Abstract
Sepsis is related to systemic inflammation and oxidative stress, the primary causes of death in intensive care units. Severe functional abnormalities in numerous organs can arise due to sepsis, with acute lung damage being the most common and significant morbidity. Spirulina, blue-green algae with high protein, vitamins, phycocyanin, and antioxidant content, shows anti-inflammatory properties by decreasing the release of cytokines. In addition, zinc (Zn) and selenium (Se) act as an antioxidant by inhibiting the oxidation of macromolecules, as well as the inhibition of the inflammatory response. The current study aimed to examine the combined properties of Zn, Se, and phycocyanin oligopeptides (ZnSePO) against lipopolysaccharide-D-galactosamine (LPS-GalN)-induced septic lung injury through survival rate, inflammatory, and histopathological changes in Balb/c mice. A total of 30 mice were allocated into three groups: normal control, LPS-GalN (100 ng of LPS plus 8 mg of D-galactosamine), LPS-GalN + ZnSePO (ZnPic, 52.5 µg/mL; SeMet, 0.02 µg/mL; and phycocyanin oligopeptide (PO), 2.00 mg/mL; at 1 h before the injection of LPS-GalN). Lung tissue from mice revealed noticeable inflammatory reactions and typical interstitial fibrosis after the LPS-GalN challenge. LPS-GalN-induced increased mortality rate and levels of IL-1, IL-6, IL-10, TGF-β, TNF-α, and NF-κB in lung tissue. Moreover, treatment of septic mice LPS-GalN + ZnSePO reduced mortality rates and inflammatory responses. ZnSePO considerably influenced tissue cytokine levels, contributing to its capacity to minimize acute lung injury (ALI) and pulmonary inflammation and prevent pulmonary edema formation in LPS-GalN-injected mice. In conclusion, ZnSePO treatment enhanced the survival rate of endotoxemia mice via improving inflammation and oxidative stress, indicating a possible therapeutic effect for patients with septic infections.
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References
P’erez-Hernandez EG, Delgado-Coello B, Luna-Reyes I, Mas-Oliva J (2021) New insights into lipopolysaccharide inactivation mechanisms in sepsis. Biomed Pharmacother 141:111890. https://doi.org/10.1016/j.biopha.2021.111890
Seemann S, Zohles F, Lupp A (2017) Comprehensive comparison of three different animal models for systemic inflammation. J Biomed Sci 24(1):60. https://doi.org/10.1186/s12929-017-0370-8
Azambuja JH, Mancuso RI, Della Via FI, Torello CO, Saad STO (2022) Protective effect of green tea and epigallocatechin-3-gallate in a LPS-induced systemic inflammation model. J Nutr Biochem 101:108920. https://doi.org/10.1016/j.jnutbio.2021.108920
Keller M, Manzocchi E, Rentsch D, Lugarà R, Giller K (2021) Antioxidant and inflammatory gene expression profiles of bovine peripheral blood mononuclear cells in response to Arthrospira platensis before and after LPS challenge. Antioxidants (Basel) 10(5):814. https://doi.org/10.3390/antiox10050814
Recknagel P, Gonnert FA, Halilbasic E, Gajda M, Jbeily N, Lupp A, Rubio I, Claus RA, Kortgen A, Trauner M, Singer M, Bauer M (2013) Mechanisms and functional consequences of liver failure substantially differ between endotoxaemia and faecal peritonitis in rats. Liver Int 33(2):283–293. https://doi.org/10.1111/liv.12012
Hajati H, Zaghari M, Oliveira HC (2020) Arthrospira (Spirulina) Platensis can be considered as a probiotic alternative to reduce heat stress in laying Japanese quails. Braz J Poult Sci 22:1–8. https://doi.org/10.1590/1806-9061-2018-0977
Pham TX, Lee Y, Bae M, Hu S, Kang H (2019) Spirulina supplementation in a mouse model of diet-induced liver fibrosis reduced the pro-inflammatory response of splenocytes. Br J Nutr 121:748–755. https://doi.org/10.1017/S0007114519000126
Grover P, Bhatnagar A, Kumari N, Bhatt AN, Nishad DK, Purkayastha J (2021) C-Phycocyanin-a novel protein from Spirulina platensis- in vivo toxicity, antioxidant and immunomodulatory studies. Saudi J Biol Sci 28(3):1853–1859. https://doi.org/10.1016/j.sjbs.2020.12.037
