Evaluation of the efficacy of silymarin and dexmedetomidine on kidney and lung tissue in the treatment of sepsis in rats with cecal perforation

Yavuz,Aydin; Küçük,Ayşegül; Ergörün,Aydan İremnur; Dursun,Ali Doğan; Yiğman,Zeynep; Alkan,Metin; Arslan,Mustafa

doi:10.3892/etm.2024.12530

Evaluation of the efficacy of silymarin and dexmedetomidine on kidney and lung tissue in the treatment of sepsis in rats with cecal perforation

Authors:
- Aydin Yavuz
- Ayşegül Küçük
- Aydan İremnur Ergörün
- Ali Doğan Dursun
- Zeynep Yiğman
- Metin Alkan
- Mustafa Arslan
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Affiliations: Department of General Surgery, Faculty of Medicine, Gazi University, Ankara 06510, Turkey, Department of Physiology, Faculty of Medicine, Kutahya Health Science University, Kutahya 43020, Turkey, Department of Anesthesiology and Reanimation, Faculty of Medicine, Gazi University, Ankara 06510, Turkey, Department of Physiology, Faculty of Medicine, Atılım University, Ankara 06830, Turkey, Department of Histology and Embryology, Faculty of Medicine, Gazi University, Ankara 06510, Turkey
Published online on: April 3, 2024 https://doi.org/10.3892/etm.2024.12530
Article Number: 242
Copyright: © Yavuz et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Sepsis is a systemic inflammatory response syndrome that develops in the host against microorganisms. This response develops away from the primary infection site and results in end‑organ damage. The present study aimed to investigate the protective and therapeutic effects on lung and kidney tissue of silymarin (S) and dexmedetomidine (DEX) applied 1 h before and after sepsis induced by the cecal ligation and puncture (CLP) method in rats. A total of 62 rats was randomly divided into eight groups: i) Control (n=6); ii) cecal perforation (CLP; n=8); iii) S + CLP (n=8; S + CLP; S administered 1 h before CPL); iv) CLP + S (n=8; S administered 1 h after CLP); v) DEX + CLP (n=8; D + CLP; DEX administered 1 h before CLP); vi) CLP + D (n=8; DEX administered 1 h after CLP); vii) SD + CLP (n=8; S and DEX administered 1 h before CLP) and viii) CLP + SD (n=8; S and DEX administered 1 h after CLP). After the cecum filled with stool, it was tied with 3/0 silk under the ileocecal valve and the anterior surface of the cecum was punctured twice with an 18‑gauge needle. A total of 100 mg/kg silymarin and 100 µg/kg DEX were administered intraperitoneally to the treatment groups. Lung and kidney tissue samples were collected to evaluate biochemical and histopathological parameters. In the histopathological examination, all parameters indicating kidney injury; interstitial edema, peritubular capillary dilatation, vacuolization, ablation of tubular epithelium from the basement membrane, loss of brush border in the proximal tubule epithelium, cell swelling and nuclear defragmentation; were increased in the CLP compared with the control group. Silymarin administration increased kidney damage, including ablation of tubular epithelium from the basement membrane, compared with that in the CLP group. DEX significantly reduced kidney damage compared with the CLP and silymarin groups. The co‑administration of DEX + silymarin decreased kidney damage, although it was not as effective as DEX‑alone. To conclude, intraperitoneal DEX ameliorated injury in CLP rats. DEX + silymarin partially ameliorated injury but silymarin administration increased damage. As a result, silymarin has a negative effects with this dosage and DEX has a protective effect. In the present study, it was determined that using the two drugs together had a greater therapeutic effect than silymarin and no differences in the effects were not observed any when the application times of the agents were changed.

