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Co-administration of Aluminum Sulfate and Propolis Regulates Matrix Metalloproteinases-2/9 Expression and Improves the Uterine Leiomyoma in Adult Rat Model

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Abstract

The aim of this study was to evaluate the effects of aluminum sulfate (alum) with propolis (PR) on uterine leiomyoma (UL) in rat model. One hundred and four female Wistar rats (180–200 g) were allocated into two main groups of control (Co, n = 8) and experiment (UL model [estradiol benzoate 200 μg/kg/IM twice/week/8 weeks] with/without treatment) defined in 13 subgroups with/without treatment with coil oil (UL + COi), PR (100 or 200 mg/kg) as UL + PR100 or 200, alum (35, 75 or 150 mg/Kg) as UL + AL 35, 75, or 150, and PR (100 mg/kg or 200) with alum (35, 75, or 150 mg/Kg) as UL + PR100 or 200 + AL35, 75, or 150. Subgroups received doses of therapeutics for 14 days (IP). In the end, rats were sacrificed, and the uteri were isolated for molecular and histopathological investigations. The myometrium thickness, collagen contents, and gene expression of MMP-2 and 9 increased significantly in experimental groups with/without treatment (P ˂ 0.05). PR administration (100 and 200 mg/kg) alone or with alum (35 and 75 mg/kg) significantly decreased myometrium collagen contents and the gene expression and protein concentration of MMP-2 and 9 compared with UL and UL + Coi subgroups (P ˂ 0.05). Alum (75 mg/kg) with PR (200 mg/kg) could improve UL features and reduce MMP-2 and 9 gene expression.

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References

  1. Wu X, Serna VA, Thomas J, Qiang W, Blumenfeld ML, Kurita T (2017) Subtype-specific tumor-associated fibroblasts contribute to the pathogenesis of uterine leiomyoma. Cancer Res 77(24):6891–6901. https://doi.org/10.1158/0008-5472.Can-17-1744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Laughlin SK, Schroeder JC, Baird DD (2010) New directions in the epidemiology of uterine fibroids. Semin Reprod Med 28(3):204–217. https://doi.org/10.1055/s-0030-1251477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wallach EE, Vlahos NF (2004) Uterine myomas: an overview of development, clinical features, and management. Obstet Gynecol 104(2):393–406. https://doi.org/10.1097/01.Aog.0000136079.62513.39

    Article  PubMed  Google Scholar 

  4. Parker WH (2007) Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril 87(4):725–736. https://doi.org/10.1016/j.fertnstert.2007.01.093

    Article  PubMed  Google Scholar 

  5. Khan AT, Shehmar M, Gupta JK (2014) Uterine fibroids: current perspectives. Int J Women's Health 6:95–114. https://doi.org/10.2147/IJWH.S51083

    Article  Google Scholar 

  6. Donnez J, Dolmans MM (2016) Uterine fibroid management: from the present to the future. Hum Reprod Update 22(6):665–686. https://doi.org/10.1093/humupd/dmw023

    Article  PubMed  PubMed Central  Google Scholar 

  7. Arslan AA, Gold LI, Mittal K, Suen T-C, Belitskaya-Levy I, Tang M-S, Toniolo P (2005) Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review. Hum Reprod 20(4):852–863

    Article  CAS  Google Scholar 

  8. Stewart EA, Friedman AJ, Peck K, Nowak RA (1994) Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle. J Clin Endocrinol Metab 79(3):900–906. https://doi.org/10.1210/jcem.79.3.8077380

    Article  CAS  PubMed  Google Scholar 

  9. Leppert PC, Jayes FL, Segars JH (2014) The extracellular matrix contributes to mechanotransduction in uterine fibroids. Obstet Gynecol Int 2014:783289–783212. https://doi.org/10.1155/2014/783289

    Article  PubMed  PubMed Central  Google Scholar 

  10. Giuliani A, Greco S, Pacilè S, Zannotti A, Delli Carpini G, Tromba G, Giannubilo SR, Ciavattini A, Ciarmela P (2019) Advanced 3D imaging of uterine Leiomyoma's morphology by propagation-based phase-contrast microtomography. Sci Rep 9(1):10580–10580. https://doi.org/10.1038/s41598-019-47048-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6(8):583–592

