Keywords
Lymphedema
Dietary supplement
Hydroxytyrosol
Nutrition
GARLIVE®
Dietary supplement
Hydroxytyrosol
Nutrition
GARLIVE®
Abstract
Lymphedema is a chronic inflammatory disorder resulting from ineffective fluid uptake by the lymphatic system, and the effects are principally felt in the lower limbs. The condition is said to be primary when caused by genetic mutations and secondary when caused by injuries, infections, or surgery. Lymphedema, a worldwide pathology, does not have an effective therapy so far. Leukotriene B4 has recently been identified as a key molecule in lymphedema pathogenesis. Surgical, nonsurgical, and pharmacological treatments have been proposed; however, they do not cure the disease and only ameliorate the symptoms. Nutrition and nutritional status are extremely important in lymphedema physiopathology. Obesity is a comorbidity that exacerbates the risk for secondary lymphedema and constitutes a negative prognostic factor. Indeed, anti-inflammatory foods and their effects on the inflammatory state and on oxidative stress are now being investigated for their possible therapeutic role in lymphedema. Although no special diet has so far been proven to be very effective, specific dietary tips could help in alleviating the edematous state of patients with lymphedema. A few supplements have been tested for lymphedema treatment. Among them, GARLIVE® containing hydroxytyrosol, hesperidin, spermidine and vitamin A, exhibited promising effects in the animal model. Hydroxytyrosol, a polyphenol from olives, showed anti-inflammatory effects and reduced leukotriene B4 synthesis, thus holding promise as a potential natural candidate for lymphedema treatment.
References
[1] Adamczyk LA, Gordon K, Kholová I, Meijer-Jorna LB, Telinius N, Gallagher PJ, van der Wal AC, Baandrup U. Lymph vessels: the forgotten second circulation in health and disease. Virchows Arch 2016;469:3-17. https://doi.org/10.1007/s00428-016-1945-6
[2] Ozdowski L, Gupta V. Physiology, Lymphatic System. In: StatPearls. Treasure Island (FL): StatPearls Publishing 2022
[3] Petrova TV, Koh GY. Biological Functions of lymphatic vessels. Science 2020;369. https://doi.org/10.1126/science.aax4063
[4] Alitalo K. The lymphatic vasculature in disease. Nat Med 2011;17:1371-80. https://doi.org/10.1038/nm.2545
[5] Maltese PE, Michelini S, Ricci M, Maitz S, Fiorentino A, Serrani R, Lazzerotti A, Bruson A, Paolacci S, Benedetti S, Bertelli M. Increasing evidence of hereditary lymphedema caused by CELSR1 loss-of-function variants. Am J Med Genet A 2019;179:171824. https://doi.org/10.1002/ajmg.a.61269
[6] Wilting J, Papoutsi M, Becker J. The lymphatic vascular system: secondary or primary? Lymphology 2004;37:98-106.