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1	Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, et al: Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 47:1181–1247. 2021.PubMed/NCBI View Article : Google Scholar
2	Beisel WR: Metabolic response to infection. Annu Rev Med. 26:9–20. 1975.PubMed/NCBI View Article : Google Scholar
3	Dyck B, Unterberg M, Adamzik M and Koos B: The impact of pathogens on sepsis prevalence and outcome. Pathogens. 13(89)2024.PubMed/NCBI View Article : Google Scholar
4	Aziz M, Jacob A, Yang WL, Matsuda A and Wang P: Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol. 93:329–342. 2013.PubMed/NCBI View Article : Google Scholar
5	Chen XH, Yin YJ and Zhang JX: Sepsis and immune response. World J Emerg Med. 2:88–92. 2011.PubMed/NCBI
6	Arina P and Singer M: Pathophysiology of sepsis. Curr Opin Anaesthesiol. 34:77–84. 2021.PubMed/NCBI View Article : Google Scholar
7	Fleischmann-Struzek C, Mellhammar L, Rose N, Cassini A, Rudd KE, Schlattmann P, Allegranzi B and Reinhart K: Incidence and mortality of hospital- and ICU-treated sepsis: Results from an updated and expanded systematic review and meta-analysis. Intensive Care Med. 46:1552–1562. 2020.PubMed/NCBI View Article : Google Scholar
8	Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, Colombara DV, Ikuta KS, Kissoon N, Finfer S, et al: Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the global burden of disease study. Lancet. 395:200–211. 2020.PubMed/NCBI View Article : Google Scholar
9	Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, Gruendling M, Huhle G, Jaschinski U, John S, et al: Epidemiology of sepsis in Germany: Results from a national prospective multicenter study. Intensive Care Med. 33:606–618. 2007.PubMed/NCBI View Article : Google Scholar
10	Karlsson S, Varpula M, Ruokonen E, Pettilä V, Parviainen I, Ala-Kokko TI, Kolho E and Rintala EM: Incidence, treatment, and outcome of severe sepsis in ICU-treated adults in Finland: The Finnsepsis study. Intensive Care Med. 33:435–443. 2007.PubMed/NCBI View Article : Google Scholar
11	Blanco J, Muriel-Bombín A, Sagredo V, Taboada F, Gandía F, Tamayo L, Collado J, García-Labattut A, Carriedo D, Valledor M, et al: Incidence, organ dysfunction and mortality in severe sepsis: A Spanish multicentre study. Crit Care. 12(R158)2008.PubMed/NCBI View Article : Google Scholar
12	Sakr Y, Elia C, Mascia L, Barberis B, Cardellino S, Livigni S, Fiore G, Filippini C and Ranieri VM: Epidemiology and outcome of sepsis syndromes in Italian ICUs: A muticentre, observational cohort study in the region of Piedmont. Minerva Anestesiol. 79:993–1002. 2013.PubMed/NCBI
13	Weng L, Xu Y, Yin P, Wang Y, Chen Y, Liu W, Li S, Peng JM, Dong R, Hu XY, et al: National incidence and mortality of hospitalized sepsis in China. Crit Care. 27(84)2023.PubMed/NCBI View Article : Google Scholar
14	Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, Kadri SS, Angus DC, Danner RL, Fiore AE, et al: Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA. 318:1241–1249. 2017.PubMed/NCBI View Article : Google Scholar
15	Lamontagne F, Rochwerg B, Lytvyn L, Guyatt GH, Møller MH, Annane D, Kho ME, Adhikari NKJ, Machado F, Vandvik PO, et al: Corticosteroid therapy for sepsis: A clinical practice guideline. BMJ. 362(k3284)2018.PubMed/NCBI View Article : Google Scholar
16	Rochwerg B, Oczkowski SJ, Siemieniuk RAC, Agoritsas T, Belley-Cote E, D'Aragon F, Duan E, English S, Gossack-Keenan K, Alghuroba M, et al: Corticosteroids in sepsis: An updated systematic review and meta-analysis. Crit Care Med. 46:1411–1420. 2018.PubMed/NCBI View Article : Google Scholar
17	Vignon P, Laterre PF, Daix T and François B: New agents in development for sepsis: Any reason for hope? Drugs. 80:1751–1761. 2020.PubMed/NCBI View Article : Google Scholar
18	Üstündağ H, Doğanay S, Kalındemirtaş FD, Demir Ö, Huyut MT, Kurt N, Özgeriş FB and Akbaba Ö: A new treatment approach: Melatonin and ascorbic acid synergy shields against sepsis-induced heart and kidney damage in male rats. Life Sci. 329(121875)2023.PubMed/NCBI View Article : Google Scholar
19	Usmani J, Khan T, Ahmad R and Sharma M: Potential role of herbal medicines as a novel approach in sepsis treatment. Biomed Pharmacother. 144(112337)2021.PubMed/NCBI View Article : Google Scholar
20	Zhang W, Jiang H, Wu G, Huang P, Wang H, An H, Liu S and Zhang W: The pathogenesis and potential therapeutic targets in sepsis. MedComm (2020). 4(e418)2023.PubMed/NCBI View Article : Google Scholar
