan J, Robinson E: Nephrotoxicity of combined treatment with cisplatin and gentamicin in the guinea pig: glomerular injury findings. Ultrastruct Pathol 2002; 26: 371-382.
    • (2002) Ultrastruct Pathol , vol.26 , pp. 371-382
    • Kohn, S.1    Fradis, M.2    Ben-David, J.3    Zidan, J.4    Robinson, E.5
  • 40
    • 46449102593 scopus 로고    scopus 로고
    • Comparative analysis of cell injury after exposure to antitumor platinum derivatives in kidney tubular epithelial cells
    • Kitada N, Takara K, Itoh C, Minegaki T, Tsujimoto M, Sakaeda T, Yokoyama T: Comparative analysis of cell injury after exposure to antitumor platinum derivatives in kidney tubular epithelial cells. Chemotherapy 2008; 54: 217-223.
    • (2008) Chemotherapy , vol.54 , pp. 217-223
    • Kitada, N.1    Takara, K.2    Itoh, C.3    Minegaki, T.4    Tsujimoto, M.5    Sakaeda, T.6    Yokoyama, T.7
  • 41
    • 3042545587 scopus 로고    scopus 로고
    • The effects of erdosteine on the activities of some metabolic enzymes during cisplatin-induced nephrotoxicity in rats
    • Yilmaz HR, Iraz M, Sogut S, et al: The effects of erdosteine on the activities of some metabolic enzymes during cisplatin-induced nephrotoxicity in rats. Pharmacol Res 2004; 50: 287-290.
    • (2004) Pharmacol Res , vol.50 , pp. 287-290
    • Yilmaz, H.R.1    Iraz, M.2    Sogut, S.3
  • 42
    • 0027932645 scopus 로고
    • Lipid hydroperoxide-induced peroxidation and turnover of endothelial cell phospholipids
    • DOI 10.1016/0891-5849(94)90016-7
    • Pacifici EH, McLeod LL, Sevanian A: Lipid hydroperoxide-induced peroxidation and turnover of endothelial cell phospholipids. Free Radic Biol Med 1994; 17: 297-309. (Pubitemid 24296150)
    • (1994) Free Radical Biology and Medicine , vol.17 , Issue.4 , pp. 297-309
    • Pacifici, E.H.K.1    McLeod, L.L.2    Sevanian, A.3
  • 43
    • 0031572838 scopus 로고    scopus 로고
    • Activation of liver mitochondrial phospholipase A2 by superoxide
    • Madesh M, Balasubramanian KA: Activation of liver mitochondrial phospholipase A2 by superoxide. Arch Biochem Biophys 1997; 15: 187-192.
    • (1997) Arch Biochem Biophys , vol.15 , pp. 187-192
    • Madesh, M.1    Balasubramanian, K.A.2
  • 44
    • 0035242430 scopus 로고    scopus 로고
    • Free fatty acid effects on mitochondrial permeability: An overview
    • Sultan A, Sokolove PM: Free fatty acid effects on mitochondrial permeability: an overview. Arch Biochem Biophys 2001; 386: 52-61.
    • (2001) Arch Biochem Biophys , vol.386 , pp. 52-61
    • Sultan, A.1    Sokolove, P.M.2
  • 45
    • 0035501243 scopus 로고    scopus 로고
    • Roles of long chain fatty acids and carnitine in mitochondrial membrane permeability transition
    • Furuno T, Kanno T, Arita K, et al: Roles of long chain fatty acids and carnitine in mitochondrial membrane permeability transition. Biochem Pharmacol 2001; 62: 1037-1046.
    • (2001) Biochem Pharmacol , vol.62 , pp. 1037-1046
    • Furuno, T.1    Kanno, T.2    Arita, K.3
  • 46
    • 0032575752 scopus 로고    scopus 로고
    • Mitochondria and apoptosis
    • Green DR, Reed JC: Mitochondria and apoptosis. Science 1998; 281: 1309-1312.
    • (1998) Science , vol.281 , pp. 1309-1312
    • Green, D.R.1    Reed, J.C.2
  • 48
    • 0031590634 scopus 로고    scopus 로고
    • Fatty acid-promoted mitochondrial permeability transition by membrane depolarization and binding to the ADP/ATP carrier
    • Schönfeld P, Bohnensack R: Fatty acid-promoted mitochondrial permeability transition by membrane depolarization and binding to the ADP/ATP carrier. FEBS Lett 1997; 420: 167-170.
    • (1997) FEBS Lett , vol.420 , pp. 167-170
    • Schönfeld, P.1    Bohnensack, R.2
  • 49
    • 0027156357 scopus 로고
    • Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition
    • Pastorino JG, Snyder JW, Serroni A, Hoek JB, Farber JL: Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition. J Biol Chem 1993; 268: 13791-13798.
    • (1993) J Biol Chem , vol.268 , pp. 13791-13798
    • Pastorino, J.G.1    Snyder, J.W.2    Serroni, A.3    Hoek, J.B.4    Farber, J.L.5
  • 50
    • 31544452785 scopus 로고    scopus 로고
    • Relationship of intracellular calcium and oxygen radicals to cisplatin-related renal cell injury
    • Kawai Y, Nakao T, Kunimura N, Kohda Y, Gemba M: Relationship of intracellular calcium and oxygen radicals to cisplatin-related renal cell injury. J Pharmacol Sci 2006; 100: 65-72.
    • (2006) J Pharmacol Sci , vol.100 , pp. 65-72
    • Kawai, Y.1    Nakao, T.2    Kunimura, N.3    Kohda, Y.4    Gemba, M.5
  • 51
    • 33746223208 scopus 로고    scopus 로고
    • Acetyl- L -carnitine up-regulates expression of voltage-dependent anion channel in the rat brain
    • Traina G, Bernardi R, Rizzo M, Calvani M, Durante M, Brunelli M: Acetyl- L -carnitine up-regulates expression of voltage-dependent anion channel in the rat brain. Neurochem Int 2006; 48: 67367-67368.
    • (2006) Neurochem Int , vol.48 , pp. 67367-67368
    • Traina, G.1    Bernardi, R.2    Rizzo, M.3    Calvani, M.4    Durante, M.5    Brunelli, M.6


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