Abstract
Seaweeds are a source of novel bioactive compounds such as sulfated polysaccharides (PLS) that are not found in plants, but that may confer health-promoting properties. Sulfated polysaccharides extracted from seaweeds have several biologically beneficial effects. The PLS extracted from the red alga Gracilaria caudata are known to have anti-inflammatory, antinociceptive, and gastroprotective activities. The present study aimed to evaluate the hepatoprotective effect of PLS obtained from G. caudata on a nimesulide-induced liver damage model. Hepatic lesions were induced in mice by oral doses of nimesulide (200 mg kg−1) administered once daily for 5 days. Once a day, 30 min after administration of nimesulide, PLS was administered intraperitoneally at concentrations of 2.5, 5, and 10 mg kg−1. Subsequently, blood was collected for biochemical tests and the liver was removed to evaluate inflammatory parameters. Administration of PLS at the dose of 10 mg kg−1 led to a significant reduction in hepatic injury, liver weight/animal weight ratio, the levels of a neutrophil migration marker (myeloperoxidase), pro-inflammatory cytokines (interleukin-1β and tumor necrosis factor-α), nitrate and nitrite, oxidative stress markers, and hepatic function markers. As per our results, the PLS extracted from G. caudata was able to modulate the inflammatory response in nimesulide-induced hepatic damage in addition to re-establishing the hepatic homeostatic functions.






Similar content being viewed by others
Explore related subjects
Discover the latest articles and news from researchers in related subjects, suggested using machine learning.References
Alencar POC, Lima GC, Barros FCN, Costa LEC, Ribeiro CVPE, Sousa WM, Sombra VG, Abreu CMWS, Abreu ES, Pontes EOB, Oliveira AC, De Paula RCM, Freitas ALP (2019) A novel antioxidant sulfated polysaccharide from the algae Gracilaria caudata: in vitro and in vivo activities. Food Hydrocoll 90:28–34
Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, García–Ruiz E, García–Muñoz B, González–Grande R, Pizarro A, Durán JA, Jiménez M, Rodrigo L, Romero–Gomez M, Navarro JM, Planas R, Costa J, Borras A, Soler A, Salmerón J, Martin–Vivaldi R (2005) Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 129:512–521
Bakr RO, Fayed MAA, Fayez AM, Gabr SK, El-Fishawy AM, El-Alfy TS (2019) Hepatoprotective activity of Erythrina × neillii leaf extract and characterization of its phytoconstituents. Phytomedicine 53:9–17
Barman PK, Mukherjee R, Prusty BK, Suklabaidya S, Senapati S, Ravindran B (2016) Chitohexaose protects against acetaminophen-induced hepatotoxicity in mice. Cell Death Dis 7:2224
Barros FCN, Da Silva DC, Sombra VG, MacIel JS, Feitosa JPA, Freitas ALP, De Paula RCM (2013) Structural characterization of polysaccharide obtained from red seaweed Gracilaria caudata (J Agardh). Carbohydr Polym 92:598–603
Bessone F (2010) Non-steroidal anti-inflammatory drugs: what is the actual risk of liver damage? World J Gastroenterol 16:5651–5661
Bilan MI, Usov AI (2008) Structural analysis of fucoidans. Nat Prod Commun 3:1639–1648
Boelsterli UA (2002) Mechanisms of NSAID-induced hepatotoxicity. Drug Saf 25:633–648
Boelsterli UA, Ho HK, Zhou S, Yeowleow K (2006) Bioactivation and hepato-toxicity of nitroaromatic drugs. Curr Drug Metab 7:715–727
Bradley PP, Priebat DA, Christensen RD, Rothstein G (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. Invest Dermatol 78:206–209
Brito TV, Prudêncio RDS, Sales AB, Vieira Júnior FDC, Candeira SJN, Franco ÁX, Aragão KS, Ribeiro RDA, Ponte De Souza MHL, Chaves LDS, Freitas ALP, Medeiros JVR, Dos Reis Barbosa AL (2013) Anti-inflammatory effect of a sulphated polysaccharide fraction extracted from the red algae Hypnea musciformis via the suppression of neutrophil migration by the nitric oxide signalling pathway. J Pharm Pharmacol 65:724–733