[7] Bhusan Tripathi Y, Pandey N, Mishra P, Tripathi P, Coatto M, Anpilogov K, Dhuli K, Donato K, Michelini S, Cecchin S, Beccari T, Ceccarini MR, Paolacci S, Bertelli M. Effect of a dietary supplement on the reduction of lymphedema-progression in mouse tail-cut model. Eur Rev Med Pharmacol Sci 2021;25:56-66. https://doi.org/10.26355/eurrev_202112_27334
[8] Bertelli M, Kiani AK, Paolacci S, Manara E, Kurti D, Dhuli K, Bushati V, Miertus J, Pangallo D, Baglivo M, Beccari T, Michelini S. Hydroxytyrosol: a natural compound with promising pharmacological activities. J Biotechnol 2020;309:29-33. https://doi.org/10.1016/j.jbiotec.2019.12.016
[9] Michelini S, Paolacci S, Manara E, Eretta C, Mattassi R, Lee B-B, Bertelli M. Genetic tests in lymphatic vascular malformations and lymphedema. J Med Genet 2018;55:222-32. https://doi.org/10.1136/jmedgenet-2017-105064
[10] McNeely ML, Peddle CJ, Yurick JL, Dayes IS, Mackey JR. Conservative and dietary interventions for cancer-related lymphedema. Cancer 2011;117:1136-48. https://doi.org/10.1002/cncr.25513
[11] Brouillard P, Witte MH, Erickson RP, Damstra RJ, Becker C, Quéré I, Vikkula M. Primary lymphoedema. Nat Rev Dis Primers 2021;7:77. https://doi.org/10.1038/s41572-021-00309-7
[12] Fossum TW, Miller MW. Lymphedema: etiopathogenesis. J Vet Intern Med 1992;6:283-93. https://doi.org/10.1111/j.1939-1676.1992.tb00353.x
[13] Johnson SM. Lymphedema-distichiasis syndrome: report of a case and review. Arch Dermatol 1999;135:347-8. https://doi.org/10.1001/archderm.135.3.347
[14] Okeke A. Lymphoedema in urological cancer. Eur Urol 2004;45:18-25. https://doi.org/10.1016/j.eururo.2003.08.010
[15] Missaglia S, Tavian D, Michelini S, Maltese PE, Bonanomi A, Bertelli M. Imbalance between expression of FOXC2 and its LncRNA in lymphedema-distichiasis caused by frameshift mutations. Genes 2021;12:650. https://doi.org/10.3390/genes12050650
[16] Tavian D, Missaglia S, Michelini S, Maltese PE, Manara E, Mordente A, Bertelli M. FOXC2 disease mutations identified in lymphedema distichiasis patients impair transcriptional activity and cell proliferation. International. Int J Mol Sci 2020;21:5112. https://doi.org/10.3390/ijms21145112
[17] Bruns F, Micke O, Bremer M. Current Status of Selenium and Other Treatments for Secondary Lymphedema. J Support Oncol 2003;1:121.30.
[18] Grada AA, Phillips TJ. Lymphedema. J Am Acad Dermatol 2017;77:1009-20. https://doi.org/10.1016/j.jaad.2017.03.022
[19] Brouillard P, Boon L, Vikkula M. Genetics of lymphatic anomalies. J Clin Invest 2014;124:898-904. https://doi.org/10.1172/JCI71614
[20] Kiani AK, Paolacci S, Scanzano P, Michelini S, Capodicasa N, D'Agruma L, Notarangelo A, Tonini G, Piccinelli D, Farshid KR, Petralia P, Fulcheri E, Buffelli F, Chiurazzi P, Terranova C, Plotti F, Angioli R, Castori M, Pös O, Szemes T, Bertelli M. Prenatal genetic diagnosis: fetal therapy as a possible solution to a positive test. Acta Biomed 2020;91:e2020021. https://doi.org/10.23750/abm.v91i13-S.10534
[21] Butler DF. Acquired lymphedema of the hand due to Herpes Simplex virus type 2. Arch Dermatol 1999;135:1125-6. https://doi.org/10.1001/archderm.135.9.1125
[22] Avraham T, Yan A, Zampell JC, Daluvoy SV, Haimovitz-Friedman A, Cordeiro AP, Mehrara BJ. Radiation therapy causes loss of dermal lymphatic vessels and interferes with lymphatic function by TGF-Β1-Mediated tissue fibrosis. Am J Physiol Cell Physiol 2010;299:C589–C605. https://doi.org/10.1152/ajpcell.00535.2009
