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Licensed Unlicensed Requires Authentication Published by De Gruyter January 17, 2018

Syphacia muris infection in rats attenuates colorectal carcinogenesis through oxidative stress and gene expression alterations. Implications for modulatory effects by Bryostatin-1

Elsayed I. Salim, Samar F. Harras, Aisha G. Abdalla and Mohmmed H. Mona
From the journal Acta Parasitologica


Accumulating evidence suggest that some infectious agents may interfere in the natural progression of neoplasia. This study examined the association between chronic infection with adult Syphacia muris parasites and 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis in rats. In addition, the conceivable therapeutic effect of Bryostatin-1, a potent extract of the marine Bryozoan, Bugulane ritina, was investigated against this combined effect.DMH administration has induced aberrant crypt foci (ACF), surrogate biomarkers for colorectal carcinogenesis, while the S. muris infection combined with DMH has significantly increased the total numbers of ACF. Nonetheless, treatment with Bryostatin-1 after infection has significantly reduced the ACF numbers particularly larger ones. This inhibition was concomitant with significant inhibition in the immunohistochemical levels of the ki67, Caspase-3 and IgM levels in colorectal epithelium, as well as serum levels of IgM and IgG. Additionally, treatment with Bryostatin-1 after S. muris + DMH has modulated enzymatic antioxidative markers levels of superoxide dismutase and catalase as well as the non-enzymatic antioxidant markers levels of reduced glutathione, lipid peroxidation, nitric oxide and total antioxidant capacity. Further, treatment with Bryostatin-1 has down-regulated the mRNA expression levels of COX-2 and APC genes in colorectal mucosa. In conclusion, infection with S. muris during colorectal carcinogenesis has significantly modulated the oxidative stress markers in the colorectum, while treatment with Bryostatin-1 has exerted significant curative potential. A mechanism could be explained that Bryostatin-1 treatment has reduced oxidative stress markers activities along with affecting host to parasite immunity possibly leading to changes in the COX-2 and APC expression, retarding cellular proliferation and subsequently reducing the colorectal carcinogenesis events.


The authors wish to thank the animal facility principal of the Zoology Department at Tanta University, Egypt and the staff members of the Central Laboratory of Tanta University, Egypt for Excellent Technical Assistance.


Alberts B., Johnson A., Lewis J., Walter P., Raff M., Roberts K., et al. 2002. Chapter 24. Molecular Biology of the Cell (4th ed.). New York: Garland Science; Molecular Biology of the Cell, 4th edition. ISBN-10: 0-8153-3218-1ISBN-10: 0-8153-4072-9Search in Google Scholar

Alkon D.L., Hongpaisan J., Sun M.K. 2017. Effects of chronic bryostatin-1 on treatment-resistant depression in rats. European Journal of Pharmacology, PII, S0014-2999(17)30304-7. 10.1016/j.ejphar.2017.05.001Search in Google Scholar PubMed

Atari-Hajipirloo S., Nikanfar S., Heydari A., Noori F., Kheradmand F. 2016. The effect of celecoxib and its combination with imatinib on human HT-29 colorectal cancer cells: Involvement of COX-2, Caspase-3, VEGF and NF-κB genes expression. Cellular and Molecular Biology, 62, 68–74Search in Google Scholar

Balaji C., Muthukumaran J., Nalini N. 2015. Effect of sinapic acid on 1,2 dimethylhydrazine induced aberrant crypt foci, biotransforming bacterial enzymes and circulatory oxidative stress status in experimental rat colon carcinogenesis. Bratislavske Lekarske Listy, 116, 560–610.4149/BLL_2015_109Search in Google Scholar PubMed

Bastide N.M., Naud N., Nassy G., Vendeuvre J.L., Taché S., Guéraud F., et al. 2017. Red Wine and Pomegranate Extracts Suppress Cured Meat Promotion of Colonic Mucin-Depleted Foci in Carcinogen-Induced Rats. Nutrition and Cancer, 69, 289–298. 10.1080/01635581.2017.1263745Search in Google Scholar PubMed

