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The targets of β-sitosterol as a novel therapeutic against cardio-renal complications in acute renal ischemia/reperfusion damage

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Abstract

This research is the first to use β-sitosterol on myocardial and renal tissues in renal ischemia/reperfusion (IR) damage. Female Wistar rats were randomly divided into three groups: control (sham), renal IR (50 min ischemia – 3 h reperfusion), and renal IR + 150 mg/kg/p.o. β-sitosterol (the rats were treated with β-sitosterol orally once 1 h before the IR procedure). β-Sitosterol pretreatment caused an increase in superoxide dismutase and glutathione activities and a decrease in malondialdehyde levels in the kidney and heart. Moreover, it alleviated histopathological changes and downregulated the levels of tumor necrosis factor-alpha and interleukin-6 and upregulated the levels of endothelial nitric oxide synthase. As conclusion, the potential of β-sitosterol for renal and cardiac necrosis and apoptosis appears to act by limiting inflammatory response and oxidative stress. Thus, the potential of this compound is noteworthy and may serve as a potential therapeutic in the treatment of acute organ damages due to renal IR.

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References

  • Amina M, Amna T, Al-Musayeib N, Zabin SA, Hassan MS, Khil MS (2017) Encapsulation of β-sitosterol in polyurethane by sol-gel electrospinning. Appl Biochem Biotechnol 182(2):624–634

    CAS  PubMed  Google Scholar 

  • Atolani O, Oguntoye H, Areh ET, Adeyemi OS, Kambizi L (2019) Chemical composition, anti-toxoplasma, cytotoxicity, antioxidant, and anti-inflammatory potentials of Cola gigantea seed oil. Pharm Biol 57(1):154–160

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bazzano T, Restel TI, Porfirio LC, Souza ASD, Silva IS (2015) Renal biomarkers of male and female Wistar rats (Rattus norvegicus) undergoing renal ischemia and reperfusion. Acta Cir Bras 30(4):277–288

    PubMed  Google Scholar 

  • Brinton EA, Hopkins PN, Hegele RA, Geller AS, Polisecki EY, Diffenderfer MR, Schaefer EJ (2018) The association between hypercholesterolemia and sitosterolemia, and report of a sitosterolemia kindred. J Clin Lipidol 12(1):152–161

    PubMed  Google Scholar 

  • Costa RT, Araújo OR, Brunialti MKC, Assunção MSC, Azevedo LCP, Freitas F, Salomão R (2019) T helper type cytokines in sepsis: time-shared variance and correlation with organ dysfunction and hospital mortality. Braz J Infect Dis 23(2):79–85

    PubMed  Google Scholar 

  • Erpicum P, Rowart P, Defraigne JO, Krzesinski JM, Jouret F (2018) What we need to know about lipid-associated injury in case of renal ischemia-reperfusion. Am J Physiol Ren Physiol 315(6):F1714–F1719

    CAS  Google Scholar 

  • Erukainure OL, Chukwuma CI, Matsabisa MG, Salau VF, Koorbanally NA, Islam MS (2019) Buddleja saligna Willd (Loganiaceae) inhibits angiotensin-converting enzyme activity in oxidative cardiopathy with concomitant modulation of nucleotide hydrolyzing enzymatic activities and dysregulated lipid metabolic pathways. J Ethnopharmacol 30:112358

    Google Scholar 

  • Gupta R, Sharma AK, Dobhal MP, Sharma MC, Gupta RS (2011) Antidiabetic and antioxidant potential of β-sitosterol in streptozotocin-induced experimental hyperglycemia. J Diabetes 3(1):29–37

    CAS  PubMed  Google Scholar 

  • Gutendorf B, Westendorf J (2001) Comparison of an array of in vitro assays for the assessment of the estrogenic potential of natural and synthetic estrogens, phytoestrogens and xenoestrogens. Toxicology 166(1–2):79–89