[23] Asch S, James WD, Castelo-Soccio L. Massive localized lymphedema: an emerging dermatologic complication of obesity. J Am Acad Dermatol 2008;59:S109–S110. https://doi.org/10.1016/j.jaad.2008.04.009
[24] Hespe GE, Nores GG, Huang J-J, Mehrara BJ. Pathophysiology of lymphedema-is there a chance for medication treatment? J Surg Oncol 2017;115:96-8. https://doi.org/10.1002/jso.24414
[25] Bertelli M, Kiani AK, Paolacci S, Manara E, Dautaj A, Beccari T, Michelini S. Molecular pathways involved in lymphedema: hydroxytyrosol as a candidate natural compound for treating the effects of lymph accumulation. J Biotechnol 2020;308:82-6. https://doi.org/10.1016/j.jbiotec.2019.11.017
[26] Ghanta S, Cuzzone DA, Torrisi JS, Albano NJ, Joseph WJ, Savetsky IL, Gardenier JC, Chang D, Zampell JC, Mehrara BJ. Regulation of inflammation and fibrosis by macrophages in lymphedema. Am J Physiol Heart Circ Physiol 2015;308:H1065–H1077. https://doi.org/10.1152/ajpheart.00598.2014
[27] Jiang X, Nicolls MR, Tian W, Rockson SG. Lymphatic dysfunction, leukotrienes, and lymphedema. Annu Rev Physiol 2018;80:49-70. https://doi.org/10.1146/annurev-physiol-022516-034008
[28] Goodarzi K, Goodarzi M, Tager AM, Luster AD, von Andrian UH. Leukotriene B4 and BLT1 control cytotoxic effector T Cell recruitment to inflamed tissues. Nat Immunol 2003;4:965-73. https://doi.org/10.1038/ni972
[29] Lee W, Su Kim H, Lee GR. Leukotrienes induce the migration of Th17 Cells. Immunol Cell Biol 2015;93:472-9. https://doi.org/10.1038/icb.2014.104
[30] Michelini S, Cestari M, Michelini S, Camilleri G, de Antoni L, Sonna WN, Bertelli M. Study of a supplement and a genetic test for lymphedema management. Acta Biomed 2020;91:e2020013. https://doi.org/10.23750/abm.v91i13-S.10658
[31] Executive Committee of the International Society of Lymphology The Diagnosis and Treatment of Peripheral Lymphedema: 2020 Consensus Document of the International Society of Lymphology. Lymphology 2020;53:3-19.
[32] Cavezzi A, Urso SU, Ambrosini L, Croci S, Campana F, Mosti G. Lymphedema and nutrition: a review. Veins and Lymphatics 2019;8. https://doi.org/10.4081/vl.2019.8220
[33] Keeley V. Pharmacological treatment for chronic oedema. Br J Community Nurs 2008;13:S4–S10. https://doi.org/10.12968/bjcn.2008.13.Sup2.29394
[34] Ramelet AA. Pharmacologic aspects of a phlebotropic drug in CVI-Associated edema. Angiology 2000;51:19-23. https://doi.org/10.1177/000331970005100105
[35] Navaei M, Haghighat S, Janani L, Vafa S, Saneei Totmaj A, Raji Lahiji M, Emamat H, Salehi Z, Amirinejad A, Izad M, Zarrati M. The effects of synbiotic supplementation on antioxidant capacity and arm volumes in survivors of breast cancer-related lymphedema. Nutr Cancer 2020;72:62-73. https://doi.org/10.108 0/01635581.2019.1616781
[36] Vafa S, Zarrati M, Malakootinejad M, Totmaj AS, Zayeri F, Salehi M, Sanati V, Haghighat S. Calorie restriction and synbiotics effect on quality of life and edema reduction in breast cancer-related lymphedema, a clinical trial. Breast 2020;54:37-45. https://doi.org/10.1016/j.breast.2020.08.008
[37] Pfister C, Dawzcynski H, Schingale F-J. Sodium selenite and cancer related lymphedema: biological and pharmacological effects. J Trace Elem Med Biol 2016;37:111-6. https://doi.org/10.1016/j.jtemb.2016.05.005
[38] Burattini S, Salucci S, Baldassarri V, Accorsi A, Piatti E, Madrona A, Espartero JL, Candiracci M, Zappia G, Falcieri E. Anti-apoptotic activity of hydroxytyrosol and hydroxytyrosyl laurate. Food Chem Toxicol 2013;55:248-56. https://doi.org/10.1016/j.fct.2012.12.049