Beutler E. (Ed.) 1982. Catalase, In: Red Cell Metabolism, a Manual of Biochemical Methods, Grune and Stratton New York, pp.105–106Search in Google Scholar

Breen L.D., Pučić-Baković M., Vučković F., Reiding K., Trbojević-Akmačić I., Šrajer Gajdošik M., et al. 2016. IgG and IgM glycosylation patterns in patients undergoing image-guided tumor ablation. Biochimica et Biophysica Acta, 1860, 1786–94. 10.1016/j.bbagen.2016.01.011Search in Google Scholar PubMed

Burkhart C.N., Burkhart C.G. 2005. Assessment of frequency, transmission, and genitourinary complications of enterobiasis (pinworms). International Journal of Dermatology, 44, 837–40. 10.1111/j.1365-4632.2004.02332.xSearch in Google Scholar PubMed

Chahid K., Laglaoui A., Zantar S., Ennabili A. 2015. Antioxidant-enzyme reaction to the oxidative stress due to alpha-cypermethrin, chlorpyriphos, and pirimicarb in tomato (Lycopersicon esculentum Mill.). Environmental Science and Pollution Research, 22, 18115–26. 10.1007/s11356-015-5024-3Search in Google Scholar PubMed

Davidson S.K., Allen S.W., Lim G.E., Anderson, C.M., Haygood, M.G. 2001. Evidence for the Biosynthesis of Bryostatins by the Bacterial Symbiont “Candidatus Endobugula sertula” of the Bryozoan Bugula neritina. Applied and Environmental Microbiology, 67, 4531–4537. 10.1128/AEM.67.10.4531-4537.2001Search in Google Scholar PubMed PubMed Central

DeWitt M., Johnson R.L., Snyder P., Fleet J.C. 2015. The effect of 1,25 dihydroxyvitamin D treatment on the mRNA levels of β catenin target genes in mice with colonic inactivation of both APC alleles. The Journal of Steroid Biochemistry and Molecular Biology, 148, 103–110. 10.1016/j.jsbmb.2015.01.009Search in Google Scholar PubMed PubMed Central

Etcheberrigaray R., Tan M., Dewachter I., Kuipéri C., Van der Auwera I., Wera S., et al.. 2004. Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice. Proceedings of the National Academy of Sciences USA, 101, 11141–11146. 10.1073/pnas.0403921101Search in Google Scholar PubMed PubMed Central

Fijneman R.J., Peham J.R., van de Wiel M.A., Meijer G.A., Matise I., Velcich A., et al. 2008. Expression of Pla2g2a prevents carcinogenesis in Muc2-deficient mice. Cancer Science, 99, 2113–9. 10.1111/j.1349-7006.2008.00924.xSearch in Google Scholar PubMed

Hale K.J., Manviazar S. 2010. New approaches to the Total Synthesis of Bryostatin Antitumor Macrolides. ChemistryAn Asian Journal, 5, 704–54. 10.1002/asia.200900634Search in Google Scholar

Hanley M.P., Hahn M.A., Li A.X., Wu X., Lin J., Wang J., et al. 2017. Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia. Oncogene. 10.1038/onc.2017.130Search in Google Scholar PubMed

Ince S., Kozan E., Kucukkurt I., Bacak E. 2010. The effect of levamisole and levamisole+vitamin C on oxidative damage in rats naturally infected with Syphacia muris. Experimental Parasitology, 124, 448–52. 10.1016/j.exppara.2009.12.017Search in Google Scholar PubMed

Jacqueline C., Tasiemski A., Sorci G., Ujvari B., Maachi F., Missá D., et al., 2017. Infections and cancer: the “fifty shades of immunity hypothesis”. BMC Cancer, 17, 257. 10.1186/s12885-017-3234-4Search in Google Scholar PubMed