Silveira ST, Burkert JF, Costa JAV, Burkert CAV, Kalil SJ (2007) Optimization of phycocyanin extraction from Spirulina platensis using factorial design. Bioresour Technol 98(8):1629–1634. https://doi.org/10.1016/j.biortech.2006.05.050
Wang H, Liu Y, Gao X, Carter CL, Liu ZR (2007) The recombinant beta subunit of C-phycocyanin inhibits cell proliferation and induces apoptosis. Cancer Lett 247(1):150–158. https://doi.org/10.1016/j.canlet.2006.04.002
Bannu SM, Lomada D, Gulla S, Chandrasekhar T, Reddanna P, Reddy MC (2019) Potential therapeutic applications of C-phycocyanin. Curr Drug Metab 20(12):967–976. https://doi.org/10.2174/1389200220666191127110857
Hamedifard Z, Farrokhian A, Reiner Ž, Bahmani F, Asemi Z, Ghotbi M, Taghizadeh M (2020) The effects of combined magnesium and zinc supplementation on metabolic status in patients with type 2 diabetes mellitus and coronary heart disease. Lipids Health Dis 19(1):112. https://doi.org/10.1186/s12944-020-01298-4
Visalakshy J, Surendran S, Pillai MPG, Rajendran A, Sherif AA (2017) Could plasma zinc be a predictor for mortality and severity in sepsis syndrome? Int J Res Med Sci 5(9):3929–3934. https://doi.org/10.18203/2320-6012.ijrms20173956
Ibs KH, Rink L (2003) Zinc-altered immune function. J Nutr 133:1452S-S1456. https://doi.org/10.1093/jn/133.5.1452S
Al-Rasheed NM, Attia HA, Mohamed RA, Al-Rasheed NM, Al-Amin MA (2013) Preventive effects of selenium yeast, chromium picolinate, zinc sulfate and their combination on oxidative stress, inflammation, impaired angiogenesis and atherogenesis in myocardial infarction in rats. J Pharm Pharm Sci 16:848–867. https://doi.org/10.18433/j34c7n
Ganatra HA, Varisco BM, Harmon K, Lahni P, Opoka A, Wong HR (2017) Zinc supplementation leads to immune modulation and improved survival in a juvenile model of murine sepsis. Innate Immun 23(1):67–76. https://doi.org/10.1177/1753425916677073
Li M, Zhang Y, Li S (2020) Effects of selenium deficiency on testis development and autophagy in chicks. Ital J Anim Sci 19(1):753–761. https://doi.org/10.1080/1828051X.2020.1786739
Cao C, Li X, Qin L, Luo J, Zhang M, Ou Z, Wang K (2018) High selenium yeast mitigates aluminum-induced cerebral inflammation by increasing oxidative stress and blocking NO production. Biometals 31(5):835–843. https://doi.org/10.1007/s10534-018-0128-0
Liu J, Wang S, Zhang Q, Li X, Xu S (2020) Selenomethionine alleviates LPS-induced chicken myocardial inflammation by regulating the miR-128-3p-p38 MAPK axis and oxidative stress. Metallomics 12(1):54–64. https://doi.org/10.1039/c9mt00216b
Fan R, Yao H, Cao C, Zhao X, Khalid A, Zhao J, Zhang Z, Xu S (2017) Gene silencing of selenoprotein K induces inflammatory response and activates heat shock proteins expression in chicken myoblasts. Biol Trace Elem Res 180(1):135–145. https://doi.org/10.1007/s12011-017-0979-1
Cao C, Luo J, Li X, Zhang M, Zhang H, Zhang J, Wang K (2018) Selenium-rich yeast protects against aluminum-induced renal inflammation and ionic disturbances. Biol Trace Elem Res 186(2):467–473. https://doi.org/10.1007/s12011-018-1324-z
Qu J, Wang W, Zhang Q, Li S (2020) Inhibition of lipopolysaccharide-induced inflammation of chicken liver tissue by selenomethionine via TLR4-NF-κB-NLRP3 signaling pathway. Biol Trace Elem Res 195(1):205–214. https://doi.org/10.1007/s12011-019-01841-0
Thoen RU, Barther NN, Schemitt E, Bona S, Fernandes S, Coral G, Marroni NP, Tovo C, Guedes RP, Porawski M (2019) Zinc supplementation reduces diet-induced obesity and improves insulin sensitivity in rats. Appl Physiol Nutr Metab 44(6):580–586. https://doi.org/10.1139/apnm-2018-0519
Chen T, Wong YS (2008) In vitro antioxidant and antiproliferative activities of selenium-containing phycocyanin from selenium-enriched Spirulina platensis. J Agric Food Chem 56(12):4352–4358. https://doi.org/10.1021/jf073399k
