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Article Citation - WoS: 3Citation - Scopus: 4Effects of Cerium Oxide on Kidney and Liver Tissue Damage in an Experimental Myocardial Ischemia-Reperfusion Model of Distant Organ Damage(Mdpi, 2024) Gunes, Isin; Dursun, Ali Dogan; Ozdemir, Cagri; Kucuk, Aysegul; Sezen, Saban Cem; Arslan, Mustafa; Ozer, AbdullahBackground and Objectives: Ischemia-reperfusion (I/R) injury is a process in which impaired perfusion is restored by restoring blood flow and tissue recirculation. Nanomedicine uses cutting-edge technologies that emerge from interdisciplinary influences. In the literature, there are very few in vivo and in vitro studies on how cerium oxide (CeO2) affects systemic anti-inflammatory response and inflammation. Therefore, in our study, we aimed to investigate whether CeO2 administration has a protective effect against myocardial I/R injury in the liver and kidneys. Materials and Methods: Twenty-four rats were randomly divided into four groups after obtaining approval from an ethics committee. A control (group C), cerium oxide (group CO), IR (group IR), and Cerium oxide-IR (CO-IR group) groups were formed. Intraperitoneal CeO2 was administered at a dose of 0.5 mg/kg 30 min before left thoracotomy and left main coronary (LAD) ligation, and myocardial muscle ischemia was induced for 30 min. After LAD ligation was removed, reperfusion was performed for 120 min. All rats were euthanized using ketamine, and blood was collected. Liver and kidney tissue samples were evaluated histopathologically. Serum AST (aspartate aminotransferase), ALT (alanine aminotransaminase), GGT (gamma-glutamyl transferase), glucose, TOS (Total Oxidant Status), and TAS (Total Antioxidant Status) levels were also measured. Results: Necrotic cell and mononuclear cell infiltration in the liver parenchyma of rats in the IR group was observed to be significantly increased compared to the other groups. Hepatocyte degeneration was greater in the IR group compared to groups C and CO. Vascular vacuolization and hypertrophy, tubular degeneration, and necrosis were increased in the kidney tissue of the IR group compared to the other groups. Tubular dilatation was significantly higher in the IR group than in the C and CO groups. TOS was significantly higher in all groups than in the IR group (p < 0.0001, p < 0.0001, and p = 0.006, respectively). However, TAS level was lower in the IR group than in the other groups (p = 0.002, p = 0.020, and p = 0.031, respectively). Renal and liver histopathological findings decreased significantly in the CO-IR group compared to the IR group. A decrease in the TOS level and an increase in the TAS level were found compared to the IR group. The AST, ALT, GGT, and Glucose levels are shown. Conclusions: CeO2 administered before ischemia-reperfusion reduced oxidative stress and ameliorated IR-induced damage in distant organs. We suggest that CeO2 exerts protective effects in the myocardial IR model.Article Effects of Pomegranate Seed Oil on Lower Extremity Ischemia-Reperfusion Damage: Insights into Oxidative Stress, Inflammation, and Cell Death(MDPI, 2025) Bozok, Ummu Gulsen; Ergorun, Aydan Iremnur; Kucuk, Aysegul; Yigman, Zeynep; Dursun, Ali Dogan; Arslan, MustafaAim: This study sought to clarify the therapeutic benefits and mechanisms of action of pomegranate seed oil (PSO) in instances of ischemia–reperfusion (IR) damage in the lower extremities. Materials and Methods: The sample size was determined, then 32 rats were randomly allocated to four groups: Control (C), ischemia–reperfusion (IR), low-dose PSO (IR + LD, 0.15 mL/kg), and high-dose PSO (IR + HD, 0.30 mL/kg). The ischemia model in the IR group was established by occluding the infrarenal aorta for 120 min. Prior to reperfusion, PSO was delivered to the IR + LD and IR + HD groups at doses of 0.15 mL/kg and 0.30 mL/kg, respectively, followed by a 120 min reperfusion period. Subsequently, blood and tissue specimens were obtained. Statistical investigation was executed utilizing Statistical Package for the Social Sciences version 20.0 (SPSS, IBM Corp., Armonk, NY, USA). Results: Biochemical tests revealed significant variations in total antioxidant level (TAS), total oxidant level (TOS), and the oxidative stress index (OSI) across the groups (p < 0.0001). The IR group had elevated TOS and OSI levels, whereas PSO therapy resulted in a reduction in these values (p < 0.05). As opposed to the IR group, TASs were higher in the PSO-treated groups. Histopathological analysis demonstrated muscle fiber degeneration, interstitial edema, and the infiltration of cells associated with inflammation in the IR group, with analogous results noted in the PSO treatment groups. Immunohistochemical analysis revealed that the expressions of Tumor Necrosis Factor-alpha (TNF-α), Nuclear Factor kappa B (NF-κB), cytochrome C (CYT C), and caspase 3 (CASP3) were elevated in the IR group, while PSO treatment