Sains Malaysiana 53(10)(2024): 3355-3367

http://doi.org/10.17576/jsm-2024-5310-10

 

Toxicological Evaluation of Sargassum polycystum in Mice with Loperamide-Induced Constipation

 (Penilaian Toksikologi Sargassum polycystum pada Tikus dengan Sembelit Akibat Loperamide)

 

CHITTIPONG TIPBUNJONG^1,*, TANAPORN HENGPRATOM¹, SARANYA PEERAKIETKHAJORN², JARUWAN MAYAKUN², NAWIYA HUIPAO¹, PISSARED KHUITUAN¹, PIYAPORN SURINLERT³ & CHUMPOL PHOLPRAMOOL⁴

 

¹Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Songkhla 90110, Thailand

²Division of Biological Science, Faculty of Science, Prince of Songkla University, Songkhla 90110, Thailand

³Chulabhorn International College of Medicine, Thammasat University, Pathum-Thani 12120, Thailand

 ⁴Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand

 

Received: 23 December 2023/Accepted: 21 August 2024

 

Abstract

Constipation gradually increases in people after the age of 50 years leading to difficulty in stool passage. Until now, there have been no effective drugs without side effects. This study investigated the preventive potential and toxicity of Sargassum polycystum extract (SPE) against loperamide-induced constipation in mice. Daily oral administration of SPE (100, 500 and 1000 mg/kg) for 14 days significantly increased defecation frequency in constipation mice. Additionally, no significant differences in blood haematological and biochemical indices between the control, constipation and SPE-treated groups were detected. Histopathological examinations revealed non-toxic effects in liver, kidney and colon tissue samples from the SPE-treated groups compared with the control and constipation groups. Real-time polymerase chain reaction showed that the administration of SPE significantly modulated Saa3, Odc1 and Clu expressions that promote the health of living organisms compared with the control group. Overall, this study showed that daily oral administration of Sargassum polycystumfor 14 days could prevent constipation without any adverse effects. Sargassum polycystumis suitable for further use as a supplement or drug to manage constipation.

 

Keywords: Constipation; histopathology; Sargassum sp.; seaweed; toxicity

 

Abstrak

Sembelit berlaku secara beransur-ansur kepada orang berusia selepas 50 tahun yang membawa kepada kesukaran untuk membuang najis. Sehingga kini, tiada ubat yang berkesan tanpa kesan sampingan. Penyelidikan ini mengkaji potensi pencegahan dan ketoksikan ekstrak Sargassum polycystum (SPE) terhadap sembelit yang disebabkan oleh loperamide pada tikus. Administrasi oral harian SPE (100, 500 dan 1000 mg/kg) selama 14 hari meningkatkan kekerapan buang air besar dengan ketara pada tikus sembelit. Selain itu, tiada perbezaan ketara dalam indeks hematologi dan biokimia darah antara kumpulan kawalan, sembelit dan rawatan SPE dikesan. Pemeriksaan histopatologi mendedahkan kesan bukan toksik dalam sampel tisu hati, buah pinggang dan kolon daripada kumpulan yang dirawat SPE berbanding kumpulan kawalan dan sembelit. Tindak balas rantai polimerase masa nyata menunjukkan bahawa administrasi SPE memodulasi pengekspresan Saa3, Odc1 dan Clu dengan ketara yang menggalakkan kesihatan organisma hidup berbanding dengan kumpulan kawalan. Secara keseluruhannya, kajian ini menunjukkan bahawa administrasi Sargassum polycystum secara oral setiap hari selama 14 hari dapat mengelakkan sembelit tanpa sebarang kesan buruk. Sargassum polycystumsesuai untuk kegunaan selanjutnya sebagai suplemen atau ubat untuk menguruskan sembelit.

 

Kata kunci: Histopatologi, ketoksikan; rumpai laut; Sargassum sp., sembelit

 

REFERENCES

Araújo, M.C.D.P.M., Barcellos, N.M.S., de Abreu Vieira, P.M., Gouveia, T.M., Guerra, M.O., Peters, V.M. & Saúde-Guimarães, D.A. 2017. Acute and sub chronic toxicity study of aqueous extract from the leaves and branches of Campomanesia velutina (Cambess) O. Berg. Journal of Ethnopharmacology 201: 17-25.