21	Holubar M, Meng L, Alegria W and Deresinski S: Bacteremia due to methicillin-resistant staphylococcus aureus: An update on new therapeutic approaches. Infect Dis Clin North Am. 34:849–861. 2020.PubMed/NCBI View Article : Google Scholar
22	Hadi A, Pourmasoumi M, Mohammadi H, Symonds M and Miraghajani M: The effects of silymarin supplementation on metabolic status and oxidative stress in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of clinical trials. Complement Ther Med. 41:311–319. 2018.PubMed/NCBI View Article : Google Scholar
23	Koltai T and Fliegel L: Role of silymarin in cancer treatment: Facts, hypotheses, and questions. J Evid Based Integr Med. 27(2515690X211068826)2022.PubMed/NCBI View Article : Google Scholar
24	Soleimani V, Delghandi PS, Moallem SA and Karimi G: Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review. Phytother Res. 33:1627–1638. 2019.PubMed/NCBI View Article : Google Scholar
25	Abenavoli L, Izzo AA, Milić N, Cicala C, Santini A and Capasso R: Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res. 32:2202–2213. 2018.PubMed/NCBI View Article : Google Scholar
26	Camini FC and Costa DC: Silymarin: Not just another antioxidant. J Basic Clin Physiol Pharmacol. 31(20190206)2020.PubMed/NCBI View Article : Google Scholar
27	Tighe SP, Akhtar D, Iqbal U and Ahmed A: Chronic liver disease and silymarin: A biochemical and clinical review. J Clin Transl Hepatol. 8:454–458. 2020.PubMed/NCBI View Article : Google Scholar
28	Aghazadeh S, Amini R, Yazdanparast R and Ghaffari SH: Anti-apoptotic and anti-inflammatory effects of Silybum marianum in treatment of experimental steatohepatitis. Exp Toxicol Pathol. 63:569–574. 2011.PubMed/NCBI View Article : Google Scholar
29	Saller R, Melzer J, Reichling J, Brignoli R and Meier R: An updated systematic review of the pharmacology of silymarin. Forsch Komplementmed. 14:70–80. 2007.PubMed/NCBI View Article : Google Scholar
30	Surai A and Surai PF: Chapter 10 Silymarin and inflammation: From understanding molecular mechanisms to practical applications. In: Silymarin Puzzle. Wageningen Academic, pp287-317, 2023.
31	Sharma S, Kumar P, Ashawat MS, Pandit V, Verma CS and Sharma DK: Silymarin: A Phytoconstituent with Significant Therapeutic Potential-A Narrative Review. Curr Drug Ther. 18:89–97. 2023.
32	Kang JS, Jeon YJ, Park SK, Yang KH and Kim HM: Protection against lipopolysaccharide-induced sepsis and inhibition of interleukin-1beta and prostaglandin E2 synthesis by silymarin. Biochem Pharmacol. 67:175–181. 2004.PubMed/NCBI View Article : Google Scholar
33	Schrieber SJ, Hawke RL, Wen Z, Smith PC, Reddy KR, Wahed AS, Belle SH, Afdhal NH, Navarro VJ, Meyers CM, et al: Differences in the disposition of silymarin between patients with nonalcoholic fatty liver disease and chronic hepatitis C. Drug Metab Dispos. 39:2182–2190. 2011.PubMed/NCBI View Article : Google Scholar
34	Shahbazi F, Sadighi S, Dashti-Khavidaki S, Shahi F, Mirzania M, Abdollahi A and Ghahremani MH: Effect of silymarin administration on cisplatin nephrotoxicity: Report from a pilot, randomized, double-blinded, placebo-controlled clinical trial. Phytother Res. 29:1046–1053. 2015.PubMed/NCBI View Article : Google Scholar
35	Fried MW, Navarro VJ, Afdhal N, Belle SH, Wahed AS, Hawke RL, Doo E, Meyers CM and Reddy KR: Silymarin in NASH and C Hepatitis (SyNCH) Study Group. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: A randomized controlled trial. JAMA. 308:274–282. 2012.PubMed/NCBI View Article : Google Scholar
36	Marmouzi I, Bouyahya A, Ezzat SM, El Jemli M and Kharbach M: The food plant Silybum marianum (L.) Gaertn.: Phytochemistry, Ethnopharmacology and clinical evidence. J Ethnopharmacol. 265(113303)2021.PubMed/NCBI View Article : Google Scholar
37	Nguyen V, Tiemann D, Park E adz and Salehi A: Alpha-2 agonists. Anesthesiol Clin. 35:233–245. 2017.PubMed/NCBI View Article : Google Scholar
38	Giovannitti JA Jr, Thoms SM and Crawford JJ: Alpha-2 adrenergic receptor agonists: A review of current clinical applications. Anesth Prog. 62:31–39. 2015.PubMed/NCBI View Article : Google Scholar
39	Cioccari L, Luethi N, Bailey M, Shehabi Y, Howe B, Messmer AS, Proimos HK, Peck L, Young H, Eastwood GM, et al: The effect of dexmedetomidine on vasopressor requirements in patients with septic shock: A subgroup analysis of the Sedation Practice in Intensive care evaluation [SPICE III] trial. Crit Care. 24(441)2020.PubMed/NCBI View Article : Google Scholar
40	Ferreira J: The Theory is out there: The use of ALPHA-2 agonists in treatment of septic shock. Shock. 49:358–363. 2018.PubMed/NCBI View Article : Google Scholar