diminished these markers and attenuated inflammation and apoptosis (p < 0.05). The findings demonstrate that PSO has a dose-dependent impact on IR injury. Discussion: This research indicates that PSO has significant protective benefits against IR injury in the lower extremities. PSO mitigated tissue damage and maintained mitochondrial integrity by addressing oxidative stress, inflammation, and apoptotic pathways. Particularly, high-dose PSO yielded more substantial enhancements in these processes and exhibited outcomes most comparable to the control group in biochemical, histological, and immunohistochemical investigations. These findings underscore the potential of PSO as an efficacious natural treatment agent for IR injury. Nevertheless, additional research is required to articulate this definitively.Article Citation - WoS: 8Citation - Scopus: 12Protective Effects of BPC 157 on Liver, Kidney, and Lung Distant Organ Damagein Rats with Experimental Lower-Extremity Ischemia–Reperfusion Injury(MDPI, 2025) Demirtas, Hueseyin; Ozer, Abdullah; Yildirim, Alperen Kutay; Dursun, Ali Dogan; Sezen, Saban Cem; Arslan, MustafaBackground and Objectives: Ischemia–reperfusion (I/R) injury can affect multiple distant organs following I/R in the lower extremities. BPC-157’s anti-inflammatory and free radical-neutralizing properties suggest its potential in mitigating ischemia–reperfusion damage. This study evaluates the protective effects of BPC-157 on remote organ damage, including the kidneys, liver, and lungs, in a rat model of skeletal muscle I/R injury. Materials and Methods: A total of 24 male Wistar albino rats were randomly divided into four groups: sham (S), BPC-157(B), lower extremity I/R(IR) and lower extremity I/R+BPC-157(I/RB). Some 45 min of ischemia of lower extremity was followed by 2 h of reperfusion of limbs. BPC-157 was applied to groups B and I/RB at the beginning of the procedure. After 2 h of reperfusion, liver, kidney and lung tissues were harvested for biochemical and histopathological analyses. Results: In the histopathological examination, vascular and glomerular vacuolization, tubular dilation, hyaline casts, and tubular cell shedding in renal tissue were significantly lower in the I/RB group compared to other groups. Lung tissue showed reduced interstitial edema, alveolar congestion, and total damage scores in the I/RB group. Similarly, in liver tissue, sinusoidal dilation, necrotic cells, and mononuclear cell infiltration were significantly lower in the I/RB group. Additionally, the evaluation of TAS, TOS, OSI, and PON-1 revealed a statistically significant increase in antioxidant activity in the liver, lung, and kidney tissues of the I/RB group. Conclusions: The findings of this study demonstrate that BPC-157 exerts a significant protective effect against distant organ damage in the liver, kidneys, and lungs following lower extremity ischemia–reperfusion injury in rats.Article Citation - WoS: 4Citation - Scopus: 4Effects of Sevoflurane and Fullerenol C60 on the Heart and Lung in Lower-Extremity Ischemia-Reperfusion Injury in Streptozotocin-Induced Diabetes Mice(Mdpi, 2024) Ornek, Ender; Alkan, Metin; Erel, Selin; Sarıkaya, Badegül; Dursun, Ali Dogan; Sarıkaya, Badegül; Arslan, MustafaBackground and Objectives: Lower-extremity ischemia-reperfusion injury can induce distant organ ischemia, and patients with diabetes are particularly susceptible to ischemia-reperfusion injury. Sevoflurane, a widely used halogenated inhalation anesthetic, and fullerenol C60, a potent antioxidant, were investigated for their effects on heart and lung tissues in lower-extremity ischemia-reperfusion injury in streptozotocin (STZ)-induced diabetic mice. Materials and Methods: A total of 41 mice were divided into six groups: control (n = 6), diabetes-control (n = 7), diabetes-ischemia (n = 7), diabetes-ischemia-fullerenol C60 (n = 7), diabetes-ischemia-sevoflurane (n = 7), and diabetes-ischemia-fullerenol C60-sevoflurane (n = 7). Diabetes was induced in mice using a single intraperitoneal dose of 55 mg/kg STZ in all groups except for the control group. Mice in the control and diabetes-control groups underwent midline laparotomy and were sacrificed after 120 min. The DIR group underwent 120 min of lower-extremity ischemia followed by 120 min of reperfusion. In the DIR-F group, mice received 100 mu g/kg fullerenol C60 intraperitoneally 30 min before IR. In the DIR-S group, sevoflurane and oxygen were administered during the IR procedure. In the DIR-FS group, fullerenol C60 and sevoflurane were administered. Biochemical and histological evaluations were performed on collected heart and lung tissues. Results: Histological examination of heart tissues showed significantly higher necrosis, polymorphonuclear leukocyte infiltration, edema, and total damage scores in the DIR group compared to controls. These effects were attenuated in fullerenol-treated groups. Lung tissue examination