[39] Nakamura K, Radhakrishnan K, Wong YM, Rockson SG. Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice. PLoS ONE 2009;4:e8380. https://doi.org/10.1371/journal.pone.0008380
[40] Tian W, Rockson SG, Jiang X, Kim J, Begaye A, Shuffle EM, Tu AB, Cribb M, Nepiyushchikh Z, Feroze AH, Zamanian RT, Dhillon GS, Voelkel NF, Peters-Golden M, Kitajewski J, Dixon JB, Nicolls MR. Leukotriene B 4 antagonism ameliorates experimental lymphedema. Sci Transl Med 2017;9. https://doi.org/10.1126/scitranslmed.aal3920
[41] Dhuli K, Ceccarini MR, Precone V, Maltese PE, Bonetti G, Paolacci S, Dautaj A, Guerri G, Marceddu G, Beccari T, Michelini S, Bertelli M. Improvement of quality of life by intake of hydroxytyrosol in patients with lymphedema and association of lymphedema genes with obesity. Eur Rev Med Pharmacol Sci 2021;25:33-42. https://doi.org/10.26355/eurrev_202112_27331
[42] Jeong JW, Cha HJ, Han MH, Hwang SJ, Lee DS, Yoo JS, Choi IW, Kim S, Kim HS, Kim GY, Hong SH, Park C, Lee HJ, Choi YH. Spermidine protects against oxidative stress in inflammation models using macrophages and zebrafish. Biomol Ther (Seoul) 2018;26:146-56. https://doi.org/10.4062/biomolther.2016.272
[43] Pecking AP, Fevrier B, Wargon C, Pillion G. Efficacy of Daflon 500 Mg in the treatment of lymphedema (secondary to conventional therapy of breast cancer). Angiology 1997;48:93-8. https://doi.org/10.1177/000331979704800115
[44] Michelini S, Ricci M, Serrani R, Stuppia L, Beccari T, Veselenyiova D, Kenanoglu S, Barati S, Kurti D, Baglivo M, Basha SH, Krajcovic J, Dundar M, Bertelli M. Possible role of the rorc gene in primary and secondary lymphedema: review of the literature and genetic study of two rare causative variants. Lymphat Res Biol 2021;19:129-33.
[45] Shaw C, Mortimer P, Judd PA. A randomized controlled trial of weight reduction as a treatment for breast cancer-related lymphedema. Cancer 2007;110:1868-74. https://doi.org/10.1002/cncr.22994
[46] Oliveira J, César T. Influência da fisioterapia complexa descongestiva associada à ingestão de triglicerídeos de cadeia média no tratamento do linfedema de membro superior. Braz. J Phys Ther 2008;12. https://doi.org/10.1590/S1413-35552008000100007
[47] Meijer K, de Vos P, Priebe MG. Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health? Curr Opin Clin Nutr Metab Care 2010;13:715-21. https://doi.org/10.1097/MCO.0b013e32833eebe5
[48] Poudyal H, Panchal SK, Diwan V, Brown L. Omega-3 fatty acids and metabolic syndrome: effects and emerging mechanisms of action. Prog Lipid Res 2011;50:372-87. https://doi.org/10.1016/j.plipres.2011.06.003
[49] Mizuno R, Isshiki M, Ono N, Nishimoto M, Fujita T. A high-salt diet differentially modulates mechanical activity of afferent and efferent collecting lymphatics in murine iliac lymph nodes. Lymphat Res Biol 2015;13:85-92. https://doi.org/10.1089/lrb.2014.0043
[50] Lemanne D, Maizes V. Advising women undergoing treatment for breast cancer: a narrative review. J Altern Complement Med 2018;24:902-9. https://doi.org/10.1089/acm.2018.0150
[51] Greene AK, Grant FD, Slavin SA. Lower-extremity lymphedema and elevated body-mass index. N Engl J Med 2012;366:2136-7. https://doi.org/10.1056/NEJMc1201684
[52] Bertelli G, Venturini M, Forno G, Macchiavello F, Dini D. An analysis of prognostic factors in response to conservative treatment of postmastectomy lymphedema. Surg Gynecol Obstet 1992;175:455-60.