41	Morelli A, Sanfilippo F, Arnemann P, Hessler M, Kampmeier TG, D'Egidio A, Orecchioni A, Santonocito C, Frati G, Greco E, et al: The effect of propofol and dexmedetomidine sedation on norepinephrine requirements in septic shock patients: A crossover trial. Crit Care Med. 47:e89–e95. 2019.PubMed/NCBI View Article : Google Scholar
42	Suzuki T, Suzuki Y, Okuda J, Kurazumi T, Suhara T, Ueda T, Nagata H and Morisaki H: Sepsis-induced cardiac dysfunction and β-adrenergic blockade therapy for sepsis. J Intensive Care. 5(22)2017.PubMed/NCBI View Article : Google Scholar
43	Ferreira JA and Bissell BD: Misdirected sympathy: The role of sympatholysis in sepsis and septic shock. J Intensive Care Med. 33:74–86. 2018.PubMed/NCBI View Article : Google Scholar
44	Pichot C, Géloën A, Ghignone M and Quintin L: Alpha-2 agonists to reduce vasopressor requirements in septic shock? Med Hypotheses. 75:652–656. 2010.PubMed/NCBI View Article : Google Scholar
45	Geloen A, Chapelier K, Cividjian A, Dantony E, Rabilloud M, May CN and Quintin L: Clonidine and dexmedetomidine increase the pressor response to norepinephrine in experimental sepsis: A pilot study. Crit Care Med. 41:e431–e438. 2013.PubMed/NCBI View Article : Google Scholar
46	Møller MH, Alhazzani W, Lewis K, Belley-Cote E, Granholm A, Centofanti J, McIntyre WB, Spence J, Al Duhailib Z, Needham DM, et al: Use of dexmedetomidine for sedation in mechanically ventilated adult ICU patients: A rapid practice guideline. Intensive Care Med. 48:801–810. 2022.PubMed/NCBI View Article : Google Scholar
47	Wiegand A, Behal M, Robbins B, Bissell B, Pandya K and Mefford B: Niche roles for dexmedetomidine in the intensive care unit. Ann Pharmacother. 57:1207–1220. 2023.PubMed/NCBI View Article : Google Scholar
48	Page V and McKenzie C: Sedation in the intensive care unit. Curr Anesthesiol Rep. 11:92–100. 2021.PubMed/NCBI View Article : Google Scholar
49	Zi SF, Li JH, Liu L, Deng C, Ao X, Chen DD and Wu SZ: Dexmedetomidine-mediated protection against septic liver injury depends on TLR4/MyD88/NF-κB signaling downregulation partly via cholinergic anti-inflammatory mechanisms. Int Immunopharmacol. 76(105898)2019.PubMed/NCBI View Article : Google Scholar
50	Chang Y, Huang X, Liu Z, Han G, Huang L, Xiong YC and Wang Z: Dexmedetomidine inhibits the secretion of high mobility group box 1 from lipopolysaccharide-activated macrophages in vitro. J Surg Res. 181:308–314. 2013.PubMed/NCBI View Article : Google Scholar
51	Zhang T, Mei Q, Dai S, Liu Y and Zhu H: Use of dexmedetomidine in patients with sepsis: A systematic review and meta-analysis of randomized-controlled trials. Ann Intensive Care. 12(81)2022.PubMed/NCBI View Article : Google Scholar
52	Zhang XY, Liu ZM, Wen SH, Li YS, Li Y, Yao X, Huang WQ and Liu KX: Dexmedetomidine administration before, but not after, ischemia attenuates intestinal injury induced by intestinal ischemia-reperfusion in rats. Anesthesiology. 116:1035–1046. 2012.PubMed/NCBI View Article : Google Scholar
53	Kuyrukluyildiz U, Delen LA, Onk D, Yazici GN, Gulaboglu M and Suleyman H: The effect of dexmedetomidine on gastric ischemia reperfusion injury in rats. Biochemical and histopathological evaluation. Acta Cir Bras. 36(e360104)2021.PubMed/NCBI View Article : Google Scholar
54	Kotanoğlu MS, Kadioğlu E, Emerce E, Kaymak C, Özcan A and Başar H: Antioxidant effects of dexmedetomidine against hydrogen peroxide-induced DNA damage in vitro by alkaline Comet assay. Turk J Med Sci. 50:1393–1398. 2020.PubMed/NCBI View Article : Google Scholar
55	Li W, Chen M, Gong Y, Lin F and Sun C: Effects of dexmedetomidine on oxidative stress, programmed cell death, liver function, and expression of peripheral immune cells in patients with primary liver cancer undergoing hepatectomy. Front Physiol. 14(1159746)2023.PubMed/NCBI View Article : Google Scholar
56	Poli-de-Figueiredo LF, Garrido AG, Nakagawa N and Sannomiya P: Experimental models of sepsis and their clinical relevance. Shock. 30 (Suppl 1):S53–S59. 2008.PubMed/NCBI View Article : Google Scholar
57	Sjaastad FV, Jensen IJ, Berton RR, Badovinac VP and Griffith TS: Inducing experimental polymicrobial sepsis by cecal ligation and puncture. Curr Protoc Immunol. 131(e110)2020.PubMed/NCBI View Article : Google Scholar
58	Alverdy JC, Keskey R and Thewissen R: Can the cecal ligation and puncture model be repurposed to better inform therapy in human sepsis? Infect Immun. 88:e00942–19. 2020.PubMed/NCBI View Article : Google Scholar
59	Drechsler S and Osuchowski M: Cecal ligation and puncture. In: Sepsis: Methods and Protocols; Walker WE (ed). Springer: New York, NY, USA, pp1-8, 2021.