Uckun FM, Carlson J, Orhan C, Powell J, Pizzimenti NM, Hv W, Ozercan IH, Mand V, Sahin K (2020) Rejuveinix shows a favorable clinical safety profile in human subjects and exhibits potent preclinical protective activity in the lipopolysaccharide-galactosamine mouse model of acute respiratory distress syndrome and multi-organ failure. Front Pharmacol 11:594321. https://doi.org/10.3389/fphar.2020.594321
Korneev KV (2019) Mouse models of sepsis and septic shock. Mol Biol (Mosk) 53(5):799–814. https://doi.org/10.1134/S0026898419050100
Sahin K, Orhan C, Kucuk O, Tuzcu M, Sahin N, Ozercan IH, Sylla S, Ojalvo SP, Komorowski JR (2022) Effects of magnesium picolinate, zinc picolinate, and selenomethionine co-supplementation on reproductive hormones, and glucose and lipid metabolism-related protein expressions in male rats fed a high-fat diet. Food Chem: Mole Sci 4:100081. https://doi.org/10.1016/j.fochms.2022.100081
Benedetti S, Benvenuti F, Pagliarani S, Francogli S, Scoglio S, Canestrari F (2004) Antioxidant properties of a novel phycocyanin extract from the blue-green alga Aphanizomenon flos-aquae. Life Sci 75(19):2353–2362. https://doi.org/10.1016/j.lfs.2004.06.004
Hassan F, Mobarez S, Mohamed M, Attia Y, Mekawy A, Mahrose K (2021) Zinc and/or selenium enriched spirulina as antioxidants in growing rabbit diets to alleviate the deleterious impacts of heat stress during summer season. Animals (Basel) 11(3):756. https://doi.org/10.3390/ani11030756
Castel T, Theron M, Pichavant-Rafini K, Guernec A, Joublin-Delavat A, Gueguen B, Leon K (2021) Can selenium-enriched spirulina supplementation ameliorate sepsis outcomes in selenium-deficient animals? Physiol Rep 9(14):e14933. https://doi.org/10.14814/phy2.14933
Finamore A, Palmery M, Bensehaila S, Peluso I (2017) Antioxidant, immunomodulating, and microbial-modulating activities of the sustainable and ecofriendly spirulina. Oxid Med Cell Longev 2017:3247528. https://doi.org/10.1155/2017/3247528
Gargouri M, Soussi A, Akrouti A, Magné C, El Feki A (2018) Ameliorative effects of Spirulina platensis against lead-induced nephrotoxicity in newborn rats: modulation of oxidative stress and histopathological changes. EXCLI J 17:215–232. https://doi.org/10.17179/excli2017-1016
Nasirian F, Dadkhah M, Moradi-kor N, Obeidavi Z (2018) Effects of Spirulina platensis microalgae on antioxidant and anti-inflammatory factors in diabetic rats. Diabetes Metabo Syndr Obes 11:375–380. https://doi.org/10.2147/DMSO.S172104
Abdel-Daim M, El-Bialy BE, Rahman HGA, Radi AM, Hefny HA, Hassan AM (2016) Antagonistic effects of Spirulina platensis against sub-acute deltamethrin toxicity in mice: biochemical and histopathological studies. Biomed Pharmacother 77:79–85. https://doi.org/10.1016/j.biopha.2015.12.003
Ou Y, Lin L, Yang X, Pan Q, Cheng X (2013) Antidiabetic potential of phycocyanin: effects on KKAy mice. Pharm Biol 51:539–544. https://doi.org/10.3109/13880209.2012.747545
Labunskyy VM, Hatfield DL, Vadim N, Gladyshe VN (2014) Selenoproteins: molecular pathways and physiological roles. Physiol Rev 94:739–777. https://doi.org/10.1152/physrev.00039.2013
Prasad AS, Bao B (2019) Molecular mechanisms of zinc as a pro-antioxidant mediator: clinical therapeutic implications. Antioxidants 8:164. https://doi.org/10.3390/antiox8060164
Powell SR (2000) The antioxidant properties of zinc. J Nutr 130(5S):1447S-S1454. https://doi.org/10.1093/jn/130.5.1447S
Alissa EM, Bahijri SM, Lamb DJ, Gordon A, Ferns GAA (2004) The effects of coadministration of dietary copper and zinc supplements on atherosclerosis, antioxidant enzymes and indices of lipid peroxidation in the cholesterol-fed rabbit. Int J Exp Pathol 85(5):265–275. https://doi.org/10.1111/j.0959-9673.2004.00392.x
Utomo MT, Sudarmo SM, Sudiana K (2020) Zinc supplementation in cytokine regulation during LPS-induced sepsis in rodent. J Int Dent Med Res 13(1):46–50