    Article  CAS  Google Scholar 

  12. Ma C, Chegini N (1999) Regulation of matrix metalloproteinases (MMPs) and their tissue inhibitors in human myometrial smooth muscle cells by TGF-β1. Mol Hum Reprod 5(10):950–954

    Article  CAS  Google Scholar 

  13. Dou Q, Tarnuzzer RW, Williams RS, Schultz GS, Chegini N (1997) Differential expression of matrix metalloproteinases and their tissue inhibitors in leiomyomata: a mechanism for gonadotrophin releasing hormone agonist-induced tumour regression. Mol Hum Reprod 3(11):1005–1014

    Article  CAS  Google Scholar 

  14. Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function1. Biochimica et Biophysica Acta (BBA)-Protein Structure and Molecular Enzymology 1477(1–2):267–283

    Article  CAS  Google Scholar 

  15. Wei M, Liu X, Cao C, Yang J, Lv Y, Huang J, Wang Y, Qin Y (2018) An engineered PD-1-based and MMP-2/9-oriented fusion protein exerts potent antitumor effects against melanoma. BMB Rep 51(11):572–577. https://doi.org/10.5483/BMBRep.2018.51.11.076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Walker CL, Stewart EA (2005) Uterine fibroids: the elephant in the room. Science 308(5728):1589–1592

    Article  CAS  Google Scholar 

  17. Chung Y-J, Chae B, Kwak S-H, Song J-Y, Lee A-W, Jo H-H, Lew Y-O, Kim J-H, Kim M-R (2014) Comparison of the inhibitory effect of gonadotropin releasing hormone (GnRH) agonist, selective estrogen receptor modulator (SERM), antiprogesterone on myoma cell proliferation in vitro. Int J Med Sci 11(3):276–281. https://doi.org/10.7150/ijms.7627

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bnyan I, Alta'ee A, Kadhum N (2014) Antibacterial activity of aluminum potassium sulfate and Syzygium aromaticum extract against pathogenic microorganisms. J Nat Sci Res 4(15):137–141

    Google Scholar 

  19. Hollander D, Tarnawski A, Gergely H (1986) Protection against alcohol-induced gastric mucosal injury by aluminum-containing compounds-sucralfate, antacids, and aluminum sulfate. Scandinavian Journal of Gastroenterology 21(sup125):151–155

    Article  CAS  Google Scholar 

  20. Worwood VA, Stonehouse J (2011) The Endometriosis Natural Treatment Program: A Complete Self-Help Plan for Improving Health and Well-Being. New World Library,

  21. El-Rahman SSA (2003) Neuropathology of aluminum toxicity in rats (glutamate and GABA impairment). Pharmacol Res 47(3):189–194. https://doi.org/10.1016/S1043-6618(02)00336-5

    Article  CAS  PubMed  Google Scholar 

  22. Turkez H, Geyikoglu F (2011) The efficacy of bismuth subnitrate against genotoxicity and oxidative stress induced by aluminum sulphate. Toxicol Ind Health 27(2):133–142

    Article  CAS  Google Scholar 

  23. Türkez H, Yousef MI, Geyikoglu F (2010) Propolis prevents aluminium-induced genetic and hepatic damages in rat liver. Food Chem Toxicol 48(10):2741–2746

    Article  Google Scholar 

  24. Elnakady YA, Rushdi AI, Franke R, Abutaha N, Ebaid H, Baabbad M, Omar MO, Al Ghamdi AA (2017) Characteristics, chemical compositions and biological activities of propolis from Al-Bahah, Saudi Arabia. Sci Rep 7:41453. https://doi.org/10.1038/srep41453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Park YK, Alencar SM, Aguiar CL (2002) Botanical origin and chemical composition of Brazilian propolis. J Agric Food Chem 50(9):2502–2506. https://doi.org/10.1021/jf011432b

    Article  CAS  PubMed  Google Scholar 

  26. Rimbach G, Fischer A, Schloesser A, Jerz G, Ikuta N, Ishida Y, Matsuzawa R, Matsugo S, Huebbe P, Terao K (2017) Anti-inflammatory properties of Brazilian green propolis encapsulated in a γ-cyclodextrin complex in mice fed a western-type diet. Int J Mol Sci 18(6):1141