60	Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, et al: The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. J Cereb Blood Flow Metab. 40:1769–1777. 2020.PubMed/NCBI View Article : Google Scholar
61	Care IoLARCo, Animals UoL: Guide for the care and use of laboratory animals: US Department of Health and Human Services, Public Health Service, National Academies Press (US), 2011.
62	Al-Kadi A, Ahmed AS, El-Tahawy NFG, Khalifa MMA and El-Daly M: Silymarin protects against sepsis-induced acute liver and kidney injury via anti-inflammatory and antioxidant mechanisms in the rat. J Adv Biomed Pharm Sci. 3:190–197. 2020.
63	Canikli Adıgüzel Ş, Pirat A, Türkoğlu S, Bayraktar N, Özen Ö and Kaya M: A rat model of acute respiratory distress silymarin's antiinflamatory and antioxidant effect. J Turk Soc Intens Care. 14:18–27. 2016.
64	Schick MA, Isbary TJ, Schlegel N, Brugger J, Waschke J, Muellenbach R, Roewer N and Wunder C: The impact of crystalloid and colloid infusion on the kidney in rodent sepsis. Intensive Care Med. 36:541–548. 2010.PubMed/NCBI View Article : Google Scholar
65	Li XH, Gong X, Zhang L, Jiang R, Li HZ, Wu MJ and Wan JY: Protective effects of polydatin on septic lung injury in mice via upregulation of HO-1. Mediators Inflamm. 2013(354087)2013.PubMed/NCBI View Article : Google Scholar
66	Abraha I, Cozzolino F, Orso M, Marchesi M, Germani A, Lombardo G, Eusebi P, De Florio R, Luchetta ML, Iorio A and Montedori A: A systematic review found that deviations from intention-to-treat are common in randomized trials and systematic reviews. J Clin Epidemiol. 84:37–46. 2017.PubMed/NCBI View Article : Google Scholar
67	Gupta SK: Intention-to-treat concept: A review. Perspect Clin Res. 2:109–112. 2011.PubMed/NCBI View Article : Google Scholar
68	Tripepi G, Chesnaye NC, Dekker FW, Zoccali C and Jager KJ: Intention to treat and per protocol analysis in clinical trials. Nephrology (Carlton). 25:513–517. 2020.PubMed/NCBI View Article : Google Scholar
69	Dardalas I, Stamoula E, Rigopoulos P, Malliou F, Tsaousi G, Aidoni Z, Grosomanidis V, Milonas A, Papazisis G, Kouvelas D and Pourzitaki C: Dexmedetomidine effects in different experimental sepsis in vivo models. Eur J Pharmacol. 856(172401)2019.PubMed/NCBI View Article : Google Scholar
70	Ni J, He J, Kang L, Zhong Z, Wang L and Yin S: Effects of dexmedetomidine pretreatment on rats with sepsis-induced acute kidney injury and miR-146a expression. Cell Mol Biol (Noisy-le-grand). 66:93–98. 2020.PubMed/NCBI
71	Ustyol L, Demiroren K, Kandemir I, Erten R, Bulan K, Kaba S, Demir N and Basunlu MT: Comparative nephroprotective effects of silymarin, N-acetylcysteine, and thymoquinone against carbon tetrachloride-induced nephrotoxicity in rats. Iran Red Crescent Med J. 19(e37746)2017.