    CAS  PubMed  Google Scholar 

  • Haushalter KJ, Schilling JM, Song Y, Sastri M, Perkins GA, Strack S, Taylor SS, Patel HH (2019) Cardiac ischemia/reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIα. Am J Physiol Heart Circ Physiol 317(6):H1231–H1242

    CAS  PubMed  PubMed Central  Google Scholar 

  • Honarpisheh M, Foresto-Neto O, Steiger S, Kraft F, Koehler P, von Rauchhaupt E, Potempa J, Adamowicz K, Koziel J, Lech M (2018) Aristolochic acid I determine the phenotype and activation of macrophages in acute and chronic kidney disease. Sci Rep 8(1):12169

    PubMed  PubMed Central  Google Scholar 

  • Hou L, Chen G, Feng B, Zhang XS, Zheng XF, Xiang Y, Zhao GY, Min WP (2016) Small interfering RNA targeting TNF-α gene significantly attenuates renal ischemia-reperfusion injury in mice. J Huazhong Univ Sci Technolog Med Sci 36(5):634–638

    CAS  PubMed  Google Scholar 

  • Ikewuchi JC (2012) Alteration of plasma biochemical, haematological and ocular oxidative indices of alloxan induced diabetic rats by aqueous extract of Tridax procumbens Linn (Asteraceae). EXCLI J 11:291–308

    PubMed  PubMed Central  Google Scholar 

  • Jiang L, Zhao X, Xu J, Li C, Yu Y, Wang W, Zhu L (2019) The protective effect of dietary phytosterols on cancer risk: a systematic meta-analysis. J Oncol 2019:7479518

    PubMed  PubMed Central  Google Scholar 

  • Kim HJ, Yoon YM, Lee JH, Lee SH (2019) Protective role of fucoidan on cisplatin-mediated ER stress in renal proximal tubule epithelial cells. Anticancer Res 39(10):5515–5524

    CAS  PubMed  Google Scholar 

  • Kleinbongard P, Heusch G (2015) Extracellular signalling molecules in the ischaemic/reperfused heart - druggable and translatable for cardioprotection? Br J Pharmacol 172:2010–2025

    CAS  PubMed  Google Scholar 

  • Kloer HU, Belardinelli R, Ruchong O, Rosenfeldt F (2019) Combining ubiquinol with a statin may benefit hypercholesterolaemic patients with chronic heart failure. Heart Lung Circ 29(2):188–195

    PubMed  Google Scholar 

  • Kuo MTH, Beckman JS, Shaw CA (2019) Neuroprotective effect of CuATSM on neurotoxin-induced motor neuron loss in an ALS mouse model. Neurobiol Dis 130:104495

    CAS  PubMed  Google Scholar 

  • Lei C, Berra L, Rezoagli E, Yu B, Dong H, Yu S, Hou L, Chen M, Chen W, Wang H, Zheng Q, Shen J, Jin Z, Chen T, Zhao R, Christie E, Sabbisetti VS, Nordio F, Bonventre JV, Xiong L, Zapol WM (2018) Nitric oxide decreases acute kidney injury and stage 3 chronic kidney disease after cardiac surgery. Am J Respir Crit Care Med 198(10):1279–1287

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lekawanvijit S (2018) Cardiotoxicity of uremic toxins: a driver of cardiorenal syndrome. Toxins (Basel) 10(9):E352

    Google Scholar 

  • Lishchuk SV, Kazantseva IA, Dubova EA, Pavlov KA, Katunina OR, Borbat AM, Udalov YD (2019) Morphological features of IgG4-related lesions at various sites. Arkh Patol 81(5):22–29

    CAS  PubMed  Google Scholar 

  • Liu SS, Chen YY, Wang SX, Yu Q (2020) Protective effect of dabrafenib on renal ischemia-reperfusion injury in vivo and in vitro. Biochem Bioph Res Co 522(2):395–401