Jaggi M., Chauhan S.C., Du C., Balaji K.C. 2008. Bryostatin 1 modulates beta-catenin subcellular localization and transcription activity through protein kinase D1 activation. Molecular Cancer Therapeutics, 7, 2703–12. 10.1158/1535-7163.MCT-08-0119Search in Google Scholar PubMed

Janakiram N.B., Rao C.V. 2014. Inflammation and Cancer, Advances in Experimental Medicine and Biology 816, 25–52, 10.1007/978-3-0348-0837-8_2Search in Google Scholar

Jiangbo Z., Xuying W., Yuping Z., Xili M., Yiwen Z., Tianbao Z. 2010. Toxicity of bryostatin-1 on the embryo-fetal development of Sprague-Dawley rats. Birth Defects Research, 89, 171–174. 10.1002/bdrb.20229Search in Google Scholar

Kello M., Drutovic D., Pilatova M.B., Tischlerova V., Perjesi P., Mojzis J. 2016. Chalcone derivatives cause accumulation of colon cancer cells in the G2/M phase and induce apoptosis. Life Science, 150, 32–8. 10.1016/j.lfs.2016.02.073Search in Google Scholar

Mutter R., Wills M. 2000. Chemistry and clinical biology of the bryostatins. Bioorganic & Medicinal Chemistry, 8, 1841–186010.1016/S0968-0896(00)00150-4Search in Google Scholar PubMed

Kosik-Bogacka D.I., Baranowska-Bosiacka I., Kolasa-Wolosiuk A., Lanocha-Arendarczyk N., Gutowska I, Korbecki J., et al. 2016. The inflammatory effect of infection with Hymenolepis diminuta via the increased expression and activity of COX-1 and COX-2 in the rat jejunum and colon. Experimental Parasitology, 169, 69–76. 10.1016/j.exppara.2016.07.009Search in Google Scholar PubMed

Lesko A.C., Goss K.H., Yang F.F., Schwertner A., Hulur I., Onel K., et al. 2015. The APC tumor suppressor is required for epithelial cell polarization and three-dimensional morphogenesis. Biochimica et Biophysica Acta, 1853, 711–23. 10.1016/j.bbamcr.2014.12.036Search in Google Scholar PubMed

Livak K.J., Schmittgen T.D. 2001. Analysis of relative gene expression data using real time quantitative PCR, the 2DDCT. Methods, 25, 402–408. 10.1006/meth.2001.1262Search in Google Scholar PubMed

Montgomery J.F., Hum S. 1995. Field diagnosis of nitrite poisoning in cattle by testing aqueous humor samples with urine test strips. Veterinary Record, 137, 593–594Search in Google Scholar

Notarnicola M., Tutino V., De Nunzio V., Dituri F., Caruso M.G., Giannelli G. 2017. Dietary ω-3 Polyunsaturated Fatty Acids Inhibit Tumor Growth in Transgenic ApcMin/+ Mice, Correlating with CB1 Receptor Up-Regulation. International Journal of Molecular Sciences, 18, E485. 10.3390/ijms18030485Search in Google Scholar

Perec-Matysiak A., Okulewicz A., Hildebrand J., Zalesny G. 2006. Helminth parasites of laboratory mice and rats. Wiadomości Parazytologiczne, 52, 99–102Search in Google Scholar PubMed

Peterson M.R., Weidner N. 2011. Gastrointestinal neoplasia associated with bowel parasitosis: real or imaginary?, Journal of Tropical Medicine, 234254. 10.1155/2011/234254Search in Google Scholar PubMed

Plummer M., de Martel C., Vignat J., Ferlay J., Bray F., Franceschi S. 2016. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Global Health, 4, e609–16. 10.1016/S2214-109X(16)30143-7Search in Google Scholar

Rana T., Bera A.K., Das S., Bhattacharya D., Pan D., Das S.K. 2016. Inhibition of Oxidative Stress and Enhancement of Cellular Activity by Mushroom Lectins in Arsenic Induced Carcinogenesis. Asian Pacific Journal of Cancer Prevention, 17, 4185–4197Search in Google Scholar

