CAPE ameliorates vascular damage caused by sepsis

Year 2024, Volume: 49 Issue: 1, 54 - 61, 29.03.2024

Leyla Çimen Aysun Çetin Ferhan Elmalı

https://doi.org/10.17826/cumj.1395532

Abstract

parameters of vascular and oxidative damage caused by sepsis and to evaluated the effects of caffeic acid phenethyl ester (CAPE) on these damages.
Materials and Methods: Wistar-Albino male rats were used for this study. Rats were divided into 4 groups (n = 10). Group 1 animals were intraperitoneally (i.p) injected with sterile saline (Control Group). Group 2 animals were i.p injected with lipopolysaccharide (LPS), 20 mg / kg-weight dose (Sepsis Group). Group 3 animals were i.p injected with lipopolysaccharide, 20 mg / kg-weight dose. Immediately after LPS injection, CAPE was i.p injected at single dose, 10 µmol / kg-body weight (Treatment Group). A single dose of CAPE, 10 µmol / kg-body weight / day, was injected i.p to Group 4 animals for 5 days. After 5th day CAPE injection, a single dose of LPS 20 mg / kg-weight was injected (Protective Group). At the 6th hour after the injections applied to all groups, blood sample were taken intracardiac and their serum were separated for the studies. Homocysteine (Hcy), asymmetric dimethyl arginine (ADMA), endothelin-1 (ET-1) and vascular cellular adhesion molecule-1 (VCAM-1) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, the protective and therapeutic effects of CAPE on these parameters was investigated.
Results: Control group Hcy, ADMA, ET-1 and VCAM-1 levels were found to be 4.987 ± 0.096 µmol/l, 0.803 ± 0.020 nmol/ml, 21.123 ± 2.575 ng/l, 3.155 ± 0.078 ng/ml, respectively. Sepsis group Hcy, ADMA, ET-1 and VCAM-1 levels were found to be 8.975 ± 0.160 µmol/l, 3.953 ± 0.678 nmol/ml, 52.446 ± 2.546 ng/l, 10.783 ± 1.068 ng/ml, respectively. Treatment group Hcy, ADMA, ET-1 and VCAM-1 levels were found to be 5.286 ± 0.037 µmol/l, 1.304 ± 0.040 nmol/ml, 27.995 ± 1.299 ng/l, 3.72 ± 0.073 ng/ml, respectively. Protective group Hcy, ADMA, ET-1 and VCAM-1 levels were found to be 5.401 ± 0.042 µmol/l, 1.431 ± 0.056 nmol/ml, 32.708 ± 1.326 ng/l, 4.058 ± 0.069 ng/ml, respectively. It was observed that the Hcy, ADMA, ET-1 and VCAM-1 levels of the sepsis group increased significantly compared to the control group (p0.05). It was observed that CAPE treatment significantly decreased these parameters levels. However, the use of CAPE as a protective was not as effective as its treatment effect.
Conclusion: Our results demonstrated that sepsis resulted in increase Hcy, ADMA, ET-1, VCAM-1 levels. All these changes indicate that sepsis-mediated vascular damage is increased. Our results demonstrated that CAPE is more effective in preventing sepsis-mediated damages when given as a treatment.

Keywords

caffeic acid phenethyl ester, sepsis, homocysteine, asymmetric dimethyl arginine, endothelin-1, vascular cellular adhesion molecule-1

Ethical Statement

This study was approved by the animal experiments local ethical committee of Erciyes University (date: 08/10/2014, number: 14/131)

Supporting Institution

The study was funded with the approval of Erciyes University Scientific Research and Project (BAP) commission with code number TDK-2016-6596