    CAS  Google Scholar 

  • Meyer IS, Jungmann A, Dieterich C, Zhang M, Lasitschka F, Werkmeister S, Haas J, Müller OJ, Boutros M, Nahrendorf M, Katus HA, Hardt SE, Leuschner F (2017) The cardiac microenvironment uses non-canonical WNT signaling to activate monocytes after myocardial infarction. EMBO Mol Med 9(9):1279–1293

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mishra S, Srivastava N, Sundaresan V, Shanker K (2019) Amruthapala (Decalepis arayalpathra (J. Joseph and V. Chandras.) Venter): a comprehensive review on diversity, therapeutic uses, and valorization of bioactive constituents. Curr Pharm Biotechnol 20(5):376–389

    CAS  PubMed  Google Scholar 

  • Moslemi F, Taheri P, Azimipoor M, Ramtin S, Hashemianfar M, Momeni-Ashjerdi A, Eshraghi-Jazi F, Talebi A, Nasri H, Nematbakhsh M (2016) Effect of angiotensin II type 1 receptor blockade on kidney ischemia/reperfusion; a gender-related difference. J Ren Inj Prev 5(3):140–143

    CAS  PubMed  Google Scholar 

  • Nepal VP, Mgbere O, Banerjee D, Arafat R (2012) Determinants of fruits and vegetables consumption among persons with doctor-diagnosed chronic diseases. J Prim Care Community Health 3(2):132–141

    PubMed  Google Scholar 

  • Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, Fulcher G, Desai M, Li Q, Deng H, Rosenthal N, Jardine MJ, Bakris G, Perkovic V (2018) Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation 138(15):1537–1550

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ono S, Matsui H, Noda M, Kasuda S, Yada N, Yoshimoto K, Akiyama M, Miyata T, Sugimoto M, Nishio K (2019) Functional regulation of von Willebrand factor ameliorates acute ischemia-reperfusion kidney injury in mice. Sci Rep 9(1):14453

    PubMed  PubMed Central  Google Scholar 

  • Parvez MK, Al-Dosari MS, Arbab AH, Alam P, Alsaid MS, Khan AA (2019) Hepatoprotective effect of Solanum surattense leaf extract against chemical- induced oxidative and apoptotic injury in rats. BMC Complement Altern Med 19(1):154

    PubMed  PubMed Central  Google Scholar 

  • Radika MK, Viswanathan P, Anuradha CV (2013) Nitric oxide mediates the insulin sensitizing effects of β-sitosterol in high fat diet-fed rats. Nitric Oxide 32:43–53

    CAS  PubMed  Google Scholar 

  • Sherif IO, Al-Shaalan NH (2018) Vildagliptin attenuates hepatic ischemia/reperfusion injury via the TLR4/NF-κB signaling pathway. Oxidative Med Cell Longev 14:3509091

    Google Scholar 

  • Shi C, Wu F, Zhu X, Xu J (2013) Incorporation of β-sitosterol into the membrane increases resistance to oxidative stress and lipid peroxidation via estrogen receptor-mediated PI3K/GSK3β signaling. BBA-General Subjects 1830(3):2538–2544

    CAS  PubMed  Google Scholar 

  • Türkoğlu S, Celik S, Keser S, Türkoğlu İ, Yilmaz Ö (2017) The effect of Pistacia terebinthus extract on lipid peroxidation, glutathione, protein, and some enzyme activities in tissues of rats undergoing oxidative stress. Turk J Zool 41(1):82–88

    Google Scholar 

  • Vivancos M, Moreno JJ (2005) β-Sitosterol modulates antioxidant enzyme response in RAW 264.7 macrophages. Free Radic Biol Med 39(1):91–97

    CAS  PubMed  Google Scholar 

  • Wang X, Yang L, Kang L, Li J, Yang L, Zhang J, Liu J, Zhu M, Zhang Q, Shen Y, Qi Z (2017) Metformin attenuates myocardial ischemia-reperfusion injury via up-regulation of antioxidant enzymes. PLoS One 12(8):e0182777