[53] Vettori A, Paolacci S, Maltese PE, Herbst KL, Cestari M, Michelini S, Michelini S, Samaja M, Bertelli M. Genetic determinants of the effects of training on muscle and adipose tissue homeostasis in obesity associated with lymphedema.. Lymphat Res Biol 2021;19:322-33. https://doi.org/10.1089/lrb.2020.0057
[54] Camilleri G, Kiani AK, Herbst KL, Kaftalli J, Bernini A, Dhuli K, Manara E, Bonetti G, Stuppia L, Paolacci S, Dautaj A, Bertelli M. Genetics of fat deposition. Eur Rev Med Pharmacol Sci 2021;25:14-22. https://doi.org/10.26355/eurrev_202112_27329
[2] Ozdowski L, Gupta V. Physiology, Lymphatic System. In: StatPearls. Treasure Island (FL): StatPearls Publishing 2022
[3] Petrova TV, Koh GY. Biological Functions of lymphatic vessels. Science 2020;369. https://doi.org/10.1126/science.aax4063
[4] Alitalo K. The lymphatic vasculature in disease. Nat Med 2011;17:1371-80. https://doi.org/10.1038/nm.2545
[5] Maltese PE, Michelini S, Ricci M, Maitz S, Fiorentino A, Serrani R, Lazzerotti A, Bruson A, Paolacci S, Benedetti S, Bertelli M. Increasing evidence of hereditary lymphedema caused by CELSR1 loss-of-function variants. Am J Med Genet A 2019;179:171824. https://doi.org/10.1002/ajmg.a.61269
[6] Wilting J, Papoutsi M, Becker J. The lymphatic vascular system: secondary or primary? Lymphology 2004;37:98-106.
[7] Bhusan Tripathi Y, Pandey N, Mishra P, Tripathi P, Coatto M, Anpilogov K, Dhuli K, Donato K, Michelini S, Cecchin S, Beccari T, Ceccarini MR, Paolacci S, Bertelli M. Effect of a dietary supplement on the reduction of lymphedema-progression in mouse tail-cut model. Eur Rev Med Pharmacol Sci 2021;25:56-66. https://doi.org/10.26355/eurrev_202112_27334
[8] Bertelli M, Kiani AK, Paolacci S, Manara E, Kurti D, Dhuli K, Bushati V, Miertus J, Pangallo D, Baglivo M, Beccari T, Michelini S. Hydroxytyrosol: a natural compound with promising pharmacological activities. J Biotechnol 2020;309:29-33. https://doi.org/10.1016/j.jbiotec.2019.12.016
[9] Michelini S, Paolacci S, Manara E, Eretta C, Mattassi R, Lee B-B, Bertelli M. Genetic tests in lymphatic vascular malformations and lymphedema. J Med Genet 2018;55:222-32. https://doi.org/10.1136/jmedgenet-2017-105064
[10] McNeely ML, Peddle CJ, Yurick JL, Dayes IS, Mackey JR. Conservative and dietary interventions for cancer-related lymphedema. Cancer 2011;117:1136-48. https://doi.org/10.1002/cncr.25513
[11] Brouillard P, Witte MH, Erickson RP, Damstra RJ, Becker C, Quéré I, Vikkula M. Primary lymphoedema. Nat Rev Dis Primers 2021;7:77. https://doi.org/10.1038/s41572-021-00309-7
[12] Fossum TW, Miller MW. Lymphedema: etiopathogenesis. J Vet Intern Med 1992;6:283-93. https://doi.org/10.1111/j.1939-1676.1992.tb00353.x
[13] Johnson SM. Lymphedema-distichiasis syndrome: report of a case and review. Arch Dermatol 1999;135:347-8. https://doi.org/10.1001/archderm.135.3.347
[14] Okeke A. Lymphoedema in urological cancer. Eur Urol 2004;45:18-25. https://doi.org/10.1016/j.eururo.2003.08.010
[15] Missaglia S, Tavian D, Michelini S, Maltese PE, Bonanomi A, Bertelli M. Imbalance between expression of FOXC2 and its LncRNA in lymphedema-distichiasis caused by frameshift mutations. Genes 2021;12:650. https://doi.org/10.3390/genes12050650
[16] Tavian D, Missaglia S, Michelini S, Maltese PE, Manara E, Mordente A, Bertelli M. FOXC2 disease mutations identified in lymphedema distichiasis patients impair transcriptional activity and cell proliferation. International. Int J Mol Sci 2020;21:5112. https://doi.org/10.3390/ijms21145112
[17] Bruns F, Micke O, Bremer M. Current Status of Selenium and Other Treatments for Secondary Lymphedema. J Support Oncol 2003;1:121.30.