Project Number

TDK-2016-6596

KAFE sepsisin neden olduğu vasküler hasarı iyileştirir

Abstract

Amaç: Bu çalışmada sepsisin neden olduğu vasküler ve oksidatif hasar parametrelerindeki değişikliği araştırmayı ve kafeik asit fenetil esterin (KAFE) bu hasarlar üzerindeki etkilerini değerlendirmeyi amaçladık.
Gereç ve Yöntem: Bu çalışma için Wistar-Albino erkek ratlar kullanıldı. Ratlar 4 gruba ayrıldı (n=10). Grup 1'deki hayvanlara intraperitoneal (i.p) olarak steril salin enjekte edildi (Kontrol Grubu). Grup 2'deki hayvanlara 20 mg/kg ağırlık dozunda lipopolisakkarit (LPS) i.p olarak enjekte edildi (Sepsis Grubu). Grup 3'teki hayvanlara 20 mg/kg ağırlık dozunda lipopolisakkarit i.p olarak enjekte edildi. LPS enjeksiyonundan hemen sonra KAFE i.p olarak tek doz 10 µmol/kg vücut ağırlığı dozunda enjekte edildi (Tedavi Grubu). Grup 4'teki hayvanlara 5 gün boyunca 10 µmol/kg-vücut ağırlığı/gün olacak şekilde tek doz KAFE i.p olarak enjekte edildi. 5. gün KAFE enjeksiyonundan sonra tek doz 20 mg/kg-ağırlık LPS enjekte edildi (Koruyucu Grup). Tüm gruplara uygulanan enjeksiyonlardan sonraki 6. saatte intrakardiyak kan örnekleri alındı ve serumları çalışmalar için ayrıldı. Homosistein (Hcy), asimetrik dimetil arginin (ADMA), endotelin-1 (ET-1) ve vasküler hücresel adezyon molekülü-1 (VCAM-1) enzime bağlı immünosorbent yöntem (ELISA) ile ölçüldü. Ayrıca KAFE'nin bu parametreler üzerindeki koruyucu ve tedavi edici etkileri araştırıldı.
Bulgular: Kontrol grubunda Hcy, ADMA, ET-1 ve VCAM-1 düzeyleri sırasıyla 4,987 ± 0,096 µmol/l, 0,803 ± 0,020 nmol/ml, 21,123 ± 2,575 ng/l, 3,155 ± 0,078 ng/ml olarak bulundu. Sepsis grubunda Hcy, ADMA, ET-1 ve VCAM-1 düzeyleri sırasıyla 8,975 ± 0,160 µmol/l, 3,953 ± 0,678 nmol/ml, 52,446 ± 2,546 ng/l, 10,783 ± 1,068 ng/ml olarak bulundu. Tedavi grubunda Hcy, ADMA, ET-1 ve VCAM-1 düzeyleri sırasıyla 5,286 ± 0,037 µmol/l, 1,304 ± 0,040 nmol/ml, 27,995 ± 1,299 ng/l, 3,72 ± 0,073 ng/ml olarak bulundu. Koruyucu grup Hcy, ADMA, ET-1 ve VCAM-1 düzeyleri sırasıyla 5,401 ± 0,042 µmol/l, 1,431 ± 0,056 nmol/ml, 32,708 ± 1,326 ng/l, 4,058 ± 0,069 ng/ml olarak bulundu. Sepsis grubunun Hcy, ADMA, ET-1 ve VCAM-1 seviyelerinin kontrol grubuna göre anlamlı düzeyde arttığı görüldü (p<0,05). KAFE tedavisinin bu parametre seviyelerini önemli derecede azalttığı görüldü. Ancak KAFE'nin koruyucu olarak kullanımı tedavi edici etkisi kadar etkili değildi.
Sonuç: Sonuçlarımız sepsisin Hcy, ADMA, ET-1, VCAM-1 seviyelerinde artışa neden olduğunu gösterdi. Bütün bu değişiklikler sepsis kaynaklı vasküler hasarının arttığını göstermektedir. Sonuçlarımız KAFE'nin tedavi edici olarak verildiğinde sepsis kaynaklı hasarları önlemede daha etkili olduğunu gösterdi.

Keywords

Kafeik asit fenetil ester, sepsis, homosistein, asimetrik dimetil arjinin, endotelin-1, vasküler hücresel adezyon molekülü-1.

Ethical Statement

This study was approved by the animal experiments local ethical committee of Erciyes University (date: 08/10/2014, number: 14/131)

Supporting Institution

The study was funded with the approval of Erciyes University Scientific Research and Project (BAP) commission with code number TDK-2016-6596