72	Guzel S, Sahinogullari ZU, Canacankatan N, Antmen SE, Kibar D and Coskun Yilmaz B: Potential renoprotective effects of silymarin against vancomycin-induced nephrotoxicity in rats. Drug Chem Toxicol. 43:630–636. 2020.PubMed/NCBI View Article : Google Scholar
73	Ozdemir A, Topçu A, Mercantepe T, Arpa M, Karakaş SM, Ozdemir A, Tümkaya L and Mercantepe F: The effects of dexmedetomidine on early acute kidney injury in severely burned rats. Eur Rev Med Pharmacol Sci. 27:1311–1321. 2023.PubMed/NCBI View Article : Google Scholar
74	Gonullu E, Ozkardesler S, Kume T, Duru LS, Akan M, Guneli ME, Ergur BU, Meseri R and Dora O: Comparison of the effects of dexmedetomidine administered at two different times on renal ischemia/reperfusion injury in rats. Braz J Anesthesiol. 64:152–158. 2014.PubMed/NCBI View Article : Google Scholar
75	Cakir M, Polat A, Tekin S, Vardi N, Taslidere E, Rumeysa Duran Z and Tanbek K: The effect of dexmedetomidine against oxidative and tubular damage induced by renal ischemia reperfusion in rats. Ren Fail. 37:704–708. 2015.PubMed/NCBI View Article : Google Scholar
76	Qiu R, Yao W, Ji H, Yuan D, Gao X, Sha W, Wang F, Huang P and Hei Z: Dexmedetomidine restores septic renal function via promoting inflammation resolution in a rat sepsis model. Life Sci. 204:1–8. 2018.PubMed/NCBI View Article : Google Scholar
77	Tanaka S, Genève C, Zappella N, Yong-Sang J, Planesse C, Louedec L, Viranaïcken W, Bringart M, Montravers P, Denamur E, et al: Reconstituted high-density lipoprotein therapy improves survival in mouse models of sepsis. Anesthesiology. 132:825–838. 2020.PubMed/NCBI View Article : Google Scholar
78	Bedet A, Voiriot G, Ternacle J, Marcos E, Adnot S, Derumeaux G and Mekontso Dessap A: Heart rate control during experimental sepsis in mice: Comparison of ivabradine and β-blockers. Anesthesiology. 132:321–329. 2020.PubMed/NCBI View Article : Google Scholar
79	Zhong M, Wu W, Wang Y, Mao H, Song J, Chen S and Zhu D: Inhibition of sphingosine kinase 1 attenuates sepsis-induced microvascular leakage via inhibiting macrophage NLRP3 inflammasome activation in mice. Anesthesiology. 132:1503–1515. 2020.PubMed/NCBI View Article : Google Scholar
80	Park D, Ro M, Lee A-J, Kwak DW, Chung Y and Kim JH: Contributory role of BLT2 in the production of proinflammatory cytokines in cecal ligation and puncture-induced sepsis. Mol Cells. 44:893–899. 2021.PubMed/NCBI View Article : Google Scholar
81	Abdelnaser M, Alaaeldin R, Attya ME and Fathy M: Hepatoprotective potential of gabapentin in cecal ligation and puncture-induced sepsis; targeting oxidative stress, apoptosis, and NF-kB/MAPK signaling pathways. Life Sci. 320(121562)2023.PubMed/NCBI View Article : Google Scholar
82	Kim GO, Kim N, Song GY and Bae JS: Inhibitory activities of rare ginsenoside Rg4 on cecal ligation and puncture-induced sepsis. Int J Mol Sci. 23(10836)2022.PubMed/NCBI View Article : Google Scholar
83	Li J, Li M, Li L, Ma J, Yao C and Yao S: Hydrogen sulfide attenuates ferroptosis and stimulates autophagy by blocking mTOR signaling in sepsis-induced acute lung injury. Mol Immunol. 141:318–327. 2022.PubMed/NCBI View Article : Google Scholar