[18] Grada AA, Phillips TJ. Lymphedema. J Am Acad Dermatol 2017;77:1009-20. https://doi.org/10.1016/j.jaad.2017.03.022
[19] Brouillard P, Boon L, Vikkula M. Genetics of lymphatic anomalies. J Clin Invest 2014;124:898-904. https://doi.org/10.1172/JCI71614
[20] Kiani AK, Paolacci S, Scanzano P, Michelini S, Capodicasa N, D'Agruma L, Notarangelo A, Tonini G, Piccinelli D, Farshid KR, Petralia P, Fulcheri E, Buffelli F, Chiurazzi P, Terranova C, Plotti F, Angioli R, Castori M, Pös O, Szemes T, Bertelli M. Prenatal genetic diagnosis: fetal therapy as a possible solution to a positive test. Acta Biomed 2020;91:e2020021. https://doi.org/10.23750/abm.v91i13-S.10534
[21] Butler DF. Acquired lymphedema of the hand due to Herpes Simplex virus type 2. Arch Dermatol 1999;135:1125-6. https://doi.org/10.1001/archderm.135.9.1125
[22] Avraham T, Yan A, Zampell JC, Daluvoy SV, Haimovitz-Friedman A, Cordeiro AP, Mehrara BJ. Radiation therapy causes loss of dermal lymphatic vessels and interferes with lymphatic function by TGF-Β1-Mediated tissue fibrosis. Am J Physiol Cell Physiol 2010;299:C589–C605. https://doi.org/10.1152/ajpcell.00535.2009
[23] Asch S, James WD, Castelo-Soccio L. Massive localized lymphedema: an emerging dermatologic complication of obesity. J Am Acad Dermatol 2008;59:S109–S110. https://doi.org/10.1016/j.jaad.2008.04.009
[24] Hespe GE, Nores GG, Huang J-J, Mehrara BJ. Pathophysiology of lymphedema-is there a chance for medication treatment? J Surg Oncol 2017;115:96-8. https://doi.org/10.1002/jso.24414
[25] Bertelli M, Kiani AK, Paolacci S, Manara E, Dautaj A, Beccari T, Michelini S. Molecular pathways involved in lymphedema: hydroxytyrosol as a candidate natural compound for treating the effects of lymph accumulation. J Biotechnol 2020;308:82-6. https://doi.org/10.1016/j.jbiotec.2019.11.017
[26] Ghanta S, Cuzzone DA, Torrisi JS, Albano NJ, Joseph WJ, Savetsky IL, Gardenier JC, Chang D, Zampell JC, Mehrara BJ. Regulation of inflammation and fibrosis by macrophages in lymphedema. Am J Physiol Heart Circ Physiol 2015;308:H1065–H1077. https://doi.org/10.1152/ajpheart.00598.2014
[27] Jiang X, Nicolls MR, Tian W, Rockson SG. Lymphatic dysfunction, leukotrienes, and lymphedema. Annu Rev Physiol 2018;80:49-70. https://doi.org/10.1146/annurev-physiol-022516-034008
[28] Goodarzi K, Goodarzi M, Tager AM, Luster AD, von Andrian UH. Leukotriene B4 and BLT1 control cytotoxic effector T Cell recruitment to inflamed tissues. Nat Immunol 2003;4:965-73. https://doi.org/10.1038/ni972
[29] Lee W, Su Kim H, Lee GR. Leukotrienes induce the migration of Th17 Cells. Immunol Cell Biol 2015;93:472-9. https://doi.org/10.1038/icb.2014.104
[30] Michelini S, Cestari M, Michelini S, Camilleri G, de Antoni L, Sonna WN, Bertelli M. Study of a supplement and a genetic test for lymphedema management. Acta Biomed 2020;91:e2020013. https://doi.org/10.23750/abm.v91i13-S.10658
[31] Executive Committee of the International Society of Lymphology The Diagnosis and Treatment of Peripheral Lymphedema: 2020 Consensus Document of the International Society of Lymphology. Lymphology 2020;53:3-19.