Project Number

TDK-2016-6596

References

• Parmely MJ, Wang F, Wright D. Gamma interferon prevents the inhibitory effects of oxidative stress on host responses to Escherichia coli infection. Infect Immun. 2001;69:2621-29.
• Aydemir O, Ozcan B, Yucel H, Bas AY, Demirel N. Asymmetric dimethylarginine and L-arginine levels in neonatal sepsis and septic shock. J Matern Fetal Neonatal Med. 2015;28:977–82.
• Parlakpınar H, Örüm MH, Acet A. Kafeik asit fenetil ester (KAFE) ve miyokardiyal iskemi reperfüzyon (Mİ/R) hasarı. İnönü Üniversitesi Sağlık Bilimleri Dergisi. 2012;1:10-5.
• Biray Ç, Gündüz C, Yılmaz B, Şahin F, Topçuoğlu N. The evaluation of cytotoxic and apoptotic effect of propolis and its extracts caffeic acid phenethyl ester and cinnamic acid in human acute T-cell lymphoblastic leukemia cell line (CCRF-CEM). Ege Tıp Dergisi. 2006;45:83-92.
• Yücel H, Özaydın M, Doğan A, Erdoğan D, Turker Y, Ceyhan BM et al. Plasma concentrations of asymmetric dimethylarginine, nitric oxide and homocysteine in patients with slow coronary flow. Scand J Clin Lab Invest. 2012;72:495–500.
• Alaçam H, Dikmen ZG, Doğan P. The metabolism of asymetric dimethyl arginine (ADMA) and its relationships between oxidative injury, endothelium damage and several diseases. Hacettepe Tıp Dergisi. 2010;41:75-81.
• Işıklar ÖÖ, Mutaf I. Asymmetric dimethylarginine and its clinical significance. Türk Klinik Biyokimya Dergisi. 2010;8:75-89.
• Amalakuhan B, Habib SA, Mangat M, Reyes LF, Rodriguez AH, Hinojosa CA et al. Endothelial adhesion molecules and multiple organ failure in patients with severe sepsis. Cytokine. 2016;88:267-73.
• Laudes IJ, Guo RF, Riedemann NC, Speyer C, Craig R, Sarma JV et al. Disturbed homeostasis of lung intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 during sepsis. Am J Pathol. 2004;164:1435-45.
• Seki Y, Jesmin S, Shimojo N, Islam MM, Rahman MA, Khatun T et al. Significant reversal of cardiac upregulated endothelin-1 system in a rat model of sepsis by landiolol hydrochloride. Life Sci. 2014;118:357–63.
• Freeman BD, Machado FS, Tanowitz HB, Desruisseaux MS. Endothelin-1 and its role in the pathogenesis of infectious diseases. Life Sci. 2014;118:110-9.
• Ueki M, Taie S, Chujo K. Asaga T, Iwanaga Y, Ono J et al. Urinary trypsin inhibitor reduces inflammatory response in kidney induced by LPS. J Biosci and Bioeng. 2007;104:315-20.
• Akyol S, Akbas A, Butun I, Toktas M, Ozyurt H, Sahin S et al. Caffeic acid phenethyl ester as a remedial agent for reproductive functions and oxidative stress-based pathologies of gonads. J Intercult Ethnopharmacol. 2015;4:187-91.
• Tolba MF, Omar HA, Azab SS, Khalifa AE, Abdel-Naim AB, Abdel-Rahman SZ. Caffeic acid phenethyl ester: A review of its antioxidant activity, protective effects against ischemia-reperfusion injury and drug adverse reactions. Crit Rev Food Sci Nutr. 2016;56:2183-90.
• Yılmaz HR, Sögüt S, Özyurt H, Iraz M, Yıldırım Z, Akyol Ö. Sıçanlarda sispilatinle olusturulan nefrotoksisitede metabolik enzim aktivitelerine kafeik asit fenetil ester’in etkisi. Van Tıp Dergisi. 2004;11:1-6.
• Koksel O, Ozdulger A, Tamer L, Cinel L, Ercil M, Değirmenci U et al. Effects of caffeic acid phenethyl ester on lipopolysaccharide-induced lung injury in rats. Pulm Pharmacol Ther. 2006;19:90-5.
• Alici O, Kavakli HS, Koca C, Altıntaş NM, Aydın M, Alıcı S. Value of caffeic acid phenethyl ester pretreatment in experimental sepsis model in rats. Mediators Inflamm. 2015;2015:810948.
• Erdoğan O, Tüz M, Yasan H, Aynalı G, Yarıktaş M. The effect of caffeic acid phenethyl ester on experimental hearing loss caused by acoustic trauma. Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi. 2012;19:81-6.
• Motawi TK, Darwish HA, Abd El Tawab AM. Effects of caffeic acid phenethyl ester on endotoxin-induced cardiac stress in rats: A Possible mechanism of protection. J Biochem Mol Toxicol. 2011;25:84-94.