Araújo, M.M. & Botelho, P.B. 2022. Probiotics, prebiotics, and synbiotics in chronic constipation: Outstanding aspects to be considered for the current evidence. Frontiers in Nutrition 9: 935830.

Brownlee, I.A. 2011. The physiological roles of dietary fibre. Food Hydrocolloids 25(2): 238-250.

Chait, A., den Hartigh, L.J., Wang, S., Goodspeed, L., Babenko, I., Altemeier, W.A. & Vaisar, T. 2020. Presence of serum amyloid A3 in mouse plasma is dependent on the nature and extent of the inflammatory stimulus. Scientific Reports 10(1): 10397.

Chen, R., Chen, Q., Zheng, J., Zeng, Z., Chen, M., Li, L. & Zhang, S. 2023. Serum amyloid protein A in inflammatory bowel disease: from bench to bedside. Cell Death Discovery 9(1): 154.

Chen, X., Wang, S., Mao, X., Xiang, X., Ye, S., Chen, J., Zhu, A., Meng, Y., Yang, X., Peng, S., Deng, M. & Wang, X. 2023. Adverse health effects of emerging contaminants on inflammatory bowel disease. Frontiers in Public Health 11: 1140786.

Cherbut, C., Ferrier, L., Rozé, C., Anini, Y., Blottière, H., Lecannu, G. & Galmiche, J.P. 1998. Short-chain fatty acids modify colonic motility through nerves and polypeptide YY release in the rat. American Journal of Physiology-Gastrointestinal and Liver Physiology 275(6): G1415-G1422.

Chichlowski, M., Croom, J., McBride, B.W., Havenstein, G.B. & Koci, M.D. 2007. Metabolic and physiological impact of probiotics or direct-fed-microbials on poultry: A brief review of current knowledge. International Journal of Poultry Science 6(10): 694-704.

Davani-Davari, D., Negahdaripour, M., Karimzadeh, I., Seifan, M., Mohkam, M., Masoumi, S.J., Berenjian, A. & Ghasemi, Y. 2019. Prebiotics: Definition, types, sources, mechanisms, and clinical applications. Foods 8(3): 92.

de Jesus Raposo, M.F., De Morais, A.M.M.B. & De Morais, R.M.S.C. 2016. Emergent sources of prebiotics: Seaweeds and microalgae. Marine Drugs 14(2): 27.

de Medeiros, V.P., de Souza, E.L., de Albuquerque, T.M., da Costa Sassi, C.F., dos Santos Lima, M., Sivieri, K., Pimentel, T.C. & Magnani, M. 2021. Freshwater microalgae biomasses exert a prebiotic effect on human colonic microbiota. Algal Research 60: 102547.

Fabian, G., Farago, N., Feher, L.Z., Nagy, L.I., Kulin, S., Kitajka, K., Bito, T., Tubak, V., Katona, R.L., Tiszlavicz, L. & Puskas, L.G. 2011. High-density real-time PCR-based in vivo toxicogenomic screen to predict organ-specific toxicity. International Journal of Molecular Sciences 12(9): 6116-6134.

Furness, J.B. 2000. Types of neurons in the enteric nervous system. Journal of the Autonomic Nervous System 81(1-3): 87-96.

Giriwono, P.E., Iskandriati, D., Tan, C.P. & Andarwulan, N. 2019. Sargassum seaweed as a source of anti-inflammatory substances and the potential insight of the tropical species: A review. Marine Drugs 17(10): 590.

Gregory, J.M., Whiten, D.R., Brown, R.A., Barros, T.P., Kumita, J.R., Yerbury, J.J., Satapathy, S., McDade, K., Smith, C., Luheshi, L.M., Dobson, C.M. & Wilson, M.R. 2017. Clusterin protects neurons against intracellular proteotoxicity. Acta Neuropathologica Communications 5(1): 81.

Higgins, P.D. & Johanson, J.F. 2004. Epidemiology of constipation in North America: A systematic review. American Journal of Gastroenterology 99(4): 750-759.

Jiang, F., Gao, Y., Dong, C. & Xiong, S. 2018. ODC1 inhibits the inflammatory response and ROS-induced apoptosis in macrophages. Biochemical and Biophysical Research Communications 504(4): 734-741.