[32] Cavezzi A, Urso SU, Ambrosini L, Croci S, Campana F, Mosti G. Lymphedema and nutrition: a review. Veins and Lymphatics 2019;8. https://doi.org/10.4081/vl.2019.8220
[33] Keeley V. Pharmacological treatment for chronic oedema. Br J Community Nurs 2008;13:S4–S10. https://doi.org/10.12968/bjcn.2008.13.Sup2.29394
[34] Ramelet AA. Pharmacologic aspects of a phlebotropic drug in CVI-Associated edema. Angiology 2000;51:19-23. https://doi.org/10.1177/000331970005100105
[35] Navaei M, Haghighat S, Janani L, Vafa S, Saneei Totmaj A, Raji Lahiji M, Emamat H, Salehi Z, Amirinejad A, Izad M, Zarrati M. The effects of synbiotic supplementation on antioxidant capacity and arm volumes in survivors of breast cancer-related lymphedema. Nutr Cancer 2020;72:62-73. https://doi.org/10.108 0/01635581.2019.1616781
[36] Vafa S, Zarrati M, Malakootinejad M, Totmaj AS, Zayeri F, Salehi M, Sanati V, Haghighat S. Calorie restriction and synbiotics effect on quality of life and edema reduction in breast cancer-related lymphedema, a clinical trial. Breast 2020;54:37-45. https://doi.org/10.1016/j.breast.2020.08.008
[37] Pfister C, Dawzcynski H, Schingale F-J. Sodium selenite and cancer related lymphedema: biological and pharmacological effects. J Trace Elem Med Biol 2016;37:111-6. https://doi.org/10.1016/j.jtemb.2016.05.005
[38] Burattini S, Salucci S, Baldassarri V, Accorsi A, Piatti E, Madrona A, Espartero JL, Candiracci M, Zappia G, Falcieri E. Anti-apoptotic activity of hydroxytyrosol and hydroxytyrosyl laurate. Food Chem Toxicol 2013;55:248-56. https://doi.org/10.1016/j.fct.2012.12.049
[39] Nakamura K, Radhakrishnan K, Wong YM, Rockson SG. Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice. PLoS ONE 2009;4:e8380. https://doi.org/10.1371/journal.pone.0008380
[40] Tian W, Rockson SG, Jiang X, Kim J, Begaye A, Shuffle EM, Tu AB, Cribb M, Nepiyushchikh Z, Feroze AH, Zamanian RT, Dhillon GS, Voelkel NF, Peters-Golden M, Kitajewski J, Dixon JB, Nicolls MR. Leukotriene B 4 antagonism ameliorates experimental lymphedema. Sci Transl Med 2017;9. https://doi.org/10.1126/scitranslmed.aal3920
[41] Dhuli K, Ceccarini MR, Precone V, Maltese PE, Bonetti G, Paolacci S, Dautaj A, Guerri G, Marceddu G, Beccari T, Michelini S, Bertelli M. Improvement of quality of life by intake of hydroxytyrosol in patients with lymphedema and association of lymphedema genes with obesity. Eur Rev Med Pharmacol Sci 2021;25:33-42. https://doi.org/10.26355/eurrev_202112_27331
[42] Jeong JW, Cha HJ, Han MH, Hwang SJ, Lee DS, Yoo JS, Choi IW, Kim S, Kim HS, Kim GY, Hong SH, Park C, Lee HJ, Choi YH. Spermidine protects against oxidative stress in inflammation models using macrophages and zebrafish. Biomol Ther (Seoul) 2018;26:146-56. https://doi.org/10.4062/biomolther.2016.272