84	Tripathi AS, Awasthi S, Maurya RK, Yasir M, Mohapatra L and Srivastav V: Protective effect of vanillin on the management of cecal ligation and puncture induced sepsis rat model. Microb Pathog. 165(105493)2022.PubMed/NCBI View Article : Google Scholar
85	Daenen K, Andries A, Mekahli D, Van Schepdael A, Jouret F and Bammens B: Oxidative stress in chronic kidney disease. Pediatr Nephrol. 34:975–991. 2019.PubMed/NCBI View Article : Google Scholar
86	Krzemińska J, Wronka M, Młynarska E, Franczyk B and Rysz J: Arterial hypertension-oxidative stress and inflammation. Antioxidants (Basel). 11(172)2022.PubMed/NCBI View Article : Google Scholar
87	Zhao X, Wang H, Yang Y, Gou Y, Wang Z, Yang D and Li C: Protective effects of silymarin against D-Gal/LPS-induced organ damage and inflammation in mice. Drug Des Devel Ther. 15:1903–1914. 2021.PubMed/NCBI View Article : Google Scholar
88	Alikiaii B, Bagherniya M, Askari G, Johnston TP and Sahebkar A: The role of phytochemicals in sepsis: A mechanistic and therapeutic perspective. Biofactors. 47:19–40. 2021.PubMed/NCBI View Article : Google Scholar
89	Mei B, Li J and Zuo Z: Dexmedetomidine attenuates sepsis-associated inflammation and encephalopathy via central α2A adrenoceptor. Brain Behav Immun. 91:296–314. 2021.PubMed/NCBI View Article : Google Scholar
90	Hu H, An S, Sha T, Wu F, Jin Y, Li L, Zeng Z, Wu J and Chen Z: Association between dexmedetomidine administration and outcomes in critically ill patients with sepsis-associated acute kidney injury. J Clin Anesth. 83(110960)2022.PubMed/NCBI View Article : Google Scholar
91	Esposito S, De Simone G, Boccia G, De Caro F and Pagliano P: Sepsis and septic shock: New definitions, new diagnostic and therapeutic approaches. J Glob Antimicrob Resist. 10:204–212. 2017.PubMed/NCBI View Article : Google Scholar
92	Fujishima S: Organ dysfunction as a new standard for defining sepsis. Inflamm Regen. 36(24)2016.PubMed/NCBI View Article : Google Scholar
93	Sun S, Chen R, Dou X, Dai M, Long J, Wu Y and Lin Y: Immunoregulatory mechanism of acute kidney injury in sepsis: A narrative review. Biomed Pharmacother. 159(114202)2023.PubMed/NCBI View Article : Google Scholar
94	Toklu HZ, Akbay TT, Velioglu-Ogunc A, Ercan F, Gedik N, Keyer-Uysal M and Sener G: Silymarin, the antioxidant component of Silybum marianum, prevents sepsis-induced acute lung and brain injury. J Surg Res. 145:214–222. 2008.PubMed/NCBI View Article : Google Scholar
95	Turgut F, Bayrak O, Catal F, Bayrak R, Atmaca AF, Koc A, Akbas A, Akcay A and Unal D: Antioxidant and protective effects of silymarin on ischemia and reperfusion injury in the kidney tissues of rats. Int Urol Nephrol. 40:453–460. 2008.PubMed/NCBI View Article : Google Scholar
96	Malekinejad H, Rahmani F, Valivande-Azar S, Taheri-Broujerdi M and Bazargani-Gilani B: Long-term administration of Silymarin augments proinflammatory mediators in the hippocampus of rats: Evidence for antioxidant and pro-oxidant effects. Hum Exp Toxicol. 31:921–930. 2012.PubMed/NCBI View Article : Google Scholar
97	Sajedianfard J, Nazifi S, Izadi A, Chahardahcherik M and Honarmand M: Effect of various doses of silymarin on the oxidative stress induced by busulfan administration in the different organs of rats. Turk J Pharm Sci. 13:233–240. 2016.