Chatterjee M, Sil PC (2006) Hepatoprotective effect of aqueous extract of Phyllanthus niruri on nimesulide-induced oxidative stress in vivo. Indian J Biochem Biophys 43:299–305
Chatterjee M, Sil PC (2007) Protective role of Phyllanthus niruri against nimesulide induced hepatic damage. Indian J Clin Biochem 22:109–116
Chaves LDS, Nicolau LAD, Silva RO, Barros FCN, Freitas ALP, Aragão KS, Ribeiro RDA, Souza MHLP, Barbosa ALDR, Medeiros JVR (2013) Antiinflammatory and antinociceptive effects in mice of a sulfated polysaccharide fraction extracted from the marine red algae Gracilaria caudata. Immunopharm Immunotoxicol 35:93–100
Costa LS, Fidelis GP, Cordeiro SL, Oliveira RM, Sabry DA, Câmara RBG, Nobre LTDB, Costa MSSP, Almeida-Lima J, Farias EHC, Leite EL, Rocha HAO (2010) Biological activities of sulfated polysaccharides from tropical seaweeds. Biomed Pharmacother 64:21–28
Dedon PC, Tannenbaum SR (2004) Reactive nitrogen species in the chemical biology of inflammation. Arch Biochem Biophys 423:12–22
Figueras A, Estevez F, Laporte JR (1999) New drugs, new adverse drug reactions, and bibliographic databases. Lancet 353:1447–1448
Gallelli L, Ferraro M, Mauro GF, De Fazio S, De Sarro G (2005) Nimesulide-induced hepatotoxicity in a previously healthy woman. Clin Drug Invest 25:421–424
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem 126:131–138
Gurpilhares D d B, Moreira TR, Bueno J d L, Cinelli LP, Mazzola PG, Pessoa A, Sette LD (2016) Algae’s sulfated polysaccharides modifications: potential use of microbial enzymes. Process Biochem 51:989–998
Holt MP, Ju C (2006) Mechanisms of drug-induced liver injury. AAPS J 8:48–54
Hsu CC, Lin CC, Liao TS, Yin MC (2006) Protective effect of s-allyl cysteine and s-propyl cysteine on acetaminophen-induced hepatotoxicity in mice. Food Chem Toxicol 44:393–397
Kang P, Dalvie D, Smith E, Renner M (2009) Bioactivation of lumiracoxib by peroxidases and human liver microsomes: identification of multiple quinone imine intermediates and GSH adducts. Chem Res Toxicol 22:106–117
Kowaltowski AJ, Castilho RF, Vercesi AE (2001) Mitochondrial permeability transition and oxidative stress. FEBS Lett 495:12–15
Kus I, Colakoglu N, Pekmez H, Seckin D, Ogetürk M, Sarsilmaz M (2004) Protective effects of caffeic acid phenethyl ester (CAPE) on carbon tetrachloride-induced hepatotoxicity in rats. Acta Histochem 106:289–297
Leone A, Nie A, Brandon PJ, Sawant S, Piechta LA, Kelley MF, Mark KL, Jim PS, Verheyen G, Johnson MD, Lord PG, Mcmillian MK (2014) Oxidative stress/reactive metabolite gene expression. Signature in rat liver detects idiosyncratic hepatotoxicants. Toxicol Appl Pharmacol 275:189–197
Liu T, Sha K, Zhang L, Liu X, Yang F, Cheng J (2019) Protective effects of alpinetin on lipopolysaccharide/D-Galactosamine-induced liver injury through inhibiting inflammatory and oxidative responses. Microbial Pathogen 126:239–244
Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, De La Cuesta FS (2001) Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 33:123–130
Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ (2007) Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130:2800–2815
Mazraati P, Minaiyan M (2018) Hepatoprotective effect of metadoxine on acetaminophen-induced liver toxicity in mice. Adv Biomed Res 7:67
Merlani G, Fox M, Oehen HP, Cathomas G, Renner EL, Fattinger K, Schnee-Mann M, Kullak-Ublick GA (2001) Fatal hepatoxicity secondary to nimesulide. Eur J Clin Pharmacol 57:321–326
Mihara M, Uchiyama M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86:271–278
Nguyen V, Huang J, Doan V, Lin X, Tang X, Huang Y, Tang A, Yang X, Huang R (2015) Hepatoprotective effects of Yulangsan polysaccharide against nimesulide-induced liver injury in mice. J Ethnopharmacol 172:273–280