[43] Pecking AP, Fevrier B, Wargon C, Pillion G. Efficacy of Daflon 500 Mg in the treatment of lymphedema (secondary to conventional therapy of breast cancer). Angiology 1997;48:93-8. https://doi.org/10.1177/000331979704800115
[44] Michelini S, Ricci M, Serrani R, Stuppia L, Beccari T, Veselenyiova D, Kenanoglu S, Barati S, Kurti D, Baglivo M, Basha SH, Krajcovic J, Dundar M, Bertelli M. Possible role of the rorc gene in primary and secondary lymphedema: review of the literature and genetic study of two rare causative variants. Lymphat Res Biol 2021;19:129-33.
[45] Shaw C, Mortimer P, Judd PA. A randomized controlled trial of weight reduction as a treatment for breast cancer-related lymphedema. Cancer 2007;110:1868-74. https://doi.org/10.1002/cncr.22994
[46] Oliveira J, César T. Influência da fisioterapia complexa descongestiva associada à ingestão de triglicerídeos de cadeia média no tratamento do linfedema de membro superior. Braz. J Phys Ther 2008;12. https://doi.org/10.1590/S1413-35552008000100007
[47] Meijer K, de Vos P, Priebe MG. Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health? Curr Opin Clin Nutr Metab Care 2010;13:715-21. https://doi.org/10.1097/MCO.0b013e32833eebe5
[48] Poudyal H, Panchal SK, Diwan V, Brown L. Omega-3 fatty acids and metabolic syndrome: effects and emerging mechanisms of action. Prog Lipid Res 2011;50:372-87. https://doi.org/10.1016/j.plipres.2011.06.003
[49] Mizuno R, Isshiki M, Ono N, Nishimoto M, Fujita T. A high-salt diet differentially modulates mechanical activity of afferent and efferent collecting lymphatics in murine iliac lymph nodes. Lymphat Res Biol 2015;13:85-92. https://doi.org/10.1089/lrb.2014.0043
[50] Lemanne D, Maizes V. Advising women undergoing treatment for breast cancer: a narrative review. J Altern Complement Med 2018;24:902-9. https://doi.org/10.1089/acm.2018.0150
[51] Greene AK, Grant FD, Slavin SA. Lower-extremity lymphedema and elevated body-mass index. N Engl J Med 2012;366:2136-7. https://doi.org/10.1056/NEJMc1201684
[52] Bertelli G, Venturini M, Forno G, Macchiavello F, Dini D. An analysis of prognostic factors in response to conservative treatment of postmastectomy lymphedema. Surg Gynecol Obstet 1992;175:455-60.
[53] Vettori A, Paolacci S, Maltese PE, Herbst KL, Cestari M, Michelini S, Michelini S, Samaja M, Bertelli M. Genetic determinants of the effects of training on muscle and adipose tissue homeostasis in obesity associated with lymphedema.. Lymphat Res Biol 2021;19:322-33. https://doi.org/10.1089/lrb.2020.0057
[54] Camilleri G, Kiani AK, Herbst KL, Kaftalli J, Bernini A, Dhuli K, Manara E, Bonetti G, Stuppia L, Paolacci S, Dautaj A, Bertelli M. Genetics of fat deposition. Eur Rev Med Pharmacol Sci 2021;25:14-22. https://doi.org/10.26355/eurrev_202112_27329