Khuituan, P., Huipao, N., Jeanmard, N., Thantongsakul, S., Promjun, W., Chuthong, S., Tipbunjong, C. & Peerakietkhajorn, S. 2022. Sargassum plagiophyllum extract enhances colonic functions and modulates gut microbiota in constipated mice. Nutrients 14(3): 496.

Koh, E.J., Shin, K.S., Sunwoo, I.Y., Kim, J. & Choi, W.Y. 2024. Brown seaweed byproduct extracts improve intestinal motility and auto-inflammation in mice with loperamide-induced constipation. Foods 13(13): 2037.

Lee, H., Selvaraj, B. & Lee, J.W. 2021. Anticancer effects of seaweed-derived bioactive compounds. Applied Sciences 11(23): 11261.

Lee, Y.H., Kim, H.R., Yeo, M.H., Kim, S.C., Hyun, H.B., Ham, Y.M., Jung, Y.H., Kim, H.S. & Chang, K.S. 2023. Anti-obesity potential of Sargassum horneri and Ulva australis extracts: Study in vitro and in vivo. Applied Sciences 13(15): 8951.

Li, R.W. & Li, C. 2006. Butyrate induces profound changes in gene expression related to multiple signal pathways in bovine kidney epithelial cells. BMC Genomics 7: 234.

Li, R., Yang, W., Yin, Y., Ma, X., Zhang, P. & Tao, K. 2021. 4-OI attenuates carbon tetrachloride-induced hepatic injury via regulating oxidative stress and the inflammatory response. Frontiers in Pharmacology 12: 651444.

Motshakeri, M., Ebrahimi, M., Goh, Y.M., Matanjun, P. & Mohamed, S. 2013. Sargassum polycystum reduces hyperglycaemia, dyslipidaemia and oxidative stress via increasing insulin sensitivity in a rat model of type 2 diabetes. Journal of the Science of Food and Agriculture 93(7): 1772-1778.

Navakanitworakul, R., Wanso, D., Phetcharat, S., Chumkaew, P. & Mayakun, J. 2023. Variations in total phenolics in Sargassum plagiophyllum and their cytotoxic activities. ScienceAsia 49: 791-796.

Olson, H., Betton, G., Robinson, D., Thomas, K., Monro, A., Kolaja, G., Lilly, P., Sanders, J., Sipes, G., Bracken, W., Dorato, M., Deun, K.V., Smith, P., Berger, B. & Heller, A. 2000. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regulatory Toxicology and Pharmacology 32(1): 56-67.

Prasedya, E.S., Padmi, H., Ilhami, B.T.K., Martyasari, N.W.R., Sunarwidhi, A.L., Widyastuti, S., Khairinisa, M.A., Cokrowati, N., Simangunsong, E.E. & Frediansyah, A. 2022. Brown macroalgae Sargassum cristaefolium extract inhibits melanin production and cellular oxygen stress in B16F10 melanoma cells. Molecules 27(23): 8585.

Premarathna, A.D., Tuvikene, R., Somasiri, M.N.R., De Silva, M.L.W.P., Adhikari, R., Ranahewa, T.H., Wijesundara, R.R.M.K.K., Wijesekera, S.K., Dissanayake, I.P.G.H.U., Wangchuk, P., Rjabovs, V., Jayasooriya, A.P. & Rajapakse, RPVJ. 2023. A novel therapeutic effect of mannitol-rich extract from the brown seaweed Sargassum ilicifolium using in vitro and in vivo models. BMC Complementary Medicine and Therapies 23: 26.

Rodrigues, D., Costa-Pinto, A.R., Sousa, S., Vasconcelos, M.W., Pintado, M.M., Pereira, L., Rocha-Santos, T.A., Costa, J.P.D., Silva, A.M., Duarte, A.C. & Gomes, A.M. 2019. Sargassum muticum and Osmundea pinnatifida enzymatic extracts: Chemical, structural, and cytotoxic characterization. Marine Drugs 17(4): 209.

Sakena, K., Peerakietkhajorn, S., Siringoringo, B., Muangnil, P., Wichienchot, S. & Khuituan, P. 2020. Oligosaccharides from Gracilaria fisheri ameliorate gastrointestinal dysmotility and gut dysbiosis in colitis mice. Journal of Functional Foods 71: 104021.