    PubMed  PubMed Central  Google Scholar 

  • Wong HS, Chen N, Leong PK, Ko KM (2014) β-Sitosterol enhances cellular glutathione redox cycling by reactive oxygen species generated from mitochondrial respiration: protection against oxidant injury in H9c2 cells and rat hearts. Phytother Res 28(7):999–1006

    CAS  PubMed  Google Scholar 

  • Wong HS, Leong PK, Chen J, Leung HY, Chan WM, Ko KM (2016) β-Sitosterol increases mitochondrial electron transport by fluidizing mitochondrial membranes and enhances mitochondrial responsiveness to increasing energy demand by the induction of uncoupling in C2C12 myotubes. J Funct Foods 23:253–260

    CAS  Google Scholar 

  • Wu MY, Yiang GT, Liao WT, Tsai AP, Cheng YL, Cheng PW, Li CY, Li CJ (2018) Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem 46(4):1650–1667

    CAS  PubMed  Google Scholar 

  • Xu Z, Zhao K, Han P, Qi X, Zhang W, Niu T (2017) Octreotide ameliorates renal ischemia/reperfusion injury via antioxidation and anti-inflammation. Transplant Proc 8:1916–1922

    Google Scholar 

  • Yin Y, Liu X, Liu J, Cai E, Zhu H, Li H, Zhang L, Li P, Zhao Y (2018) Beta-sitosterol and its derivatives repress lipopolysaccharide/d-galactosamine-induced acute hepatic injury by inhibiting the oxidation and inflammation in mice. Bioorg Med Chem Lett 28(9):1525–1533

    CAS  PubMed  Google Scholar 

  • Zankar S, Rodriguez RA, Vinas JL, Burns KD (2019) The therapeutic effects of microRNAs in preclinical studies of acute kidney injury: a systematic review protocol. Syst Rev 8(1):235

    PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Liu M, Yang Y, Cao J, Mi W (2019) Dexmedetomidine exerts a protective effect on ischemia-reperfusion injury after hepatectomy: a prospective, randomized, controlled study. J Clin Anesth 25:109631

    Google Scholar 

  • Zheng Z, Deng G, Qi C, Xu Y, Liu X, Zhao Z, Zhang Z, Chu Y, Wu H, Liu J (2019) Porous Se@SiO2 nanospheres attenuate ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) and inflammation by antioxidative stress. Int J Nanomedicine 27(14):215–229

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Author contribution statement

All the experiments were carried out by using the infrastructure of the Biology Department of Ataturk University and East Anatolia Research and Application Center (DAYTAM) with the contribution of the authors. Authors declared that the research and the experiments were done by the participation of the researchers in the manuscript.

KK and FG constructed the hypothesis and designed the study. They planned the methodology to reach the conclusion and interpreted the data and finally wrote the paper. OC and AK organized and supervised the histopathological assessments. FA, AY, and KK carried out the oxidative stress and inflammation assays. OC, KK, FG, FA, and AY drafted and revised the work. OC, ZK, FA, AY, and HA performed the experiments and contributed to the data acquisition and data management processes. All authors discussed the results, contributed to the final manuscript, and approved the manuscript. All authors provided critical feedback for the revision of the manuscript. They also reviewed the article before resubmission not only for spelling and grammar but also for its intellectual content.

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Correspondence to Ozge Cakmak.

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Experiments were performed according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1996). All experimental procedures were approved by the Atatürk University Local Ethics Committee for Animal Experiments (No. 194, 04.11.2019).

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The authors declare that they have no conflict of interest.

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Koc, K., Geyikoglu, F., Cakmak, O. et al. The targets of β-sitosterol as a novel therapeutic against cardio-renal complications in acute renal ischemia/reperfusion damage. Naunyn-Schmiedeberg's Arch Pharmacol 394, 469–479 (2021). https://doi.org/10.1007/s00210-020-01984-1

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  • DOI: https://doi.org/10.1007/s00210-020-01984-1

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