    Article  Google Scholar 

  27. Endo MM, Estrela CR, Alencar AHG, Silva JA, Decurcio DA, Estrela C (2017) Antibacterial action of red and green propolis extract in infected root canal. Revista Odonto Ciência 32(2):99–103

    Article  Google Scholar 

  28. Nina N, Quispe C, Jiménez-Aspee F, Theoduloz C, Feresín GE, Lima B, Leiva E, Schmeda-Hirschmann G (2015) Antibacterial activity, antioxidant effect and chemical composition of propolis from the Región del Maule, Central Chile. Molecules 20(10):18144–18167

    Article  CAS  Google Scholar 

  29. Oršolić N (2010) A review of propolis antitumor action in vivo and in vitro. Journal of ApiProduct and ApiMedical Science 2(1):1–20

    Article  Google Scholar 

  30. Ali AFM, Farid L, Shaker S (2018) Bee propolis, Luperon depot 3.75 mg treatment of uterine fibroid. A randomized, controlled clinical trial. Life Science Journal 15(11)

  31. Ali AFM, Farid L, Shaker S (2018) Bee Propolis treatment of uterine Myoma a new modality. Life Science Journal 15(11)

  32. Wu J, Omene C, Karkoszka J, Bosland M, Eckard J, Klein CB, Frenkel K (2011) Caffeic acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer. Cancer Lett 308(1):43–53. https://doi.org/10.1016/j.canlet.2011.04.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vilela P, de Oliveira JR, de Barros PP, Leão MV, de Oliveira LD, Jorge AO (2015) In vitro effect of caffeic acid phenethyl ester on matrix metalloproteinases (MMP-1 and MMP-9) and their inhibitor (TIMP-1) in lipopolysaccharide-activated human monocytes. Arch Oral Biol 60(9):1196–1202. https://doi.org/10.1016/j.archoralbio.2015.04.009

    Article  CAS  PubMed  Google Scholar 

  34. Li H, Qiu Z, Li F, Wang C (2017) The relationship between MMP-2 and MMP-9 expression levels with breast cancer incidence and prognosis. Oncol Lett 14(5):5865–5870. https://doi.org/10.3892/ol.2017.6924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen HG, Lan Z, Cui QC, Lang JH, Li B (2011) Estrogen induced rat model of uterine leiomyoma. Zhongguo yi xue ke xue yuan xue bao Acta Academiae Medicinae Sinicae 33(4):408–411. https://doi.org/10.3881/j.issn.1000-503X.2011.04.012

    Article  PubMed  Google Scholar 

  36. Flake GP, Andersen J, Dixon D (2003) Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect 111(8):1037–1054

    Article  CAS  Google Scholar 

  37. Tal R, Segars JH (2013) The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy. Hum Reprod Update 20(2):194–216

    Article  Google Scholar 

  38. Chegini N Proinflammatory and profibrotic mediators: principal effectors of leiomyoma development as a fibrotic disorder. In: Seminars in reproductive medicine, 2010. Vol 3. NIH Public Access, p 180

  39. Malik M, Norian J, McCarthy-Keith D, Britten J, Catherino WH Why leiomyomas are called fibroids: the central role of extracellular matrix in symptomatic women. In: Seminars in reproductive medicine, 2010. vol 03. Published in 2010 by Thieme Medical Publishers, pp 169–179

  40. Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92(8):827–839. https://doi.org/10.1161/01.Res.0000070112.80711.3d

    Article  CAS  PubMed  Google Scholar 

  41. Lohi J, Wilson CL, Roby JD, Parks WC (2001) Epilysin, a novel human matrix metalloproteinase (MMP-28) expressed in testis and keratinocytes and in response to injury. J Biol Chem 276(13):10134–10144

    Article  CAS  Google Scholar 

  42. Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69(3):562–573

    Article  CAS  Google Scholar 

  43. Yasong W, Donghua L, Xin X, Ruiya Q, Yalan Z, Yuhua H, Jianguo G, Xiaoli Z, Hongjuan H, Wufang Z (2016) Lichong decoction reduces matrix metalloproteinases-2 expression but increases tissue inhibitors of matrix metalloproteinases-2 expression in a rat model of uterine leiomyoma. J Tradit Chin Med 36(4):479–485