Santos, E.W., de Oliveira, D.C., Hastreiter, A., da Silva, G.B., de Oliveira Beltran, J.S., Tsujita, M., Crisma, A.R., Neves, S.M.P., Fock, R.A. & Borelli, P. 2016. Hematological and biochemical reference values for C57BL/6, Swiss Webster and BALB/c mice. Brazilian Journal of Veterinary Research and Animal Science 53(2): 138-145.

Sato, M., Toyama, T., Kim, M.S., Lee, J.Y., Hoshi, T., Miura, N., Naganuma, A. & Hwang, G.W. 2020. Increased putrescine levels due to ODC1 overexpression prevents mitochondrial dysfunction-related apoptosis induced by methylmercury. Life Sciences 256: 118031.

Sengkhim, R., Peerakietkhajorn, S., Jeanmard, N., Pongparadon, S., Khuituan, P., Thitiphatphuvanon, T., Surinlert, P. & Tipbunjong, C. 2021. Effects of Sargassum plagiophyllum extract pretreatment on tissue histology of constipated mice. Tropical Journal of Pharmaceutical Research 20(11): 2339-2346.

Shaidullov, I.F., Sorokina, D.M., Sitdikov, G., Hermann, A., Abdulkhakov, S. R. & Sitdikova, G.F. 2021. Short chain fatty acids and colon motility in a mouse model of irritable bowel syndrome. BMC Gastroenterology 21(1): 37.

Sinurat, E., Marraskuranto, E. & Subaryono, S. 2021. Evaluation of fucoidan from Sargassum duplicatum on performance immune responses, serum biochemical, and hematological testing in rats. Journal of Applied Pharmaceutical Science 11(6): 146-153.

Siringoringo, B., Huipao, N., Tipbunjong, C., Nopparat, J., Wichienchot, S., Hutapea, A.M. & Khuituan, P. 2021. Gracilaria fisheri oligosaccharides ameliorate inflammation and colonic epithelial barrier dysfunction in mice with acetic acid-induced colitis. Asian Pacific Journal of Tropical Biomedicine 11(10): 440.

Teschke, R., Frenzel, C., Glass, X., Schulze, J. & Eickhoff, A. 2013. Herbal hepatotoxicity: A critical review. British Journal of Clinical Pharmacology 75(3): 630-636.

Tipbunjong, C., Sengkhim, R., Thantongsakul, S., Peerakietkhajorn, S., Mayakun, J., Huipao, N. & Khuituan, P. 2023. Toxicological evaluation of Sargassum plagiophyllum extract in male mice. Tropical Journal of Pharmaceutical Research 22(11): 2319-2326.

Wang, L., Oh, J.Y., Yang, H.W., Hyun, J., Ahn, G., Fu, X., Xu, J., Gao, X., Cha, S.H. & Jeon, Y.J. 2023. Protective effect of Sargassum fusiforme fucoidan against ethanol-induced oxidative damage in in vitro and in vivo models. Polymers 15(8): 1912.

Xu, X., Zhu, R., Ying, J., Zhao, M., Wu, X., Cao, G. & Wang, K. 2020. Nephrotoxicity of herbal medicine and its prevention. Frontiers in Pharmacology 11: 569551.

Yang, B., Xie, Y., Guo, M., Rosner, M.H., Yang, H. & Ronco, C. 2018. Nephrotoxicity and Chinese herbal medicine. Clinical Journal of the American Society of Nephrology 13(10): 1605-1611.

Yang, J., Yu, Y.L., Jin, Y., Zhang, Y. & Zheng, C.Q. 2016. Clinical characteristics of drug-induced liver injury and primary biliary cirrhosis. World Journal of Gastroenterology 22(33): 7579-7586.

Yuvaraj, N., Kanmani, P., Satishkumar, R., Paari, A., Pattukumar, V. & Arul, V. 2013. Antinociceptive and anti-inflammatory activities of Sargassum wightii and Halophila ovalis sulfated polysaccharides in experimental animal models. Journal of Medicinal Food 16(8): 740-748.

Zhang, L., Liu, C., Yin, L., Huang, C. & Fan, S. 2023. Mangiferin relieves CCl4-induced liver fibrosis in mice. Scientific Reports 13(1): 4172.

Zheng, Z., Tang, J., Hu, Y. & Zhang, W. 2022. Role of gut microbiota-derived signals in the regulation of gastrointestinal motility. Frontiers in Medicine 9: 961703.

 

*Corresponding author; email: chittipong.t@psu.ac.th