Michalak I, Mahrose KM (2020) Seaweeds, intact and processed, as a valuable component of poultry feed. J Mar Sci Eng 8(8):620. https://doi.org/10.3390/jmse8080620
Gabr GA, El-Sayed SM, Hikal MS (2020) Antioxidant activities of phycocyanin: a bioactive compound from Spirulina platensis. J Pharm Res Int 32(2):73–85. https://doi.org/10.9734/JPRI/2020/v32i230407
Hu X, Chi Q, Liu Q, Wang D, Zhang Y, Li S (2019) Atmospheric H2S triggers immune damage by activating the TLR-7/MyD88/NF-kB pathway and NLRP3 inflammasome in broiler thymus. Chemosphere 237:124427. https://doi.org/10.1016/j.chemosphere.2019.124427
Wessels I, Cousins RJ (2015) Zinc dyshomeostasis during polymicrobial sepsis in mice involves zinc transporter Zip14 and can be overcome by zinc supplementation. Am J Physiol Gastrointest Liver Physiol 309:G768–G778. https://doi.org/10.1152/ajpgi.00179.2015
Shalihat A, Hasanah AN, Mutakin LR, Budiman A, Gozali D (2021) The role of selenium in cell survival and its correlation with protective effects against cardiovascular disease: a literature review. Biomed Pharmacother 134:111125. https://doi.org/10.1016/j.biopha.2020.111125
Huang TS, Shyu YC, Chen HY, Lin LM, Lo CY, Yuan SS, Chen PJ (2013) Effect of parenteral selenium supplementation in critically ill patients: a systematic review and metaanalysis. PLoS ONE 8(1):e54431. https://doi.org/10.1371/journal.pone.0054431
Landucci F, Mancinelli P, De Gaudio AR (2014) Selenium supplementation in critically ill patients: a systematic review and meta-analysis. J Crit Care 29(1):150–156. https://doi.org/10.1016/j.jcrc.2013.08.017
Nithiananthan S, Crawford A, Knock JC, Lambert DW, Whawell SA (2017) Physiological fluid flow moderates fibroblast responses to TGF-β1. J Cell Biochem 118:878–890. https://doi.org/10.1002/jcb.25767
Mahmoud YI, Abd El-Ghffar EA (2019) Spirulina ameliorates aspirin-induced gastric ulcer in albino mice by alleviating oxidative stress and inflammation. Biomed Pharmacother 109:314–321. https://doi.org/10.1016/j.biopha.2018.10.118
Luo J, Li X, Li X, He Y, Zhang M, Cao C, Wang K (2018) Selenium-rich yeast protects against aluminum-induced peroxidation of lipide and inflammation in mice liver. Biometals 31(6):1051–1059. https://doi.org/10.1007/s10534-018-0150-2
Wang J, Liu Z, He X, Lian S, Liang J, Yu D, Sun D, Wu R (2018) Selenium deficiency induces duodenal villi cell apoptosis via an oxidative stress-induced mitochondrial apoptosis pathway and an inflammatory signaling-induced death receptor pathway. Metallomics 10:1390–1400. https://doi.org/10.1039/c8mt00142a
Wang X, Yang B, Cao HL, Wang RY, Lu ZY, Chi RF, Li B (2021) Selenium supplementation protects against lipopolysaccharide-induced heart injury via sting pathway in mice. Biol Trace Elem Res 199(5):1885–1892. https://doi.org/10.1007/s12011-020-02295-5
Knoell DL, Julian MW, Bao S, Besecker B, Macre JE, Leikauf GD, DiSilvestro RA, Crouser ED (2009) Zinc deficiency increases organ damage and mortality in a murine model of polymicrobial sepsis. Crit Care Med 37(4):1380–1388. https://doi.org/10.1097/CCM.0b013e31819cefe4
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This work was supported by KOSGEB (Elazig, Turkey) and the Turkish Academy of Sciences (KS).
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K.S. designed the study; P.O., B.E., and C.O. performed the experiment; P.O. drafted the study; and K.S. edited the manuscript.
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Oner, P., Er, B., Orhan, C. et al. Combination of Phycocyanin, Zinc, and Selenium Improves Survival Rate and Inflammation in the Lipopolysaccharide-Galactosamine Mouse Model. Biol Trace Elem Res 201, 1377–1387 (2023). https://doi.org/10.1007/s12011-022-03433-x
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DOI: https://doi.org/10.1007/s12011-022-03433-x