Ong MM, Wang AS, Leow KY, Khoo YM, Boelsterli UA (2006) Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2+/− mice. Free Rad Biol Med 40:420–429
Oren A, Taylor JM (1995) The subcellular localization of defensins and myeloperoxidase in human neutrophils: immunocytochemical evidence for azurophil granule heterogeneity. J Lab Clin Med 125:340–347
Qu B, Li QT, Wong KP, Tan TM, Halliwell B (2001) Mechanism of clofibrate hepatotoxicity: mitochondrial damage and oxidative stress in hepatocytes. Free Ras Biol Med 31:659–669
Quinderé ALG, Fontes BP, Vanderlei EDSO, De Queiroz INL, Rodrigues JAG, De Araújo IWF, Jorge RJB, De Menezes DB, Silva AAR, Chaves HV, Evangelista JSAM, Bezerra MM, Benevides NMB (2013) Peripheral antinociception and anti-edematogenic effect of a sulfated polysaccharide from Acanthophora muscoides. Pharmacol Rep 65:600–613
Romero-Gomez M, Santos MN, Fernandez MAO, Fovelo MJ, Suarez-Garcia E, Fernandez MC (1999) Acute cholestatic hepatites induced by nimesulide. Liver 19:164–165
Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, Guarner C, Forné M, Solà R, Castellote J, Rigau J, Laporte JR (2007) Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Ailement Pharmacol Ther 25:1401–1409
Schattner A, Sokolovskaya N, Cohen J (2000) Fatal hepatitis and renal failure during treatment with nimesulide. J Intern Med 247:153–155
Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 24:1992–2005
Silva RO, Pereira Dos Santos GM, Duarte Nicolau LA, Lucetti LT, Macedo Santana AP, De Souza CL, Nogueira Barros FC, Ponte Freitas AL, Ponte Souza MHL, Medeiros JVR (2011) Sulfated-polysaccharide fraction from red algae Gracilaria caudata protects mice gut against ethanol-induced damage. Mar Drugs 9:2188–2200
Singh BK, Tripathi M, Chaudhari BP, Pandey PK, Kakkar P (2012) Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats. PLoS One 7:e0034200
Stadlmann S, Zoller H, Vogel W, Offner FA (2002) COX-2 inhibitor (nimesulide) induced acute liver failure. Virchows Arch 440:553–555
Tan HH, Ong WM, Lai SH, Chow WC (2007) Nimesulide-induced hepatotoxicity and fatal hepatic failure. Singap Med J 48:582–585
Van Steenbergen W, Peeters P, De Bondt J, Staessen D, Büscher H, Laporta T, Roskams T, Desmet V (1998) Nimesulide induced acute hepatitis: evidence from six cases. J Hepatol 29:135–141
Vasconcelos DFP, Pereira da Silva FR, Pinto MSC, Santana LAB, Souza IG, Miranda de Souza LK, Oliveira NCM, Ventura CA, Novaes PD, Barbosa ALR, Medeiros JVR, Mikolasevic I, Mani A, Soares de Oliveira J (2017) Decrease of pericytes is associated with liver disease caused by ligature-induced periodontitis in rats. J Periodontol 88:49–57
Wang Y, Zeng Y, Xu F (2011) Drug safety issues of nimesulide in China-nimesulide-induced liver injury. Pharmacoepidemiol Drug Saf:778–779
Wells ML, Potin P, Craigie JS, Raven JA, Merchant SS, Helliwell KE, Smith AG, Camire ME, Brawley SH (2017) Algae as nutritional and functional food sources: revisiting our understanding. J Appl Phycol 29:949–982
Xu XY, Hu JN, Liu Z, Zhang R, He YF, Hou W, Wang ZQ, Yang G, Li W (2017) Saponins (Ginsenosides) from the leaves of Panax quinquefolius ameliorated acetaminophen-induced hepatotoxicity in mice. J Agric Food Chem 65:3684
Funding
The authors received financial and structural support from the Brazilian Agency for Scientific and Technological Development-CNPq (Brazil) and Federal University of Piauí, UFPI (Brazil).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there is no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Júnior, G.J.D., Lemos, S.I.A., de Brito, T.V. et al. Macromolecule extracted from Gracilaria caudata reduces inflammation and restores hepatic function in nimesulide-induced hepatic damage. J Appl Phycol 32, 1511–1520 (2020). https://doi.org/10.1007/s10811-020-02039-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10811-020-02039-x