    Article  Google Scholar 

  44. Nagase H (2016) A personal journey with matrix metalloproteinases. Biol Chem 397(9):805–813

    Article  CAS  Google Scholar 

  45. Auguściak-Duma A, Sieroń A (2008) Molecular characteristics of leiomyoma uteri based on selected compounds of the extracellular matrix. Postepy higieny i medycyny doswiadczalnej (Online) 62:148–165

    Google Scholar 

  46. Bogusiewicz M, Stryjecka-Zimmer M, Postawski K, Jakimiuk AJ, Rechberger T (2007) Activity of matrix metalloproteinase-2 and -9 and contents of their tissue inhibitors in uterine leiomyoma and corresponding myometrium. Gynecol Endocrinol 23(9):541–546. https://doi.org/10.1080/09513590701557416

    Article  CAS  PubMed  Google Scholar 

  47. Halder SK, Osteen KG, Al-Hendy A (2013) Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and -9 in human uterine fibroid cells. Human reproduction (Oxford, England) 28(9):2407–2416. https://doi.org/10.1093/humrep/det265

    Article  CAS  Google Scholar 

  48. Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52–67. https://doi.org/10.1016/j.cell.2010.03.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tarighi P, Khoroushi M (2014) A review on common chemical hemostatic agents in restorative dentistry. Dent Res J (Isfahan) 11(4):423–428

    Google Scholar 

  50. Darbandi MP, Taheri J (2018) Using sulfur-containing minerals in medicine: Iranian traditional documents and modern pharmaceutical terminology. Earth Sciences History 37(1):25–33

    Article  Google Scholar 

  51. Brown EM, Dudley RL (2005) Approach to a tanning mechanism: study of the interaction of aluminum sulfate with collagen. J Am Leather Chem Assoc

  52. Shen Y, Liu S, Jin F, Mu T, Li C, Jiang K, Tian W, Yu D, Zhang Y, Fang X (2012) Aluminum ammonium sulfate dodecahydrate purified from traditional Chinese medicinal herb Korean monkshood root is a potent matrix metalloproteinase inhibitor. BioMetals 25(3):541–551

    Article  CAS  Google Scholar 

  53. Kumar S (1998) Biphasic effect of aluminium on cholinergic enzyme of rat brain. Neurosci Lett 248(2):121–123. https://doi.org/10.1016/s0304-3940(98)00267-5

    Article  CAS  PubMed  Google Scholar 

  54. Kumar S (1999) Aluminium-induced biphasic effect. Med Hypotheses 52(6):557–559. https://doi.org/10.1054/mehy.1997.0693

    Article  CAS  PubMed  Google Scholar 

  55. Çabuş N, Oğuz EO, Tufan A, Adıgüzel E (2015) A histological study of toxic effects of aluminium sulfate on rat hippocampus. Biotech Histochem 90(2):132–139. https://doi.org/10.3109/10520295.2014.965277

    Article  CAS  PubMed  Google Scholar 

  56. Saha K (2019) Measurement of aluminum ions across the mordanting process of wool substrates with potassium aluminum sulfate and effluent characterization

  57. Abreo K, Alvarez-Hernandez X, Jain S (2004) Antioxidants prevent aluminum-induced toxicity in cultured hepatocytes. J Inorg Biochem 98(6):1129–1134

    Article  CAS  Google Scholar 

  58. Zakaria M, Hajipour B, Estakhri R, Saleh B (2017) Anti-oxidative effect of resveratrol on aluminum induced toxicity in rat cerebral tissue. Bratislava Medical Journal 118(5):269–272

    Article  CAS  Google Scholar 

  59. Wen Y-F, Zhao J-Q, Nirala SK, Bhadauria M (2012) Aluminum-induced toxicity and its response to combined treatment of HEDTA and propolis in rats. Pol J Environ Stud 21(5)

  60. Kubiliene L, Jekabsone A, Zilius M, Trumbeckaite S, Simanaviciute D, Gerbutaviciene R, Majiene D (2018) Comparison of aqueous, polyethylene glycol-aqueous and ethanolic propolis extracts: antioxidant and mitochondria modulating properties. BMC Complement Altern Med 18(1):165. https://doi.org/10.1186/s12906-018-2234-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Song YS, Park EH, Jung KJ, Jin C (2002) Inhibition of angiogenesis by propolis. Arch Pharm Res 25(4):500–504