• Uysal E. Ratlarda siklofosfamid ile indüklenen hemorajik sistitte kafeik asit fenetil esterin koruyucu etkilerinin araştırılması (Uzmanlık Tezi). Isparta, Süleyman Demirel Üniversitesi, 2009.
• Uzar E, Acar A, Fırat U, Evliyaoğlu O, Alp H, Tüfek A et al. Deneysel serebral iskemi/reperfüzyon hasarında kafeik asit fenetil esterin koruyucu etkisi. Turk Norol Derg. 2011;17:131-6.
• Cimen B, Türközkan N, Seven I, Unlü A, Karasu C. Impaired Na-K-ATPase activity as a mechanism of reactive nitrogen species induced cytotoxicity in guinea pig liver exposed to lipopolysaccharides. Mol Cell Biochem. 2004;259:53-7.
• Türközkan N, Seven I, Erdamar H, Cimen B. Effect of vitamin A pretreatment on Escherichia coli-induced lipid peroxidation and level of 3-nitroyrosine in kidney of guinea pig. Mol Cell Biochem. 2005;278:33-7.
• Cimen B, Türközkan N, Unlü A, Erbil MK. Effects of melatonin on 3-nitrotyrosine formation and energy charge ratio in rat kidney in LPS-induced stress. Cell Biochem Funct. 2005;23:273-7.
• Toth I, Heard SO. Nitric oxide does not mediate lipopolysaccharide-induced myocardial depression in guinea pigs. Crit Care Med. 1997;25:684-8.
• Knowles RG, Merrett M, Salter M, Moncada S. Differential induction of brain, lung and liver nitric oxide synthase by endotoxin in the rat. Biochem J. 1990;270:833-6.
• Bekpinar S, Develi-Is S, Unlucerci Y, Kusku-Kiraz Z, Uysal M, Gurdol F. Modulation of arginine and asymmetric dimethylarginine concentrations in liver and plasma by exogenous hydrogen sulfide in LPS-induced endotoxemia. Can J Physiol Pharmacol. 2013;91:1071-5.
• Nakamura T, Sato E, Fujiwara N, Kawagoe Y, Suzuki T, Ueda Y et al. Circulating levels of advanced glycation end products (AGE) and interleukin-6 (IL-6) are independent determinants of serum asymmetric dimethylarginine (ADMA) levels in patients with septic shock. Pharmacol Res. 2009:60;515–8.
• Iapichino G, Umbrello M, Albicini M, Spanu P, Bellani G, Polli F et al. Time course of endogenous nitric oxide inhibitors in severe sepsis in humans. Minerva Anestesiol. 2010;76:325–33.
• Davis JS, Darcy CJ, Yeo TW, Jones C, McNeil YR, Stephens DP et al. Asymmetric dimethylarginine, endothelial nitric oxide bioavailability and mortality in sepsis. Plos One 2011;6: e17260.
• Gough MS, Morgan MA, Mack CM, Darling DC, Frasier LM, Doolin KP et al. The ratio of arginine to dimethylarginines is reduced and predicts outcomes in patients with severe sepsis. Crit Care Med. 2011;39:1351–8.
• Shindo T, Kurihara H, Kurihara Y, Morita H, Yazaki Y. Upregulation of endothelin-1 and adrenomedullin gene expression in the mouse endotoxin shock model. J Cardiovasc Pharmacol. 1998;31:541–4.
• Ogura Y, Jesmin S, Yamaguchi N, Oki M, Shimojo N, Islam MM et al. Potential amelioration of upregulated renal HIF-1alpha–endothelin-1system by landiolol hydrochloride in a rat model of endotoxemia. Life Sci. 2014;118:347–56.
• Jesmin S, Yamaguchi N, Zaedi S, Sultana SN, Iwashima Y, Sawamura A et al. Time-dependent expression of endothelin-1 in lungs and the effects of TNF-α blocking peptide on acute lung injury in a endotoxemic rat model. Biomed Res. 2011;32:9-17.
• Leng W, Lei X, Meng H, Ouyang X, Liang Z. EOLA1 inhibits lipopolysaccharide-induced vascular cell adhesion molecule-1 expression by association with MT2A in ECV304 cells. Int J Inflam. 2015;2015:301562.
• Su CM, Cheng HH, Tsai TC, Hsiao SY, Tsai NW, Chang WN et al. Elevated serum vascular cell adhesion molecule-1 is associated with septic encephalopathy in adult community-onset severe sepsis patients. Biomed Res Int. 2014;2014:598762.
• Whalen MJ, Doughty LA, Carlos TM, Wisniewski SR, Kochanek PM, Carcillo JA. Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 are increased in the plasma of children with sepsis-induced multiple organ failure. Crit Care Med. 2000;28:2600-7.
• Sreckovic B, Sreckovic VD, Soldatovic I, Colak E, Dumanovic MS, Janeski H et al. Homocysteine is a marker for metabolic syndrome and atherosclerosis. Diabetes Metab Syndr. 2017;11:179-82.