98	Yardımcı M, Göz M, Aydın MS, Kankılıç N and Temiz E: Antioxidant actions of thymoquinone, silymarin, and curcumin on experimental aortic ischemia-reperfusion model in wistar albino rats. Braz J Cardiovasc Surg. 37:807–813. 2022.PubMed/NCBI View Article : Google Scholar
99	Azizoğlu M, Arslan S, Gökalp Özkorkmaz E, Aşır F, Basuguy E, Okur MH, Aydoğdu B, Alagöz Karabel M and Kaplan I: Protective effects of Silymarin on testicular torsion/detorsion in rats. Eur Rev Med Pharmacol Sci. 27:10446–10453. 2023.PubMed/NCBI View Article : Google Scholar
100	Surai PF: Silymarin as a natural antioxidant: An overview of the current evidence and perspectives. Antioxidants (Basel). 4:204–247. 2015.PubMed/NCBI View Article : Google Scholar
101	Taleb A, Ahmad KA, Ihsan AU, Qu J, Lin N, Hezam K, Koju N, Hui L and Qilong D: Antioxidant effects and mechanism of silymarin in oxidative stress induced cardiovascular diseases. Biomed Pharmacother. 102:689–698. 2018.PubMed/NCBI View Article : Google Scholar
102	Kim MJ, Kim DU, Choi JW, Kim DG, Song HJ, Bae GS and Park SJ: Silymarin attenuates the severity of cerulein-induced acute pancreatitis. Pancreas. 49:89–95. 2020.PubMed/NCBI View Article : Google Scholar
103	Cormack JR, Orme RM and Costello TG: The role of alpha2-agonists in neurosurgery. J Clin Neurosci. 12:375–378. 2005.PubMed/NCBI View Article : Google Scholar
104	Carollo DS, Nossaman BD and Ramadhyani U: Dexmedetomidine: A review of clinical applications. Curr Opin Anaesthesiol. 21:457–461. 2008.PubMed/NCBI View Article : Google Scholar
105	Aidoni Z, Pourzitaki C, Stamoula E, Kotzampassi K, Tsaousi G, Kazakos G, Foroulis CN, Skourtis C, Vasilakos DG and Grosomanidis V: Circulatory effects of dexmedetomidine in early sepsis: A randomised controlled experimental study. Naunyn Schmiedebergs Arch Pharmacol. 393:89–97. 2020.PubMed/NCBI View Article : Google Scholar
106	Wang C, Yuan W, Hu A, Lin J, Xia Z, Yang CF, Li Y and Zhang Z: Dexmedetomidine alleviated sepsis-induced myocardial ferroptosis and septic heart injury. Mol Med Rep. 22:175–184. 2020.PubMed/NCBI View Article : Google Scholar
107	Koca U, Olguner ÇG, Ergür BU, Altekin E, Taşdöğen A, Duru S, Girgin P, Gündüz K, Cilaker Mıcılı S, Güzeldağ S and Akkuş M: The effects of dexmedetomidine on secondary acute lung and kidney injuries in the rat model of intra-abdominal sepsis. ScientificWorldJournal. 2013(292687)2013.PubMed/NCBI View Article : Google Scholar
108	Li Y, Wu B, Hu C, Hu J, Lian Q, Li J and Ma D: The role of the vagus nerve on dexmedetomidine promoting survival and lung protection in a sepsis model in rats. Eur J Pharmacol. 914(174668)2022.PubMed/NCBI View Article : Google Scholar
109	Wu Y, Liu Y, Huang H, Zhu Y, Zhang Y, Lu F and Zhou C, Huang L, Li X and Zhou C: Dexmedetomidine inhibits inflammatory reaction in lung tissues of septic rats by suppressing TLR4/NF-κB pathway. Mediators Inflamm. 2013(562154)2013.PubMed/NCBI View Article : Google Scholar
110	Şengel N, Köksal Z, Dursun AD, Kurtipek Ö, Sezen ŞC, Arslan M and Kavutçu M: Effects of dexmedetomidine administered through different routes on kidney tissue in rats with spinal cord ischaemia-reperfusion injury. Drug Des Devel Ther. 16:2229–2239. 2022.PubMed/NCBI View Article : Google Scholar
111	Hernández G, Tapia P, Alegría L, Soto D, Luengo C, Gomez J, Jarufe N, Achurra P, Rebolledo R, Bruhn A, et al: Effects of dexmedetomidine and esmolol on systemic hemodynamics and exogenous lactate clearance in early experimental septic shock. Crit Care. 20(234)2016.PubMed/NCBI View Article : Google Scholar
112	Zhao W, Jia L, Yang HJ, Xue X, Xu WX, Cai JQ, Guo RJ and Cao CC: Taurine enhances the protective effect of dexmedetomidine on sepsis-induced acute lung injury via balancing the immunological system. Biomed Pharmacother. 103:1362–1368. 2018.PubMed/NCBI View Article : Google Scholar
113	Yang CL, Chen CH, Tsai PS, Wang TY and Huang CJ: Protective effects of dexmedetomidine-ketamine combination against ventilator-induced lung injury in endotoxemia rats. J Surg Res. 167:e273–e281. 2011.PubMed/NCBI View Article : Google Scholar
114	Özkan F, Yüksek A, Demirel A and Kantekin Ç: Effects of dexmetatomidine and midazolam on immunity in sepsis-induced rats. Med J Bakirkoy. 19:180–185. 2023.
115	Choi MW, Ko DR, Kong T, Choa MH, You JS and Chung SP: Comparison of silymarin, penicillin, N-acetylcysteine in patient with amatoxin poisoning: A systematic review. J Korean Soc Clin Toxicol. 16:33–41. 2018.
116	Abdel Salam OM, Sleem AA, Omara EA and Hassan NS: Effect of ribavirin alone or combined with silymarin on carbon tetrachloride induced hepatic damage in rats. Drug Target Insights. 2:19–27. 2007.PubMed/NCBI