    Article  CAS  Google Scholar 

  62. Newairy A, Abdou H (2013) Effect of propolis consumption on hepatotoxicity and brain damage in male rats exposed to chlorpyrifos. Afr J Biotechnol 12(33):5232–5243

    Article  CAS  Google Scholar 

  63. Xuan H, Li Z, Yan H, Sang Q, Wang K, He Q, Wang Y, Hu F (2014) Antitumor activity of Chinese propolis in human breast cancer MCF-7 and MDA-MB-231 cells. Evid Based Complement Alternat Med 2014, 2014, 1, 11

  64. Demir S, Aliyazicioglu Y, Turan I, Misir S, Mentese A, Yaman SO, Akbulut K, Kilinc K, Deger O (2016) Antiproliferative and proapoptotic activity of Turkish propolis on human lung cancer cell line. Nutr Cancer 68(1):165–172

    Article  Google Scholar 

  65. Kimoto T, Koya-Miyata S, Hino K, Micallef MJ, Hanaya T, Arai S, Ikeda M, Kurimoto M (2001) Pulmonary carcinogenesis induced by ferric nitrilotriacetate in mice and protection from it by Brazilian propolis and artepillin C. Virchows Arch 438(3):259–270

    Article  CAS  Google Scholar 

  66. Kakehashi A, Ishii N, Fujioka M, Doi K, Gi M, Wanibuchi H (2016) Ethanol-extracted Brazilian propolis exerts protective effects on tumorigenesis in Wistar Hannover rats. PLoS One 11(7):e0158654

    Article  Google Scholar 

  67. Yasui Y, Miyamoto S, Kim M, Kohno H, Sugie S, Tanaka T (2008) Aqueous and ethanolic extract fractions from the Brazilian propolis suppress azoxymethane-induced aberrant crypt foci in rats. Oncol Rep 20(3):493–499

    PubMed  Google Scholar 

  68. Grunberger D, Banerjee R, Eisinger K, Oltz E, Efros L, Caldwell M, Estevez V, Nakanishi K (1988) Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia 44(3):230–232

    Article  CAS  Google Scholar 

  69. Jin U-H, Chung T-W, Kang S-K, Suh S-J, Kim J-K, Chung K-H, Gu Y-H, Suzuki I, Kim C-H (2005) Caffeic acid phenyl ester in propolis is a strong inhibitor of matrix metalloproteinase-9 and invasion inhibitor: isolation and identification. Clin Chim Acta 362(1):57–64. https://doi.org/10.1016/j.cccn.2005.05.009

    Article  CAS  PubMed  Google Scholar 

  70. Benson HL, Mobashery S, Chang M, Kheradmand F, Hong JS, Smith GN, Shilling RA, Wilkes DS (2011) Endogenous matrix metalloproteinases 2 and 9 regulate activation of CD4+ and CD8+ T cells. Am J Respir Cell Mol Biol 44(5):700–708. https://doi.org/10.1165/rcmb.2010-0125OC

    Article  CAS  PubMed  Google Scholar 

  71. Juric V, O'Sullivan C, Stefanutti E, Kovalenko M, Greenstein A, Barry-Hamilton V, Mikaelian I, Degenhardt J, Yue P, Smith V, Mikels-Vigdal A (2018) MMP-9 inhibition promotes anti-tumor immunity through disruption of biochemical and physical barriers to T-cell trafficking to tumors. PLoS One 13(11):e0207255–e0207255. https://doi.org/10.1371/journal.pone.0207255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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This study was funded by Semnan University of Medical Sciences with a register number of A-10-65-7.

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Correspondence to Hoda Doustmohammadi.

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All procedures on animals were carried out in accordance with the Animal Ethics Committee and the support of Semnan University of Medical Sciences, Semnan, Iran.

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Yousefi, B., Semnani, V., Mokhtari, T. et al. Co-administration of Aluminum Sulfate and Propolis Regulates Matrix Metalloproteinases-2/9 Expression and Improves the Uterine Leiomyoma in Adult Rat Model. Biol Trace Elem Res 199, 1002–1012 (2021). https://doi.org/10.1007/s12011-020-02200-0

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  2. Mehdi Barati