Salim, E.I., Morimura K., Menesi A., El-Lity M., Fukushima S. and Wanibuchi H. 2008. Elevated oxidative stress and DNA damage and repair levels in urinary bladder carcinomas associated with Schistosomiasis. International Journal of Cancer, 123, 601–8. 10.1002/ijc.23547Search in Google Scholar PubMed

Shiraishi N., Ohta Y., Nishikimi M. 2000. The octapeptide repeat region of prion protein binds Cu(II) in the redox inactive states. Biochemical and Biophysical Research Communications, 267, 398–402. 10.1006/bbrc.1999.1944Search in Google Scholar

Sinha A.K. 1972. Colorimetric assay of catalase. Analytical Biochemistry, 47, 389–39410.1016/0003-2697(72)90132-7Search in Google Scholar PubMed

Staff C., Magnusson C.G., Hojjat-Farsangi M., Mosolits S., Liljefors M., Frödin J.E. 2012. Induction of IgM, IgA and IgE antibodies in colorectal cancer patients vaccinated with a recombinant CEA protein. Journal of Clinical Immunology, 32, 855–65. 10.1007/s10875-012-9662-7Search in Google Scholar PubMed

Theodoratou E., Thaçi K., Agakov F., Timofeeva M.N., Štambuk J., Pučić-Baković M., et al. 2016. Glycosylation of plasma IgG in colorectal cancer prognosis. Scientific Reports, 6, 28098. 10.1038/srep28098Search in Google Scholar PubMed PubMed Central

Su L.K., Vogelstein B., Kinzler K.W. 1993. Association of the APC tumor suppressor protein with catenins, Science, 262, 1734–173710.1126/science.8259519Search in Google Scholar PubMed

Sun M.K. and Alkon D.L. 2008. Synergistic effects of chronic bryostatin-1 and alpha-tocopherol on spatial learning and memory in rats. European Journal of Pharmacology, 584, 328–37. 10.1016/j.ejphar.2008.02.014Search in Google Scholar PubMed

Wang L., Hu T., Shen J., Zhang L., Chan R.L., et al. 2015. Dihydrotanshinone I induced apoptosis and autophagy through caspase dependent pathway in colon cancer. Phytomedicine, 22, 1079–87. 10.1016/j.phymed.2015.08.009Search in Google Scholar PubMed

Yamasaki T., Takahashi A., Pan J., Yamaguchi N., Yokoyama K.K. 2009. Phosphorylation of Activation Transcription Factor-2 at Serine 121 by Protein Kinase C Controls c-Jun-mediated Activation of Transcription. The Journal of Biological Chemistry, 284, 8567–81. 10.1074/jbc.M808719200Search in Google Scholar PubMed

Ye B., Yu-Xia Zhang Y-X., Fei Yang F., Hong-Lei Chen H-L., et al. 2007. Induction of lung lesions in Wistar rats by 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone and its inhibition by aspirin and phenethyl isothiocyanate. BMC Cancer, 7, 90. 10.1186/1471-2407-7-90Search in Google Scholar

Yoshioka T., Kawada K., Shimada T., Mori M. 1979. Lipid peroxidation in maternal and cord blood and protective mechanism against activated oxygen toxicity in the blood. American Journal of Obstetrics & Gynecology, 135, 37210.1016/0002-9378(79)90708-7Search in Google Scholar

Zoon C.K., Wan W., Graham L., Bear H.D. 2017. Expansion of T Cells with Interleukin-21 for Adoptive Immunotherapy of Murine Mammary Carcinoma. International Journal of Molecular Sciences, 18, E270. 10.3390/ijms18020270Search in Google Scholar PubMed PubMed Central

Received: 2017-7-28
Revised: 2017-11-20
Accepted: 2017-11-30
Published Online: 2018-1-17
Published in Print: 2018-3-26

© 2018 W. Stefański Institute of Parasitology, PAS

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