revealed more alveolar wall edema, hemorrhage, vascular congestion, polymorphonuclear leukocyte infiltration, and higher total damage scores in the DIR group compared to controls, with reduced injury parameters in the fullerenol-treated groups. Biochemical analyses indicated significantly higher total oxidative stress, oxidative stress index, and paraoxonase-1 levels in the DIR group compared to the control and diabetic groups. These levels were lower in the fullerenol-treated groups. Conclusions: Distant organ damage in the lung and heart tissues due to lower-extremity ischemia-reperfusion injury can be significantly reduced by fullerenol C60.Article Protective Role of Bromelain’s Antioxidant and Anti-Inflammatory Effects in Experimental Lower Limb Ischemia-Reperfusion Injury(Nature Portfolio, 2025) Sezen, Saban Cem; Demirtas, Huseyin; Yildirim, Alperen Kutay; Ozer, Abdullah; Dursun, Ali Dogan; Kucuk, Aysegul; Arslan, MustafaIschemia-reperfusion (IR) injury is a multifaceted pathological process characterized by excessive oxidative stress and inflammatory responses upon restoration of blood flow. Bromelain, a proteolytic enzyme complex derived from pineapple, exhibits robust antioxidant and anti-inflammatory activities. This study aimed to evaluate the protective effects and underlying mechanisms of bromelain on oxidative stress and inflammation in an experimental rat model of lower limb ischemia-reperfusion injury. Twenty-four male Wistar Albino rats were randomly allocated into four groups: Sham-operated control (SHAM), Bromelain-only (BR), Ischemia-Reperfusion (IR), and Ischemia-Reperfusion with Bromelain treatment (IR + BR). Bromelain (40 mg/kg) was administered intraperitoneally before ischemia induction. The IR model involved 45 min of infrarenal abdominal aorta occlusion followed by 120 min of reperfusion. Oxidative biomarkers (total antioxidant status [TAS], total oxidant status [TOS], oxidative stress index [OSI]) and histopathological parameters (muscle atrophy, degeneration, leukocyte infiltration, internalization of nuclei, fragmentation, and hyalinization) were analyzed. Significant increases in muscle degeneration, leukocyte infiltration, nuclear internalization, fragmentation, and elevated oxidative stress biomarkers (increased TOS and OSI, decreased TAS) were observed in the IR group compared to controls. Bromelain treatment (IR + BR) significantly ameliorated these effects, reducing muscle tissue damage, inflammation, and oxidative imbalance compared to the untreated IR group. Bromelain effectively mitigates lower limb ischemia-reperfusion injury by reducing oxidative stress, restoring antioxidant capacity, and suppressing inflammatory responses. These protective effects suggest that bromelain holds potential as a therapeutic agent for managing oxidative and inflammatory damages associated with IR conditions, warranting further clinical investigation.Article The Effect of Cerium Oxide on Liver and Kidney in Lower Extremity Ischemia Reperfusion Injury in Streptozotocin -Induced Diabetic Mice(Springernature, 2025) Erel, Selin; Ozdemir, Miray Gozde; Kucuk, Aysegul; Sarikaya, Badegul; Sezen, Saban Cem; Atli, Muharrem; Arslan, MustafaIntroductionIschemia-reperfusion injury (IRI) is a major concern in diabetic patients undergoing vascular procedures, causing significant damage to the liver and kidneys. The purpose of this study was to evaluate the protective effects of cerium oxide on the liver and kidneys of diabetic mice with lower extremity IRI.Materials and MethodsThirty Swiss albino mice were divided into five experimental groups: control (C), control diabetes (D), diabetes with cerium oxide (D-CEO2), diabetes with IRI (D-IRI), and diabetes with IRI treated with cerium oxide (D-IRI-CEO2). Diabetes was induced with streptozotocin (125 mg/kg) and lower-extremity IRI was induced by clamping the infrarenal aorta. Cerium oxide was administered intraperitoneally to the 0.5 mg/kg cerium oxide groups 30 min before ischemia. Liver and kidney tissue samples were subsequently analyzed through biochemical assays measuring the total antioxidant status, total oxidant status, oxidative stress index, and paraoxonase-1, as well as histopathological examinations.ResultsThe D-IRI group exhibited greater liver and kidney damage than the control group. The D-IRI-CeO2 group displayed reduced liver and kidney damage compared to the D-IRI group. In both the D-IRI and D-IRI-CeO2 groups, the total oxidant status, oxidative stress index, and paraoxonase-1 acitivity were higher, whereas the total antioxidant status levels were lower. In the D-IRI-CeO2 group, there was a decrease in total oxidant status, oxidative stress index, and paraoxonase-1, whereas total antioxidant status increased compared to D-IRI.ConclusionIntraperitoneal cerium oxide reduces oxidative stress and mitigates liver and kidney damage in diabetic mice subjected to lower extremity ischemia-reperfusion injury.